Biaryl ring compound, intermediate thereof, preparation method therefor and use thereof

Abstract

Provided are a biaryl ring compound, an intermediate thereof, a preparation method therefor and a use thereof. Specifically provided are a compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotope compound thereof. The ATPase activity and the inhibitory effect on proteins of the provided biaryl ring compound are greatly improved compared with the prior art.

Description

Biaryl ring compounds, intermediates thereof, preparation methods and applications

[0001] This application claims priority to Chinese Patent Application No. 202311124367X filed on September 1, 2023, Chinese Patent Application No. 2023114104077 filed on October 27, 2023, and Chinese Patent Application No. 2023118384594 filed on December 28, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a biaryl ring compound, an intermediate thereof, a preparation method and application. Background Art

[0003] DNA damage is an important mechanism by which many chemotherapy drugs exert their anti-tumor effects. Double-strand breaks (DSBs) in DNA are the most common type of damage in cells. They can be caused directly by ionizing radiation or induced by ultraviolet rays, reactive oxygen species (ROS), or other mutagens, such as the common chemotherapy drugs cisplatin, 5-FU, and etoposide. Unrepaired DNA damage can lead to functional blockade of cells such as transcription and replication, inducing apoptosis or necrosis, and being eliminated by immune cells. Tumor cells have efficient damage repair or alternative repair pathways. Targeting key proteins in the DNA damage repair pathway, causing the continuous accumulation of unrepaired DNA damage and ultimately leading to cell death, is one of the important strategies for cancer treatment.

[0004] DNA double-strand breaks (DSBs) are typically repaired by three pathways: non-homologous end joining (NHEJ), homologous recombination (HR), and alternative non-homologous end joining (Alt-NHEJ, also known as microhomology end joining (MMEJ) or TMEJ). The HR repair pathway occurs exclusively during G2 and S phases, in the presence of sister chromatids, and is error-free. In mammals, over 90% of DSBs are repaired by NHEJ. This pathway is error-prone, resulting in deletions <30 bp, insertions <5 bp, or microhomology <2 bp. Recent studies have shown that when HR and / or NHEJ are deficient, cells rely heavily on the third pathway, MMEJ, to repair DNA breaks. Inhibition of MMEJ leads to apoptosis. MMEJ, also an error-prone repair pathway, relies on the DNA polymerase theta to ligate microhomology end sequences (TMEJ) to repair DNA double-strand breaks.

[0005] DNA polymerase theta (Pol theta or Polθ) is a key protein in the MMEJ repair pathway. It is a unique multifunctional polymerase composed of an N-terminal helicase domain, a central domain, and a C-terminal polymerase domain. Basic research has revealed that the polymerase domain is essential for DNA extension at DSB repair sites, while the helicase domain and central domain play a key role in the recognition and binding of Polθ to its substrate. Polθ can dissociate the interaction between DNA and the damage repair complex (e.g., competing with RAD51 for single-stranded DNA binding), inhibiting the HR repair pathway. Furthermore, the helicase domain of Polθ is involved in DNA replication arrest, and its functional loss can lead to increased replication stress in tumor cells, leading to apoptosis.

[0006] Polθ is not expressed or expressed at low levels in normal tissue cells, but is highly expressed in a variety of tumors, including lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, and colon cancer, and is associated with a poor prognosis. Polθ is overexpressed in approximately 70% of breast cancers. These findings suggest that Polθ may play an important role in these cancers and is a potential tumor-specific target.

[0007] Studies that knock down or eliminate Polθ in tumor cells have found that Polθ deficiency can sensitize these cells to radiation, induce the formation of DSBs, enhance replication fork instability, and sensitize tumor cells to genotoxic agents, potentially enhancing the effects of radiotherapy and chemotherapy, making it a potential drug target. Studies have also found that Polθ and HR deficiency have a combined lethal effect, and its small molecule inhibitors can kill HR-deficient tumor cells in vitro and in vivo. In particular, in tumors resistant to PARP inhibitors (such as Olaparib) with HR defect reversion mutations, Polθ inhibitors can resensitize cells to PARPi, providing a valuable therapeutic opportunity. Furthermore, given that Polθ is a key protein in the MMEJ pathway, its functional impairment can also lead to enhanced genomic instability in cancer cells, increase somatic mutations, and facilitate the production of tumor neoantigens. Furthermore, reports have shown that Polθ is involved in cGAS-STING-mediated immune activation, so targeting Polθ also has the potential to enhance immunotherapy.

[0008] In short, Polθ is a highly promising target for cancer treatment. By designing ATPase activity inhibitors targeting Polθ protein and inhibiting intracellular MMEJ, it can be used alone or in combination with other chemotherapy, radiotherapy, antibody therapy, immunotherapy, etc. to kill tumor cells. It has great potential in the treatment of tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, colon cancer, prostate cancer, and pancreatic cancer.

[0009] Summary of the Invention

[0010] The present invention aims to overcome the relatively monotonous structure of existing polymerase theta inhibitor compounds. To this end, the present invention provides a biaryl ring compound, its intermediate, preparation method, and application. These compounds exhibit significantly improved ATPase activity and protein inhibition compared to existing technologies.

[0011] The present invention solves the above technical problems through the following technical solutions.

[0012] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof or an isotope compound thereof,

[0013] in,

[0014] m and n are independently 0, 1, 2, 3 or 4;

[0015] X 1 and X 4 are independently N or CR a ;

[0016] X 2and X 3 are independently N or CH;

[0017] Each R a are independently hydrogen, halogen, CN, OH, deuterium, cyano, -NHR f 、-C(O)NHR g , unsubstituted or replaced by one or more R 1-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 1-2 Substituted C 1-6 alkoxy;

[0018] Each R 1-1 and R 1-2 are independently halogen;

[0019] R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k 、-C(O)N(R m )2, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0020] R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and Rm are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl;

[0021] Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently deuterium, halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2;

[0022] Each R 2 are independently deuterium, halogen, cyano, amino, hydroxy, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 2-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 2-3 Substituted C 2-6 Alkenyl, unsubstituted or substituted with one or more R 2-4 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 2-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 2-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-13 Substituted 4-12 membered heterocycloalkenyl, -COOR 2- 7 、-C(O)R 2-8 、-C(O)N(R 2-9 )2. or N(R 2-12 )2;

[0023] Each R 2-1 、R2-2 、R 2-3 、R 2-4 、R 2-5 、R 2-6 and R 2-13 are independently deuterium, hydroxy, cyano or halogen;

[0024] Each R 2-7 、R 2-8 、R 2-9 and R 2-12 are independently hydrogen or C 1-6 alkyl;

[0025] Each R 2-10 and R 2-11 are independently hydroxy or C 1-6 alkyl;

[0026] Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-2 Substituted C 2-6 Alkenyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-4 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, -O-5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl, -N(R 3-7 )2 or

[0027] Each R 3-1 、R 3-2 and R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-1-2 substituted 5-12 membered heteroaryl or

[0028] Each R 3-4 、R 3-5 and R 3-9 are independently oxo, halogen, cyano, hydroxy, unsubstituted or substituted with one or more R 3-5-1 Substituted C1-6 Alkyl, unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 3-5-5 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5-6 Substituted 3-12 membered heterocycloalkyl, -N(R 3-5-3 )2.

[0029] Each R 3-6 and R 3-10 are independently oxo, halogen, cyano, hydroxy, unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 3-5-5 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-6-2 Substituted 3-12 membered heterocycloalkyl, -N(R 3-6-3 )2.

[0030] Each R 3-7 are independently hydrogen, unsubstituted or replaced by one or more R 3-7-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3- 8-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-7-2 substituted 5-12 membered heteroaryl or

[0031] Each R 3-8 are independently unsubstituted or substituted with one or more R 3-7-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-8-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-7-2 substituted 5-12 membered heteroaryl or

[0032] Each R 3-1-1 and R 3-1-2 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0033] Each R 3-1-3 are independently unsubstituted or substituted with one or more R 3-1-3-1substituted 3-12 membered heterocycloalkyl;

[0034] Each R 3-1-3-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0035] Each R 3-4-1 、R 3-5-3 and R 3-6-3 are independently hydrogen or C 1-6 alkyl;

[0036] Each R 3-5-1 、R 3-5-2 and R 3-7-1 are independently deuterium, hydroxy, cyano or halogen;

[0037] Each R 3-5-4 and R 3-7-3 Independently C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0038] Each R 3-5-5 、R 3-5-6 and R 3-6-2 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0039] Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 alkoxy;

[0040] Each R 3-7-2 and R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0041] The heteroatoms in each 3-12 membered heterocycloalkyl group and 5-12 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3;

[0042] The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, 5-12 membered heteroaryl and -O-5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0043] In a preferred embodiment, in the compound of Formula I, its pharmaceutically acceptable salt or isotope compound; the definitions of certain groups may be as described below, and the definitions of other groups may be as described in any of the above embodiments (hereinafter referred to as "in a preferred embodiment").

[0044] In a preferred embodiment, R 1is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k 、-C(O)N(R m )2, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0045] Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2.

[0046] In a preferred embodiment, each R a wherein the halogen is independently fluorine, chlorine, bromine or iodine.

[0047] In a preferred embodiment, each R a wherein the unsubstituted or replaced by one or more R 1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0048] In a preferred embodiment, each R a wherein the unsubstituted or replaced by one or more R 1-2 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0049] In a preferred embodiment, each R 1-1 and R 1-2 wherein the halogen is independently fluorine, chlorine, bromine or iodine.

[0050] In a preferred embodiment, R 1 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0051] In a preferred embodiment, R 1 wherein the halogen is independently fluorine or chlorine.

[0052] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, isopropyl or tert-butyl.

[0053] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, n-propyl, isopropyl or tert-butyl.

[0054] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-4 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0055] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-5 Substituted C 3-10 C in cycloalkyl 3-10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0056] In a preferred embodiment, R 1wherein the unsubstituted or replaced by one or more R 1-5 Substituted C 3-10 C in cycloalkyl 3-10 Cycloalkyl is independently cyclopropyl or cyclobutyl.

[0057] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-6 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently a 5- to 8-membered heterocycloalkyl group.

[0058] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-6 The heteroatoms of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group are independently N and / or O.

[0059] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-6 The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently 1 or 2, for example, 2.

[0060] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-6 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is independently monocyclic, bridged, fused or spirocyclic;

[0061] The number of rings in the spiro ring, fused ring or bridged ring may be 2;

[0062] The spiro ring may be a 3-membered spiro 5-membered heterocyclyl, a 3-membered spiro 6-membered heterocyclyl, a 4-membered spiro 4-membered heterocyclyl, a 4-membered spiro 5-membered heterocyclyl, a 4-membered spiro 6-membered heterocyclyl, a 4-membered spiro 7-membered heterocyclyl, a 5-membered spiro 4-membered heterocyclyl, a 5-membered spiro 5-membered heterocyclyl, a 5-membered spiro 6-membered heterocyclyl, a 5-membered spiro 7-membered heterocyclyl, a 6-membered spiro 4-membered heterocyclyl, a 6-membered spiro 5-membered heterocyclyl or a 6-membered spiro 6-membered heterocyclyl; for example, a 4-membered spiro 4-membered heterocyclyl;

[0063] The cyclic group may be a 3-membered and 5-membered heterocyclic group, a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group, or a 6-membered and 6-membered heterocyclic group; for example, a 3-membered and 5-membered heterocyclic group or a 5-membered and 5-membered heterocyclic group; preferably, the cyclic group may be a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group, or a 6-membered and 6-membered heterocyclic group; for example, a 5-membered and 5-membered heterocyclic group;

[0064] The bridged ring can be a 4-membered bridged 5-membered heterocyclic group, a 4-membered bridged 6-membered heterocyclic group, a 5-membered bridged 6-membered heterocyclic group or a 6-membered bridged 6-membered heterocyclic group; for example, a 4-membered bridged 6-membered heterocyclic group.

[0065] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-6 The 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently a 5-8-membered heterocycloalkyl group, wherein the heteroatom of the 5-8-membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2; for example

[0066] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-6 The 3-12 membered heterocycloalkyl groups in the substituted 3-12 membered heterocycloalkyl groups are independently

[0067] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 C in aromatic groups 6-12 Aryl is independently phenyl or naphthyl, for example phenyl.

[0068] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-8 The 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is a monocyclic ring.

[0069] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-8 The 5- to 12-membered heteroaryl in the substituted 5- to 12-membered heteroaryl is independently a 5- to 6-membered heteroaryl.

[0070] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-8 The heteroatom of the 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is N and / or O.

[0071] In a preferred embodiment, R 1 wherein said unsubstituted or replaced by one or more R 1-8 The heteroatom of the 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is N.

[0072] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-8 The number of heteroatoms in the 5- to 12-membered heteroaryl group is 1 or 2.

[0073] In a preferred embodiment, R 1wherein the unsubstituted or replaced by one or more R 1-8 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl, wherein the heteroatoms of the 5-6-membered heteroaryl are N and / or O, and the number of heteroatoms is 1 or 2, for example

[0074] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-8 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl, the heteroatom of the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2, for example

[0075] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 C in cycloalkyl 3-10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

[0076] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is independently a monocyclic, bridged or fused ring;

[0077] The number of rings in the cyclic or bridged ring may be 2;

[0078] The cyclic group may be a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group or a 6-membered and 6-membered heterocyclic group; for example, a 5-membered and 5-membered heterocyclic group;

[0079] The bridged ring can be a 4-membered bridged 5-membered heterocyclic group, a 4-membered bridged 6-membered heterocyclic group, a 5-membered bridged 6-membered heterocyclic group or a 6-membered bridged 6-membered heterocyclic group; for example, a 4-membered bridged 6-membered heterocyclic group.

[0080] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently a 4- to 8-membered heterocycloalkyl group.

[0081] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The heteroatoms of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group are independently N and / or O.

[0082] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently 1 or 2.

[0083] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、Ri 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently a 4-8-membered heterocycloalkyl group, wherein the heteroatom of the 4-8-membered heterocycloalkyl group is N and / or O, and the number of heteroatoms is 1 or 2; for example

[0084] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 C in aromatic groups 6-12 Aryl is independently phenyl or naphthyl, for example phenyl.

[0085] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-12 The 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is a monocyclic ring.

[0086] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-12 The 5- to 12-membered heteroaryl in the substituted 5- to 12-membered heteroaryl is independently a 5- to 6-membered heteroaryl.

[0087] In a preferred embodiment, Rb 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j and R k wherein the unsubstituted or replaced by one or more R 1-12 The heteroatom of the 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is N.

[0088] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-12 The number of heteroatoms in the 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is independently 1 or 2.

[0089] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R 1-12 The 5-12-membered heteroaryl groups in the substituted 5-12-membered heteroaryl groups are independently 5-6-membered heteroaryl groups, the heteroatom of the 5-6-membered heteroaryl groups is N, and the number of heteroatoms is 1 or 2; for example

[0090] In a preferred embodiment, R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j 、R k and R m wherein the unsubstituted or replaced by one or more R1-13 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0091] In a preferred embodiment, each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0092] In a preferred embodiment, each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 In the C 1-6 Alkyl, the -S(O)2C 1-6 C in the alkyl group 1-6 Alkyl and the -P(O)(C 1-6 C in alkyl)2 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0093] In a preferred embodiment, each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 In the -S(O)2C 1-6 Alkyl is

[0094] In a preferred embodiment, each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 In the case of -P(O)(C 1-6 Alkyl)2 is

[0095] In a preferred embodiment, R 1 In each of the plurality, the plurality is 2 or 3, for example, 2.

[0096] In a preferred embodiment, each R 2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, fluorine or chlorine.

[0097] In a preferred embodiment, each R 2 wherein the unsubstituted or replaced by one or more R 2-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0098] In a preferred embodiment, each R 2 In each of the plurality, the plurality is 2 or 3, for example, 2.

[0099] In a preferred embodiment, each R 2 wherein the unsubstituted or replaced by one or more R 2-2 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0100] In a preferred embodiment, each R 2-1 and R 2-2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0101] In a preferred embodiment, each R 2 In the above, one or more R 2-1 Substituted C 1-6 Alkyl is

[0102] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-1 Substituted C 1-6 C in the alkyl group 1-6Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl.

[0103] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4-12 membered heterocycloalkenyl group in the substituted 4-12 membered heterocycloalkenyl group is a monocyclic ring or a fused ring;

[0104] The number of rings in the ring combination may be 2;

[0105] The cycloalkyl group may be a 4-membered and 5-membered heterocycloalkenyl group, a 4-membered and 6-membered heterocycloalkenyl group, a 5-membered and 5-membered heterocycloalkenyl group, a 5-membered and 6-membered heterocycloalkenyl group or a 6-membered and 6-membered heterocycloalkenyl group, for example, a 5-membered and 6-membered heterocycloalkenyl group.

[0106] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4- to 12-membered heterocycloalkenyl group in the substituted 4- to 12-membered heterocycloalkenyl group is independently a 5- to 9-membered heterocycloalkenyl group, for example, a 5- to 6-membered heterocycloalkenyl group.

[0107] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The heteroatom of the 4- to 12-membered heterocycloalkenyl group in the substituted 4- to 12-membered heterocycloalkenyl group is N.

[0108] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The number of heteroatoms in the 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is 1 or 2, for example, 1.

[0109] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The number of double bonds in the 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is 1 or 2, for example, 2.

[0110] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is independently a 5-9-membered heterocycloalkenyl group, the heteroatom of the 5-9-membered heterocycloalkenyl group is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-9-membered heterocycloalkenyl group is 1 or 2; for example

[0111] In a preferred embodiment, each R3 wherein the unsubstituted or replaced by one or more R 3-3 Substituted C 2-6 C in alkynyl 2-6 Alkynyl is independently ethynyl, propynyl or propargyl, for example ethynyl.

[0112] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is independently a bridged ring or a spiro ring;

[0113] The number of rings in the spiro ring or bridge ring may be 2, and the spiro ring may be a 3-membered spiro 5-membered heterocyclyl, a 3-membered spiro 6-membered heterocyclyl, a 4-membered spiro 4-membered heterocyclyl, a 4-membered spiro 5-membered heterocyclyl, a 4-membered spiro 6-membered heterocyclyl, a 4-membered spiro 7-membered heterocyclyl, a 5-membered spiro 4-membered heterocyclyl, a 5-membered spiro 5-membered heterocyclyl, a 5-membered spiro 6-membered heterocyclyl, a 5-membered spiro 7-membered heterocyclyl, a 6-membered spiro 4-membered heterocyclyl, a 6-membered spiro 5-membered heterocyclyl or a 6-membered spiro 6-membered heterocyclyl; for example, a 3-membered spiro 6-membered heterocycloalkyl;

[0114] The bridged ring can be a 4-membered bridged 5-membered heterocycloalkyl, a 4-membered bridged 6-membered heterocycloalkyl, a 5-membered bridged 6-membered heterocycloalkyl or a 6-membered bridged 6-membered heterocycloalkyl; for example, a 4-membered bridged 6-membered heterocycloalkyl.

[0115] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently a 6- to 8-membered heterocycloalkyl group.

[0116] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The heteroatom of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is N.

[0117] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is independently 1 or 2.

[0118] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 6-8-membered heterocycloalkyl, the heteroatom of the 6-8-membered heterocycloalkyl is N, and the number of heteroatoms is 1 or 2; for example

[0119] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 C in aromatic groups 6-12 Aryl is phenyl or naphthyl, for example phenyl.

[0120] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5-12 membered heteroaryl in the substituted 5-12 membered heteroaryl is a monocyclic or fused ring,

[0121] The number of the parallel rings may be 2.

[0122] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is a 5- to 9-membered heteroaryl group.

[0123] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The heteroatom of the 5- to 12-membered heteroaryl group in the substituted 5- to 12-membered heteroaryl group is N and / or O.

[0124] In a preferred embodiment, each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-9-membered heteroaryl, wherein the heteroatoms of the 5-9-membered heteroaryl are N and / or O, and the number of heteroatoms is 1, 2 or 3; for example For example,

[0125] In a preferred embodiment, each R 3 In each of the plurality, the plurality is 2 or 3, for example, 2.

[0126] In a preferred embodiment, each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a monocyclic ring.

[0127] In a preferred embodiment, each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group.

[0128] In a preferred embodiment, each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The heteroatom of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is N and / or O, for example O.

[0129] In a preferred embodiment, each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The number of heteroatoms in the 3-12-membered heterocycloalkyl group is 1 or 2, for example, 1.

[0130] In a preferred embodiment, each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group, wherein the heteroatoms of the 5-6-membered heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2; for example

[0131] In a preferred embodiment, each R 3-5 and R 3-9 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0132] In a preferred embodiment, each R 3-5 and R 3-9 wherein the unsubstituted or replaced by one or more R 3-5-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0133] In a preferred embodiment, each R 3-5 and R 3-9 wherein the unsubstituted or replaced by one or more R 3-5-1 Substituted C 1-6 C in alkoxy 1-6 Alkyl is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy.

[0134] In a preferred embodiment, each R 3-6 and R 3-10 wherein the unsubstituted or replaced by one or more R 3-6-1 Substituted C 1-6 C in the alkyl group1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

[0135] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a monocyclic ring.

[0136] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group.

[0137] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The heteroatom of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is N and / or O.

[0138] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The number of heteroatoms in the 3-12-membered heterocycloalkyl group is 1 or 2, for example, 2.

[0139] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group, wherein the heteroatoms of the 5-6-membered heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2; for example

[0140] In a preferred embodiment, each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a monocyclic ring.

[0141] In a preferred embodiment, each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is a 5- to 6-membered heterocycloalkyl group.

[0142] In a preferred embodiment, each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The heteroatom of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is N and / or O.

[0143] In a preferred embodiment, each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The number of heteroatoms in the 3-12-membered heterocycloalkyl group is 1 or 2, for example, 2.

[0144] In a preferred embodiment, each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group, wherein the heteroatoms of the 5-6-membered heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2; for example

[0145] In a preferred embodiment, each R 3-5-1 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0146] In a preferred embodiment, each R 3-5 and R 3-9 In the above, one or more R 3-5-1 Substituted C 1-6 Alkyl is

[0147] In a preferred embodiment, any one of the C 2-6 Alkenyl is independently ethenyl, propenyl or allyl.

[0148] In a preferred embodiment, any one of the C 2-6 Alkynyl is independently ethynyl, propynyl or propargyl.

[0149] In a preferred embodiment, any one of the C 3-10 Cycloalkyl and C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0150] In a preferred embodiment, the 3-12 membered heterocycloalkyl group described in any one of the present invention is a monocyclic, fused, bridged or spirocyclic ring;

[0151] The number of rings in the spiro ring, fused ring or bridged ring may be 2;

[0152] The spiro ring may be a 3-membered spiro 5-membered heterocyclic group, a 3-membered spiro 6-membered heterocyclic group, a 4-membered spiro 4-membered heterocyclic group, a 4-membered spiro 5-membered heterocyclic group, a 4-membered spiro 6-membered heterocyclic group, a 4-membered spiro 7-membered heterocyclic group, a 5-membered spiro 4-membered heterocyclic group, a 5-membered spiro 5-membered heterocyclic group, a 5-membered spiro 6-membered heterocyclic group, a 5-membered spiro 7-membered heterocyclic group, a 6-membered spiro 4-membered heterocyclic group, a 6-membered spiro 5-membered heterocyclic group or a 6-membered spiro 6-membered heterocyclic group;

[0153] The cyclic group may be a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group or a 6-membered and 6-membered heterocyclic group;

[0154] The bridged ring can be a 4-membered bridged 5-membered heterocyclic group, a 4-membered bridged 6-membered heterocyclic group, a 5-membered bridged 6-membered heterocyclic group or a 6-membered bridged 6-membered heterocyclic group.

[0155] In a preferred embodiment, the 3-12 membered heterocycloalkyl group described in any one of the present invention is a 5-6 membered heterocycloalkyl group.

[0156] In a preferred embodiment, the heteroatom of the 3-12 membered heterocycloalkyl group described in any one of the present invention is N and / or O.

[0157] In a preferred embodiment, the number of heteroatoms in the 3-12 membered heterocycloalkyl group described in any one of the present invention is 1 or 2, for example, 2.

[0158] In a preferred embodiment, the 3-12 membered heterocycloalkyl groups described in any one of the present invention are independently

[0159] In a preferred embodiment, the 4-12 membered heterocycloalkenyl group described in any one of the present invention is a monocyclic ring or a cyclic ring;

[0160] The number of rings in the ring combination may be 2;

[0161] The cycloalkyl group may be a 4-membered and 5-membered heterocycloalkenyl group, a 4-membered and 6-membered heterocycloalkenyl group, a 5-membered and 5-membered heterocycloalkenyl group, a 5-membered and 6-membered heterocycloalkenyl group or a 6-membered and 6-membered heterocycloalkenyl group.

[0162] In a preferred embodiment, the 4-12 membered heterocycloalkenyl group described in any one of the present invention is independently a 5-9 membered heterocycloalkenyl group.

[0163] In a preferred embodiment, the heteroatom of the 4-12 membered heterocycloalkenyl group described in any one of the present invention is N.

[0164] In a preferred embodiment, the number of heteroatoms in the 4-12 membered heterocycloalkenyl group described in any one of the present invention is 1 or 2, for example, 1.

[0165] In a preferred embodiment, the number of double bonds in the 4-12 membered heterocycloalkenyl group described in any one of the present invention is 1 or 2, for example, 2.

[0166] In a preferred embodiment, the 4-12 membered heterocycloalkenyl groups described in any one of the present invention are independently

[0167] In a preferred embodiment, the halogen described in any one of the present invention is independently fluorine, chlorine, bromine or iodine.

[0168] In a preferred embodiment, any one of the C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0169] In a preferred embodiment, the 5-12 membered heteroaryl group described in any one of the present invention is a monocyclic or fused ring.

[0170] The number of the parallel rings may be 2.

[0171] In a preferred embodiment, the 5-12 membered heteroaryl group described in any one of the present invention is a 5-9 membered heteroaryl group.

[0172] In a preferred embodiment, the heteroatom of the 5-12 membered heteroaryl group described in any one of the present invention is N and / or O.

[0173] In a preferred embodiment, the 5-12 membered heteroaryl groups described in any one of the present invention are independently

[0174] In a preferred embodiment, any one of the C 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0175] In a preferred embodiment, R a For hydrogen.

[0176] In a preferred embodiment, X 2 is N.

[0177] In a preferred embodiment, X 3 is N.

[0178] In a preferred embodiment, X 4 is N.

[0179] In a preferred embodiment, R b is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl.

[0180] In a preferred embodiment, R b is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0181] In a preferred embodiment, R b is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-13 Substituted C 1-6 alkyl.

[0182] In a preferred embodiment, R b is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-11 Substituted C 6-12 Aryl.

[0183] In a preferred embodiment, R b For unsubstituted C 3-10 Cycloalkyl, unsubstituted C 6-12 Aryl or unsubstituted C 1-6 Alkyl, preferably unsubstituted C 1-6 alkyl.

[0184] In a preferred embodiment, R b For unsubstituted C 3-10 Cycloalkyl or unsubstituted C 6-12 Aryl.

[0185] In a preferred embodiment, R c is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 Substituted 3-12 membered heterocycloalkyl.

[0186] In a preferred embodiment, R c is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl.

[0187] In a preferred embodiment, R c For unsubstituted C 3-10 Cycloalkyl.

[0188] In a preferred embodiment, R d is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 Substituted 3-12 membered heterocycloalkyl.

[0189] In a preferred embodiment, R d is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl.

[0190] In a preferred embodiment, R d For unsubstituted C 3-10 Cycloalkyl.

[0191] In a preferred embodiment, R e is unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl.

[0192] In a preferred embodiment, R e For unsubstituted C 1-6 alkyl.

[0193] In a preferred embodiment, R f is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0194] In a preferred embodiment, R f is unsubstituted or replaced by one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0195] In a preferred embodiment, R f is an unsubstituted 3-12 membered heterocycloalkyl, an unsubstituted C 6-12aryl or unsubstituted 5- to 12-membered heteroaryl.

[0196] In a preferred embodiment, R g is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 Substituted 3-12 membered heterocycloalkyl.

[0197] In a preferred embodiment, R g is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl.

[0198] In a preferred embodiment, R g For unsubstituted C 3-10 Cycloalkyl.

[0199] In a preferred embodiment, R h is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0200] In a preferred embodiment, R h is unsubstituted or replaced by one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0201] In a preferred embodiment, R h For unsubstituted C 3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 aryl or unsubstituted 5- to 12-membered heteroaryl.

[0202] In a preferred embodiment, R h is an unsubstituted 3-12 membered heterocycloalkyl, an unsubstituted C 6-12 aryl or unsubstituted 5- to 12-membered heteroaryl.

[0203] In a preferred embodiment, R i is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10Cycloalkyl, unsubstituted or substituted with one or more R 1-10 Substituted 3-12 membered heterocycloalkyl or unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl.

[0204] In a preferred embodiment, R i is unsubstituted or replaced by one or more R 1-10 Substituted 3-12 membered heterocycloalkyl or unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl.

[0205] In a preferred embodiment, R i is an unsubstituted 3-12 membered heterocycloalkyl or an unsubstituted C 6-12 Aryl.

[0206] In a preferred embodiment, R j is unsubstituted or replaced by one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0207] In a preferred embodiment, R j is unsubstituted or replaced by one or more R 1-10 Substituted 3-12 membered heterocycloalkyl or unsubstituted or replaced by one or more R 1-12 Substituted 5-12 membered heteroaryl.

[0208] In a preferred embodiment, R j is an unsubstituted 3-12 membered heterocycloalkyl group or an unsubstituted 5-12 membered heteroaryl group.

[0209] In a preferred embodiment, R k is unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl.

[0210] In a preferred embodiment, R k is unsubstituted or replaced by one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C1-6 alkyl.

[0211] In a preferred embodiment, R k is an unsubstituted 5-12 membered heteroaryl or an unsubstituted C 1-6 alkyl.

[0212] In a preferred embodiment, each R 1-3 are independently halogen.

[0213] In a preferred embodiment, each R 1-4 are independently halogen.

[0214] In a preferred embodiment, each R 1-5 are independently halogen or C 1-6 alkyl.

[0215] In a preferred embodiment, each R 1-5 Independently C 1-6 alkyl.

[0216] In a preferred embodiment, each R 1-5 are independently halogen.

[0217] In a preferred embodiment, each R 1-6 are independently halogen or C 1-6 alkyl.

[0218] In a preferred embodiment, each R 1-6 Independently C 1-6 alkyl.

[0219] In a preferred embodiment, each R 1-7 are independently halogen or C 1-6 alkyl.

[0220] In a preferred embodiment, each R 1-7 are independently halogen.

[0221] In a preferred embodiment, each R 1-8 Independently C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2.

[0222] In a preferred embodiment, each R 1-8 Independently C 1-6 alkyl.

[0223] In a preferred embodiment, R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6- 12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0224] In a preferred embodiment, R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6- 12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0225] In a preferred embodiment, R 1is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0226] In a preferred embodiment, R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0227] In a preferred embodiment, R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0228] In a preferred embodiment, R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0229] In a preferred embodiment, R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted C 6-12 aryl or unsubstituted 5- to 12-membered heteroaryl.

[0230] In a preferred embodiment, R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 Substituted 5-12 membered heteroaryl.

[0231] In a preferred embodiment, m is 1, 2 or 3.

[0232] In a preferred embodiment, m is 1 or 2.

[0233] In a preferred embodiment, m is 2.

[0234] In a preferred embodiment, n is 1, 2 or 3.

[0235] In a preferred embodiment, n is 1.

[0236] In a preferred embodiment, each R 2-1 and R 2-2 are independently halogen.

[0237] In a preferred embodiment, each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2-2 Substituted C 1-6 Alkoxy.

[0238] In a preferred embodiment, each R 2 are independently halogen, one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted C 1-6 Alkoxy.

[0239] In a preferred embodiment, each R 3-1 Independently

[0240] In a preferred embodiment, each R 3-1-3 and independently unsubstituted 3-12 membered heterocycloalkyl.

[0241] In a preferred embodiment, each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 Substituted 3-12 membered heterocycloalkyl.

[0242] In a preferred embodiment, each R 3-3 and independently unsubstituted 3-12 membered heterocycloalkyl.

[0243] In a preferred embodiment, each R 3-5 is independently oxo or unsubstituted or substituted by one or more R 3-5-1 Substituted C 1-6 alkyl.

[0244] In a preferred embodiment, each R 3-5 are independently oxo or unsubstituted C 1-6 alkyl.

[0245] In a preferred embodiment, each R 3-6 is independently cyano or unsubstituted or substituted by one or more R 3-6-1 Substituted C 1-6 alkyl.

[0246] In a preferred embodiment, each R 3-6 are independently cyano or unsubstituted C 1-6 alkyl.

[0247] In a preferred embodiment, each R 3-10 are independently hydroxyl.

[0248] In a preferred embodiment, each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 Substituted 3-12 membered heterocycloalkyl.

[0249] In a preferred embodiment, each R 3-8 and independently unsubstituted 3-12 membered heterocycloalkyl.

[0250] In a preferred embodiment, each R 3-9 are independently oxo, halogen, cyano, hydroxy, unsubstituted or substituted with one or more R 3-5- 1Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-5-2 Substituted C1-C6 alkoxy.

[0251] In a preferred embodiment, each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy.

[0252] In a preferred embodiment, each R 3-9 are independently oxo, halogen, or one or more R 3-5-1 Substituted C 1-6 Alkyl or unsubstituted C 1-6 Alkoxy.

[0253] In a preferred embodiment, each R 3-9 are independently oxo or halogen.

[0254] In a preferred embodiment, each R 3-5-1 are independently halogen.

[0255] In a preferred embodiment, each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or

[0256] In a preferred embodiment, each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-4 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5 Substituted 3-12 membered heterocycloalkyl or unsubstituted or replaced by one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

[0257] In a preferred embodiment, each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

[0258] In a preferred embodiment, each R 3 are independently unsubstituted C 1-6 Alkyl or one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

[0259] In a preferred embodiment, each R 3 Independently by one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

[0260] In a preferred embodiment, R 1 For hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl,

[0261] In a preferred embodiment, R 1 For hydrogen, methyl,

[0262] In a preferred embodiment, R 1 For hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl,

[0263] In a preferred embodiment, R 1 For hydrogen, methyl,

[0264] In a preferred embodiment, for

[0265] In a preferred embodiment, for

[0266] In a preferred embodiment, for

[0267] In a preferred embodiment, for

[0268] In a preferred embodiment, for

[0269] Preferably, for

[0270] In a preferred embodiment, R 2 for F or Cl.

[0271] In a preferred embodiment, R 2 for or Cl.

[0272] In a preferred embodiment, for

[0273] In a preferred embodiment, for

[0274] In a preferred embodiment, R 3 Methyl,

[0275] In a preferred embodiment, R 3 for or methyl; preferably

[0276] In a preferred embodiment, m and n are independently 1, 2 or 3;

[0277] X 1 N or CH;

[0278] X 2 N or CH;

[0279] X 3 is N;

[0280] X 4 N or CH;

[0281] R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0282] R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl;

[0283] Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2;

[0284] Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0285] Each R 2-1 and R 2-2 are independently halogen;

[0286] Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or

[0287] Each R 3-1 Independently

[0288] Each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 substituted 3-12 membered heterocycloalkyl;

[0289] Each R 3-5 is independently oxo or unsubstituted or substituted by one or more R 3-5-1 Substituted C 1-6 alkyl;

[0290] Each R 3-6 is independently cyano or unsubstituted or substituted by one or more R 3-6-1 Substituted C 1-6 alkyl;

[0291] Each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 alkoxy;

[0292] Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 substituted 3-12 membered heterocycloalkyl;

[0293] Each R 3-10 are independently hydroxyl groups;

[0294] Each R 3-1-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0295] Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl;

[0296] Each R 3-5-1 and R 3-5-2 are independently deuterium, hydroxy, cyano or halogen;

[0297] Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 alkoxy;

[0298] Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0299] The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0300] In a preferred embodiment, m and n are independently 1, 2 or 3;

[0301] X 1 N or CH;

[0302] X 2 N or CH;

[0303] X 3 is N;

[0304] X 4 N or CH;

[0305] R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SRi 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0306] R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl;

[0307] Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2;

[0308] Each R2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0309] Each R 2-1 and R 2-2 are independently halogen;

[0310] Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or

[0311] Each R 3-1 Independently

[0312] Each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 substituted 3-12 membered heterocycloalkyl;

[0313] Each R 3-5 is independently oxo or unsubstituted or substituted by one or more R 3-5-1 Substituted C 1-6 alkyl;

[0314] Each R 3-6 is independently cyano or unsubstituted or substituted by one or more R 3-6-1 Substituted C 1-6 alkyl;

[0315] Each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 alkoxy;

[0316] Each R 3-8are independently unsubstituted or substituted with one or more R 3-8-1 substituted 3-12 membered heterocycloalkyl;

[0317] Each R 3-10 are independently hydroxyl groups;

[0318] Each R 3-1-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0319] Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl;

[0320] Each R 3-5-1 and R 3-5-2 are independently deuterium, hydroxy, cyano or halogen;

[0321] Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 alkoxy;

[0322] Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0323] The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0324] In a preferred embodiment, m is 1 or 2;

[0325] n is 1;

[0326] X 1 N or CH;

[0327] X 2 N or CH;

[0328] X 3 is N;

[0329] X 4 is N;

[0330] R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d 、 -NHR f 、-C(O)NHR g 、-OR h 、-SR i、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0331] R b 、R c 、R d , each R e 、R f 、R g 、R h 、R i 、R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or replaced by one or more R 1-13 Substituted C 1-6 alkyl;

[0332] Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2;

[0333] Each R 2are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0334] Each R 2-1 and R 2-2 are independently halogen;

[0335] Each R 3 are independently unsubstituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-9 substituted 4-12 membered heterocycloalkenyl;

[0336] Each R 3-9 are independently oxo or halogen;

[0337] The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0338] In a preferred embodiment, m is 1 or 2;

[0339] n is 1;

[0340] X 1 N or CH;

[0341] X 2 、X 3 and X 4 is N;

[0342] R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0343] Each R 1-3 and R 1-4are independently halogen;

[0344] Each R 1-5 、R 1-6 、R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl;

[0345] R b For unsubstituted C 1-6 alkyl;

[0346] Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0347] Each R 2-1 and R 2-2 are independently halogen;

[0348] Each R 3 are independently unsubstituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-9 substituted 4-12 membered heterocycloalkenyl;

[0349] Each R 3-9 are independently oxo or halogen;

[0350] The heteroatoms in each 4-12 membered heterocycloalkenyl group and 5-12 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0351] In a preferred embodiment, m is 1 or 2;

[0352] n is 1;

[0353] X 1 N or CH;

[0354] X 2 、X 3 and X 4 is N;

[0355] R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0356] Each R 1-3 and R 1-4 are independently halogen;

[0357] Each R 1-5 、R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl;

[0358] Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0359] Each R 2-1 and R 2-2 are independently halogen;

[0360] Each R 3 are independently unsubstituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 3-9 substituted 4-12 membered heterocycloalkenyl;

[0361] Each R 3-9 are independently oxo or halogen;

[0362] The heteroatoms in each 4-12 membered heterocycloalkenyl group and 5-12 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0363] In a preferred embodiment, m is 1 or 2;

[0364] n is 1;

[0365] X 1 N or CH;

[0366] X 2 、X 3 and X 4 is N;

[0367] R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0368] Each R 1-8 Independently C 1-6 alkyl;

[0369] Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0370] Each R 2-1 and R 2-2 are independently halogen;

[0371] R 3 is unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl;

[0372] Each R 3-9 are independently oxo or halogen;

[0373] The heteroatoms in each 4-12 membered heterocycloalkenyl group and 5-12 membered heteroaryl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0374] In a preferred embodiment, m is 1 or 2;

[0375] n is 1;

[0376] X 2 and X 3 is N;

[0377] for

[0378] Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl is unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 alkoxy;

[0379] Each R 2-1 and R 2-2 are independently halogen;

[0380] R 3 is unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl;

[0381] Each R 3-9 are independently oxo or halogen;

[0382] The heteroatoms in each 4-12 membered heterocycloalkenyl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

[0383] In a preferred embodiment, the compound shown in Formula I is any of the following compounds:

[0384] The present invention provides a pharmaceutical composition comprising:

[0385] (1) (a therapeutically effective amount of) substance A, wherein substance A is a compound of formula I according to any one of the present invention, or a pharmaceutically acceptable salt or isotope thereof; and

[0386] (2) Pharmaceutical excipients.

[0387] The present invention provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a polymerase theta inhibitor, wherein the substance A is a compound represented by formula I as described above, or a pharmaceutically acceptable salt or isotope compound thereof.

[0388] The present invention provides a use of a substance A in the preparation of a polymerase theta inhibitor, wherein the substance A is a compound represented by formula I as described above, or a pharmaceutically acceptable salt or isotope compound thereof.

[0389] The present invention provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug, wherein the substance A is a compound represented by formula I according to any one of the present invention, a pharmaceutically acceptable salt, or an isotope compound thereof; the drug can be used to treat and / or prevent lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer.

[0390] The present invention provides a use of a substance A in the preparation of a medicament, wherein the substance A is a compound represented by formula I according to any one of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof; the medicament can be used to treat and / or prevent lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer, or colon cancer.

[0391] The present invention provides a use of a substance A or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases related to polymerase theta, wherein the substance A is a compound represented by formula I according to any one of the present invention, a pharmaceutically acceptable salt or isotope compound thereof; and the disease related to polymerase theta is lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

[0392] The present invention provides a substance A or the above-mentioned pharmaceutical composition as a drug, wherein the substance A is a compound represented by formula I according to any one of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.

[0393] The present invention provides a substance A or the above-mentioned pharmaceutical composition for treating and / or preventing lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer, wherein the substance A is a compound represented by formula I according to any one of the present invention, or a pharmaceutically acceptable salt or isotope compound thereof.

[0394] The present invention provides a method for treating a disease, comprising the following steps: administering (a therapeutically effective amount of) substance A or the above-mentioned pharmaceutical composition to a subject, wherein substance A is a compound represented by formula I according to any one of the present invention, a pharmaceutically acceptable salt or isotope compound thereof; and the disease is lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

[0395] The present invention provides a compound as shown in Formula II or a salt thereof:

[0396] R v It is a halogen.

[0397] In a preferred embodiment, the compound shown in formula II is

[0398] Explanation of terms

[0399] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0400] The term "a group B which is unsubstituted or substituted by one or more groups A" means that one or more hydrogen atoms in the group B are independently replaced by a group A or B is unsubstituted. When multiple A groups appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "C substituted by 3 halogens" 6-10 "Aryl" refers to C6-10 The aryl group may be substituted by three halogens, the definitions of which are independent of each other and do not affect each other, including but not limited to: wait.

[0401] The term "plurality" refers to 2 or more, such as 2, 3, 4, 5; preferably 2 or 3.

[0402] In the claims of this application, the term "multiple" in the phrase "satisfies one or more of the following conditions" means 2, 3, 4, or more conditions. The maximum value of "more" is the maximum number of conditions recited in each claim. For example, if a claim recites 8 conditions, the term "one or more" in the phrase "satisfies one or more of the following conditions" in that claim can be any integer between 1 and 8, such as 1, 2, 3, 4, 5, 6, 7, or 8.

[0403] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0404] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, and ammonium salts. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, formates, and methanesulfonates. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0405] The "-" in a group means that the group is attached to the rest of the molecule through that site. For example, -NHC(O)R b It means that the nitrogen atom is connected to the rest of the molecule.

[0406] The term "halogen" refers to fluorine, chlorine, bromine or iodine. Halogen substitution in the present invention includes, but is not limited to, substitution by one halogen, substitution by two halogens, substitution by three halogens, and generally multiple substitutions occur on one carbon atom.

[0407] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0408] The term "alkyl" refers to a group having the specified number of carbon atoms (e.g., C 1-6 ) is a linear or branched, saturated, monovalent hydrocarbon group. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0409] The term "alkoxy" refers to a group R X -O-, R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0410] The term "alkenyl" refers to a group having the specified number of carbon atoms (e.g., C 2-6 ) is a linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 Double bond. Alkenyl groups include but are not limited to: vinyl, wait.

[0411] The term "alkynyl" refers to a group having the specified number of carbon atoms (e.g., C 2-6 ) is a linear or branched, unsaturated, monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp 3 Triple bond. Alkynyl includes but is not limited to: ethynyl, wait.

[0412] Unless otherwise specified in the present invention, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 3 to 10 members), which is a monocyclic ring. Monocyclic rings include, but are not limited to: wait.

[0413] Unless otherwise specified in the present invention, the term "aryl" refers to a cyclic, unsaturated, monovalent hydrocarbon group with a specified number of carbon atoms (e.g., 6 to 12 members), which is monocyclic or polycyclic (e.g., 2 or 3). When it is polycyclic, the monocyclic rings share two atoms and one bond, and (at least one ring / each ring) has aromaticity. The aryl group is connected to the rest of the molecule through an aromatic ring or a non-aromatic ring. Aryl groups include but are not limited to: phenyl, naphthyl, wait.

[0414] Unless otherwise specified in the present invention, the term "cycloalkenyl" refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 4-12 members), which is monocyclic or polycyclic (e.g., 2 or 3, bridged, spiro, or fused rings). Monocyclic cycloalkenyl groups include, but are not limited to: etc. Bridged ring cycloalkenyl groups include but are not limited to: Spirocyclic cycloalkenyl groups include but are not limited to Etc. Cycloalkenyl includes but is not limited to wait.

[0415] Unless otherwise specified herein, the term "heterocycloalkyl" refers to a monocyclic, bridged, spirocyclic, or fused ring having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). Monocyclic heterocycloalkyl groups are attached to the rest of the molecule via a carbon atom or a heteroatom. Monocyclic heterocycloalkyl groups include, but are not limited to: Spirocyclic heterocycloalkyl groups include but are not limited to: etc. Bridged heterocycloalkyl groups include but are not limited to: Etc. Cycloheterocycloalkyl includes but is not limited to wait.

[0416] Unless otherwise specified in the present invention, the term "heterocycloalkenyl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 4-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic (e.g., 2 or 3, spirocyclic). Monocyclic heterocycloalkenyl groups include, but are not limited to: Spirocyclic heterocycloalkenyl groups include but are not limited to wait.

[0417] Unless otherwise specified in the present invention, the term "heteroaryl" refers to a cyclic, unsaturated, monovalent group with a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic rings, and at least one ring having aromatic properties. Heteroaryl groups are linked to the rest of the molecule through carbon atoms or heteroatoms; heteroaryl groups are linked to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; heteroaryl groups are linked to the rest of the molecule through a ring with aromatic properties or a ring without aromatic properties. Heteroaryl groups include, but are not limited to: wait.

[0418] The term "isotopic compound" refers to a compound in which one or more atoms have an isotopic abundance that differs from its natural abundance. For example, one or more atoms in a compound is replaced by an atom of a lower mass number than occurs naturally - a hydrogen atom in a compound is replaced by deuterium, or a C is replaced by 13 C replacement.

[0419] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For a complete list, see Part IV of the Pharmacopoeia of the People's Republic of China (2015 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0420] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0421] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0422] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0423] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0424] In the present invention, "room temperature" means "20 to 40°C".

[0425] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0426] The reagents and raw materials used in the present invention are commercially available.

[0427] The positive progress of the present invention is that the ATPase activity and the protein inhibition effect of the compound of the present invention are greatly improved compared with the prior art. DETAILED DESCRIPTION

[0428] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0429] All compounds of the present invention can be synthesized by different methods by those skilled in the art of organic chemistry. The following describes general synthetic schemes for preparing the compounds of the present invention. These schemes are general and are not meant to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be apparent to those skilled in the art. In addition, the various steps in the synthesis can be performed in an alternating order to obtain the desired compound or compounds. The preparation and examples described below provide examples of the preparation of the compounds of the present invention by the methods described in the general schemes. The preparation of compounds containing chiral center embodiments can be performed by techniques known to those skilled in the art. For example, chiral compounds can be prepared by chiral separation of racemic products by HPLC; alternatively, the example compounds can be prepared by known methods to obtain chiral compounds.

[0430] The chemical reactions and synthetic techniques described herein are performed in the reagents and corresponding solvents described herein, and the corresponding reaction yields will also be affected by the reagents and solvents used. Furthermore, it should be understood that in the synthetic methods described below, all reaction conditions mentioned, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and reaction feed sequence, should be considered standard operating conditions for the reaction, as readily recognized by those skilled in the art. This is also understood by those skilled in the art of organic synthesis. The functional groups present on various parts of the molecule must be compatible with the reagents used and the reaction itself. Limitations such as incompatibility of some functional groups on various parts of the molecule with the reaction conditions necessitate alternative methods, as will be readily apparent to those skilled in the art. The need to adjust the order of synthetic steps or select a specific synthetic process scheme to obtain the desired compounds of the present invention is readily apparent to those skilled in the art of organic synthesis. It should also be recognized that another key consideration in any synthetic route designed in this field is the tolerance of the appropriate protecting groups used to protect the reactive functional groups present in the compounds described herein. For details, please refer to the work of Greene et al., an authority in the field of chemistry (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0431] Example

[0432] The preparation of the compounds and the intermediates used in the preparation of the compounds can be prepared using the procedures shown in the following examples and related procedures. The methods and conditions used in these examples and the actual compounds prepared in these examples are not meant to be limiting, but rather to illustrate how to prepare the relevant compounds. The starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally commercially available or reported in the relevant chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0433] In the examples given herein, the term "drying and concentrating" generally refers to adding anhydrous sodium sulfate or magnesium sulfate drying solution to an organic solvent, followed by filtration and removal of the solvent from the filtrate (usually performed under reduced pressure and at a temperature suitable for the stability of the prepared compound). Column chromatography is generally performed using conventional column chromatography or flash column chromatography for column separation and purification, or using a medium pressure chromatograph (Biotage Isola One) pre-packed silica gel column and eluting in a specified solvent or solvent mixture. In some cases, the final product is quickly purified by preparative thin layer chromatography using a 20cm x 20cm x 0.5mm or 20cm x 20cm x 1mm silica gel plate in an appropriate solvent system. Preparative high performance liquid chromatography (HPLC) is performed using a reversed-phase column (Waters Sunfire C18, Waters Xbridge C18, or similar) of a size appropriate to the amount of compound being separated. Elution is typically performed using a gradient of methanol or acetonitrile added to the aqueous phase, with the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid, or 10 mM ammonium acetate, at an elution rate that matches the size of the reversed-phase column used and the resolution of the preparation being prepared.

[0434] List of abbreviations

[0435] Table 1

[0436] Example 1: N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)-2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxamide

[0437] Step 1: Benzyl 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylate

[0438] To a solution of benzyl 6-chloro-4-iodonicotinate (5.0 g, 13.40 mmol) in 1,4-dioxane (50 mL) and water (10 mL) at room temperature under nitrogen was added 2-difluoromethyl-5-methoxy-4-borylpyridine (4.58 g, 16.08 mmol), potassium phosphate (8.53 g, 40.21 mmol), and (1,1'-bis(di-tert-butylphosphino)ferrocene)palladium dichloride (865 mg, 0.294 mmol). The reaction mixture was stirred at 90°C under nitrogen for 1.5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-30% ethyl acetate) to afford the title compound as a white solid, 3.06 g, 56.5% yield. LC / MS(ESI)m / z:405.1[M+H] + .

[0439] Step 2: Benzyl 2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxylate

[0440] Under nitrogen protection at room temperature, benzyl 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylate (3.0 g, 7.42 mmol), 3-fluoropyridin-2(1H)one (1.26 g, 11.15 mmol), cuprous iodide (707 mg, 3.71 mmol), 8-hydroxyquinoline (108 mg, 0.74 mmol) and potassium carbonate (2.05 g, 14.85 mmol) were dissolved in dimethyl sulfoxide (30 mL). The reaction mixture was replaced with nitrogen three times and stirred at 100 ° C under nitrogen protection for 1 hour. After the reaction was complete, water was added to the reaction solution and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30%-70% ethyl acetate) to obtain the title compound (white solid, 1.41 g, yield 39.5%). LC / MS (ESI) m / z: 482.2 [M+H] + .

[0441] Step 3: 2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxylic acid

[0442] To a solution of 2-difluoromethyl-3-fluoro-5-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxylic acid benzyl ester (1.4 g, 2.91 mmol) in methanol (14 mL) was added 10% palladium on carbon (300 mg). The mixture was purged with nitrogen three times and stirred at room temperature under a hydrogen atmosphere at 1 atmosphere for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (brown solid, 1.01 g, 88.7% yield). LC / MS (ESI) m / z: 392.1 [M+H] + .

[0443] Step 4: N-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)-2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxamide

[0444] 2"-Difluoromethyl-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxylic acid (20 mg, 0.051 mmol), 3-cyclopropyl-1,2,4-thiadiazol-5-amine (10.8 mg, 0.077 mmol), and 1-methylimidazole (16.80 mg, 0.21 mmol) were dissolved in acetonitrile (2 mL) at room temperature, and the mixture was stirred at 75°C for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (21.5 mg, 0.077 mmol) was then added, and the mixture was stirred at 75°C for another hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase preparative purification to afford the title compound (white solid, 6 mg, 22.8% yield).

[0445] 1 H NMR (400MHz, DMSO-d6) δ13.85-13.53(m,1H),9.03(s,1H),8.50(s,1H),8.06(s,1H),7.86(d,J=7.1Hz,1H),7.73(s,1H),7.62-7.48(m,1H),7 .00(t,J=55.1Hz,1H),6.47-6.36(m,1H),3.66(s,3H),2.25-2.13(m,1H),1.06-0.99(m,2H),0.99-0.93(m,2H).LC / MS(ESI)(m / z):515[M+H] + .

[0446] The compounds in Table 2 were synthesized using commercially available raw materials according to the synthesis steps of Example 1.

[0447] Table 2:

[0448] Example 23: N-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)-2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxamide

[0449] Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0450] Under nitrogen, 3-bromo-5-chloro-1,2,4-thiadiazole (500 mg, 2.51 mmol) was dissolved in anhydrous ethanol (5 mL). Ammonia (0.34 mL, 5.01 mmol, 25% w / w) was then slowly added dropwise. The mixture was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (10 mL) was added, resulting in the precipitation of a white solid. The filter cake was filtered and concentrated under reduced pressure to afford the title compound (white solid, 220 mg, 48.8% yield). LC / MS (ESI) m / z: 179.9 [M+H] + .

[0451] Step 2: N-(3-bromo-1,2,4-thiadiazol-5-yl)-2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxamide

[0452] At room temperature, 2"-difluoromethyl-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxylic acid (200 mg, 0.511 mmol), 3-bromo-1,2,4-thiadiazole-5-amine (92.01 mg, 0.511 mmol), and N-methylimidazole (168 mg, 2.04 mmol) were dissolved in acetonitrile (3 mL) and N,N-dimethylformamide (1 mL). After stirring at 70°C for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphorus was added to the reaction solution. The reaction mixture was stirred at 70°C for 1 hour, and the reaction mixture turned clear. Ethyl acetate and water were added to the reaction mixture, and the organic phase was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-55% ethyl acetate) to obtain the title compound (white solid, 160 mg, yield 56%). LC / MS (ESI) m / z: 553.3 [M+H] + .

[0453] Step 3: N-(3-(4-chlorophenyl)-1,2,4-thiadiazol-5-yl)-2″-difluoromethyl-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-tripyridine]-5′-carboxamide

[0454] Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazol-5-yl)-2"-difluoromethyl-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxamide (20 mg, 0.036 mmol), 4-chlorophenylboronic acid (8.5 mg, 0.054 mmol) and potassium carbonate (15 mg, 0.108 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.6 mL), and then added under nitrogen protection. 1,1'-Bis(diphenylphosphino)diphenylferric palladium(II) chloride (5.3 mg, 0.007 mmol) was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, then ethyl acetate and water were added. The ethyl acetate phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-3% methanol) and reverse phase chromatography to afford the title compound (white solid, 1 mg, 4.7% yield). 1H NMR (400MHz, DMSO-d6) δ14.01(s,1H),9.12(s,1H),8.50(s,1H),8.19(d,J=8. 6Hz,2H),8.11-7.97(m,1H),7.88(d,J=7.1Hz,1H),7.73(s,1H),7.60-7.54(m, 3H),7.00(t,J=55.1Hz,1H),6.45-6.40(m,1H),3.68(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-113.43(s),-132.05(s).LC / MS(ESI)m / z:585.3[M+H] + .

[0455] Example 24: 2″-(Difluoromethyl)-3-fluoro-5″-methoxy-N-(3-morpholin-1,2,4-thiadiazol-5-yl)-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0456] Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0457] Dissolve 3-bromo-5-chloro-1,2,4-thiadiazole (5.5 g, 27.6 mmol) in ethanol (16 mL), add aqueous ammonia (4 mL), and stir the reaction at 70°C for 3 hours. Add saturated ammonium chloride solution to the mixture, filter, and dry the filter cake under reduced pressure to obtain the title compound (white solid, 4 g, 80.6% yield). LC / MS (ESI) m / z: 182.0 [M+H] + .

[0458] Step 2: tert-Butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate

[0459] 3-Bromo-1,2,4-thiadiazol-5-amine (300 mg, 1.67 mmol) was dissolved in tetrahydrofuran (10 mL). 4-Dimethylaminopyridine (10 mg, 0.082 mmol) and di-tert-butyl dicarbonate (436 mg, 2.0 mmol) were added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to obtain the title compound (white solid, 430 mg, 91.5% yield). LC / MS (ESI) m / z: 280.0 [M+H] + .

[0460] Step 3: tert-Butyl (3-morpholino-1,2,4-thiadiazol-5-yl)carbamate

[0461] Dissolve tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.357 mmol) in morpholine (1 mL), and stir the reaction at 120°C for 3 hours. Dilute the reaction solution with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 20-30% ethyl acetate) to obtain the title compound (white solid, 80 mg, 78.3% yield). LC / MS (ESI) m / z: 287.2 [M+H] + .

[0462] Step 4: 3-morpholino-1,2,4-thiadiazol-5-amine hydrochloride

[0463] Dissolve tert-butyl (3-morpholinyl-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 0.279 mmol) in 4N hydrochloric acid / dioxane (3 mL). Stir the reaction mixture at room temperature for 16 hours. Concentrate under reduced pressure to obtain the title compound (60 mg, white solid, 96.4% yield). LC / MS (ESI) m / z: 187.2 [M+H] + .

[0464] Step 5: 2"-(Difluoromethyl)-3-fluoro-5"-methoxy-N-(3-morpholinyl-1,2,4-thiadiazol-5-yl)-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0465] At room temperature, 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (20 mg, 0.051 mmol), 3-morpholino-1,2,4-thiadiazole-5-amine hydrochloride (14 mg, 0.061 mmol), and N-methylimidazole (17 mg, 0.207 mmol) were dissolved in acetonitrile (3 mL). After stirring at 70°C for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (22 mg, 0.078 mmol) was added to the reaction solution, and the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered and purified by HPLC to obtain the title compound (8.16 mg, white solid, 28.5% yield). 1H NMR(400MHz,DMSO-d6)δ13.60(s,1H),9.02(s,1H),8.52(s,1H),8.08(s,1H),7.89-7.83(m,1H),7.74(s,1H),7.61-7.53(m,1 H),7.01(t,J=55.1Hz,1H),6.47-6.39(m,1H),3.70(s,3H),3.69-3.65(m,4H),3.54-3.49(m,4H).LC / MS(ESI)m / z:560.2[M+H) + .

[0466] Example 25: N-(3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-bipyridine]-5′-carboxamide

[0467] Step 1: tert-Butyl (3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0468] Dissolve tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 0.178 mmol) in 2-oxa-6-azaspiro[3.3]heptane (0.5 mL) and stir the reaction at 100°C for 3 hours. Dilute the reaction with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30-50% ethyl acetate) to yield the title compound (white solid, 20 mg, 37.6% yield). LC / MS (ESI) m / z: 299.2 [M+H] + .

[0469] Step 2: 3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-amine

[0470] Dissolve tert-butyl (3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)carbamate (20 mg, 0.067 mmol) in dichloromethane (2 mL). Add trifluoroacetic acid (0.2 mL) and stir at room temperature for 1 hour. Adjust the pH of the reaction mixture to 7-8 with sodium bicarbonate and extract three times with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the title compound (10 mg, white solid, 75.3% yield). LC / MS (ESI) m / z: 199.1 [M+H] + .

[0471] Step 3: N-(3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-bipyridine]-5′-carboxamide

[0472] At room temperature, 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (20 mg, 0.051 mmol), 3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-amine (10 mg, 0.050 mmol), and N-methylimidazole (17 mg, 0.207 mmol) were dissolved in acetonitrile (3 mL). After stirring at 70°C for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (22 mg, 0.078 mmol) was added to the reaction solution. The reaction solution was essentially dissolved, and the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered and purified by preparative HPLC to give the title compound (1.29 mg, white solid, 4.4% yield). 1 H NMR(400MHz,DMSO-d6)δ13.65(s,1H),9.00(s,1H),8.51(s,1H),8.07(s,1H),7.86(m,1H),7.73(s,1H),7.61-7.5 2(m,1H),7.00(t,J=55.1Hz,1H),6.42(m,1H),4.71(s,4H),4.19(s,4H),3.68(s,3H).LC / MS(ESI)m / z:572.2[M+H] + .

[0473] Example 26: 2″-chloro-N-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0474] Step 1: tert-Butyl 3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-ylcarbamate

[0475] Under nitrogen, tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.357 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (95 mg, 0.428 mmol), cesium fluoride (108 mg, 0.711 mmol), and dichlorobis(di-tert-butyl-(4-dimethylaminophenyl)phosphine)palladium(II) (25 mg, 0.035 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL). The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10-20% ethyl acetate) to give the title compound (white solid, 100 mg, 94.9% yield). LC / MS (ESI) m / z: 296.2 [M+H] + .

[0476] Step 2: 3-(1,4-Dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-amine hydrochloride

[0477] Dissolve tert-butyl 3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-ylcarbamate (100 mg, 0.339 mmol) in 4N hydrochloric acid in dioxane (5 mL). Stir the reaction mixture at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and slurried in ethyl acetate to obtain the title compound (70 mg, light yellow solid, 89.2% yield). LC / MS (ESI) m / z: 196.1 [M+H] + .

[0478] Step 3: 2″-chloro-N-(3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0479] 2"-Chloro-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (30 mg, 0.080 mmol), 3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-amine hydrochloride (22 mg, 0.097 mmol), and N-methylimidazole (26 mg, 0.317 mmol) were dissolved in acetonitrile (5 mL) and N,N-dimethylformamide (2 mL) at room temperature. After stirring at 70°C for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (45 mg, 0.160 mmol) was added to the reaction solution, and the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC to give the title compound (8.06 mg, white solid, 18.3% yield). 1 H NMR(400MHz,DMSO-d6)δ13.98(s,1H),9.10(s,1H),8.24(s,1H),8.10(s,1H),7.91-7.85(m,1H),7.60(s,1H),7.60 -7.54(m,1H),7.39(s,1H),6.50-6.38(m,1H),4.15(s,3H),3.61(s,3H),2.31(s,3H).LC / MS(ESI)m / z:553.1[M+H] + .

[0480] Example 27: N-(3-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0481] Step 1: tert-Butyl 3-(5-(2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide)-1,2,4-thiadiazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0482] Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide (150 mg, 0.271 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL) solution, and then tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (108 mg, 0.545 mmol), cesium carbonate (353 mg, 1.08 mmol) and methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1, 1'-Biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) (12 mg, 0.014 mmol) was added. The reaction mixture was stirred at 130°C under nitrogen for 1 hour. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to obtain the title compound (white solid, 35 mg, 19.3% yield). LC / MS (ESI) m / z: 671.2 [M+H] + .

[0483] Step 2: N-(3-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0484] Under an ice-water bath, tert-butyl 3-(5-(2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (35 mg, 0.052 mmol) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (0.5 mL) was then added to the reaction solution. After the addition, the mixture was warmed to room temperature and stirred for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O and 0.1% FA) to afford the title compound (13.42 mg, light yellow solid, 45.1% yield). 1H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.47(s,1H),7.89(s,1H),7.87-7.82(m,1H),7.65(s,1H),7.59-7.51(m,1H),6.97(t,J=55.1Hz,1H),6.4 7-6.39(m,1H),4.35(d,J=6.3Hz,2H),3.97-3.88(m,4H),3.69(s,3H),2.88-2.79(m,1H),1.84(d,J=10.0Hz,1H).LC / MS(ESI)(m / z):571[M+H] + .

[0485] Example 28: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0486] Step 1: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0487] Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide (50 mg, 0.09 mmol) was dissolved in anhydrous dioxane (3 mL) solution, and then 3-azabicyclo[3.1.0]hexane hydrochloride (22 mg, 0.18 mmol), cesium carbonate (118 mg, 0.3 The reaction mixture was stirred at 110°C for 3 hours under nitrogen. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O and 0.1% FA) to afford the title compound as a white solid, 1.52 mg, 3.0% yield. 1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),9.00(s,1H),8.51(s,1H),8.07(s,1H),7.89-7.82(m,1H),7.73(s,1H) ,7.60-7.53(m,1H),7.00(t,J=55.0Hz,1H),6.46-6.38(m,1H),3.73-3.70(m,1H),3.69(s,3H),3.68-3.66(m, 1H),3.49-3.45(m,2H),1.67-1.59(m,2H),0.75-0.66(m,1H),0.23-0.17(m,1H).LC / MS(ESI)(m / z):556[M+H] + .

[0488] Example 29: 2″-(Difluoromethyl)-3-fluoro-5″-methoxy-N-(3-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0489] Step 1: 2"-(difluoromethyl)-3-fluoro-5"-methoxy-N-(3-(6-methyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0490] At room temperature, N-(3-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide (10 mg, 0.018 mmol) was dissolved in methanol (3 mL). Paraformaldehyde (2 mg, 0.067 mmol) and acetic acid (one drop) were added to the reaction solution. The mixture was stirred at room temperature for 1 hour. Sodium acetate borohydride (3 mg, 0.048 mmol) was then added to the reaction solution. The mixture was stirred at 50°C for 16 hours. The reaction solution was filtered and analyzed by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O and 0.1% The residue was purified by FA to afford the title compound (3.60 mg, white solid, 35.1% yield). 1H NMR(400MHz, CDCl3)δ10.93(s,1H),8.82(s,1H),8.17(s,1H),8.12(s,1H),7 .90-7.86(m,1H),7.62(s,1H),7.34-7.27(m,1H),6.66(t,J=55.5Hz,1H),6. 44-6.34(m,1H),4.06-4.03(m,1H),4.03-3.98(m,5H),3.59(s,3H),3.51-3. 42(m,1H),2.66(s,3H),1.79(d,J=10.0Hz,1H).LC / MS(ESI)(m / z):585[M+H] + .

[0491] Example 30: N-(3-amino-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0492] Step 1: Benzyl (5-(2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-formamido)-1,2,4-thiadiazol-3-yl)carbamate

[0493] Under nitrogen protection, 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (78.2 mg, 0.20 mmol), benzyl (5-amino-1,2,4-thiadiazol-3-yl)carbamate (50 mg, 0.20 mmol) and N-methylimidazole (65.6 mg, 0.78 mmol) were dissolved in anhydrous acetonitrile (2 mL) and heated at 70 °C. After stirring for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (84.1 mg, 0.30 mmol) was added to the reaction solution, and the reaction solution was stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-3% methanol) to obtain the title compound (white solid, 75 mg, 60% yield). LC / MS (ESI) m / z: 624.3 [M+H] + .

[0494] Step 2: N-(3-amino-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0495] To a bottle containing benzyl (5-(2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-formamido)-1,2,4-thiadiazol-3-yl)carbamate (70 mg, 0.11 mmol) was added trifluoroacetic acid (2 mL), and the reaction was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the trifluoroacetic acid. The residue was diluted with ethyl acetate and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The aqueous phase was then extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (Welch-Ultimate AQ-C18, 21.2*250 mm, 5 μm, 10-95% acetonitrile in H2O containing 0.1% FA) to afford the title compound as a white solid, 6 mg, 33% yield. 1 H NMR (400MHz, DMSO-d6) δ13.29(s,1H),8.99(s,1H),8.52(s,1H),8.07(s,1H),7.86(d,J=7.1Hz,1H),7.74(s, 1H),7.62-7.46(m,1H),7.00(t,J=55.0Hz,1H),6.48-6.29(m,3H),3.70(s,3H).LC / MS(ESI)(m / z):490[M+H] + .

[0496] Example 31: N-(3-acetylamino-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0497] Step 1: N-(3-acetylamino-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0498] Under nitrogen protection, N-(3-amino-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide (15 mg, 0.03 mmol), acetic acid (0.02 mL, 0.305 mmol) and N,N-diisopropylethylamine (11.9 mg, 0.092 mmol) were dissolved in anhydrous N,N-dimethylformamide (1 mL), and then 2-(7-azobenzotriazole)-N,N,N",N"-tetramethyluronium hexafluorophosphate (17.5 mg, 0.046 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered and the filtrate was purified by preparative HPLC (Welch XBridge C18 The resulting product was purified by HPLC (250*21 mm, 10-95% acetonitrile in H2O containing 0.1% FA) to afford the title compound (white solid, 7 mg, 43% yield). 1 H NMR (400MHz, DMSO-d6) δ13.79(s,1H),10.88(s,1H),9.04(s,1H),8.51(s,1H),8.10(s,1H),7.86(d,J=7.2Hz,1H),7.76(s ,1H),7.60-7.52(m,1H),7.01(t,J=55.1Hz,1H),6.45-6.40(m,1H),3.68(s,3H),2.12(s,3H).LC / MS(ESI)(m / z):532[M+H] + .

[0499] Example 32: 2″-(Difluoromethyl)-N-(3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0500] Step 1: tert-Butyl (3-(methoxy(methyl)carbamoyl)-1,2,4-thiadiazol-5-yl)carbamate

[0501] 5-((tert-Butoxycarbonyl)amino)-1,2,4-thiadiazole-3-carboxylic acid (600 mg, 2.45 mmol, crude), dimethylhydroxylamine hydrochloride (358.3 mg, 3.67 mmol), N,N-diisopropylethylamine (1 mL, 6.12 mmol), and 1-hydroxybenzotriazole (495.9 mg, 3.67 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701.6 mg, 3.67 mmol) was then added. The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, the layers were separated, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to give the title compound (white solid, 450 mg, yield 64%). LC / MS (ESI) (m / z): 289 [M+H] + .

[0502] Step 2: tert-Butyl (3-propionyl-1,2,4-thiadiazol-5-yl)carbamate

[0503] Under nitrogen, tert-butyl (3-(methoxy(methyl)carbamoyl)-1,2,4-thiadiazol-5-yl)carbamate (450 mg, 1.56 mmol) was dissolved in tetrahydrofuran (5 mL). The reaction solution was cooled to -78°C, and 1.0 M ethylmagnesium bromide (2.0 mL, 2.03 mmol) was slowly added dropwise. The reaction solution was stirred at -78°C for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride at 0°C and extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to yield the title compound as a white solid, 160 mg, 40% yield. LC / MS (ESI) (m / z): 258 [M+H] + .

[0504] Step 3: tert-Butyl (Z)-(3-(2-(hydroxyimino)propionyl)-1,2,4-thiadiazol-5-yl)carbamate

[0505] Under nitrogen, tert-butyl (3-propionyl-1,2,4-thiadiazol-5-yl)carbamate (250 mg, 0.97 mmol) and trimethylsilyl chloride (126.7 mg, 1.17 mmol) were dissolved in anhydrous dichloromethane (5 mL). The reaction solution was cooled to -20°C and isoamyl nitrite (136.6 mg, 1.17 mmol) was added. After the addition, the mixture was warmed to room temperature and stirred for 16 hours. Dichloromethane and water were added to the reaction solution, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (brown solid, 210 mg, 75% yield). LC / MS (ESI) m / z: 287.2 [M+H] + .

[0506] Step 4: 5-(5-((tert-Butyloxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-1,4-dimethyl-1H-imidazole 3-oxide

[0507] At room temperature, tert-butyl (Z)-(3-(2-(hydroxyimino)propionyl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 0.175 mmol) was added to a bottle containing anhydrous ethanol (3 mL). Then, 1,3,5-trimethylhexahydro-1,3,5-triazine (67.6 mg, 0.524 mmol) was added at room temperature. The reaction mixture was stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (yellow solid, 50 mg, crude product, 100% yield). LC / MS (ESI) m / z: 312 [M+H] + .

[0508] Step 5: tert-Butyl (3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0509] Under nitrogen protection, 5-(5-((tert-Butyloxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-1,4-dimethyl-1H-imidazole 3-oxide (50 mg, 0.161 mmol) was dissolved in anhydrous methanol (1 mL), and Raney nickel (10 mg) was added under nitrogen protection. The reaction solution was replaced with nitrogen three times, and then stirred at room temperature under a 1 atmosphere hydrogen atmosphere for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (brown oil, 26 mg, 55% yield). LC / MS (ESI) m / z: 296.3 [M+H] + .

[0510] Step 6: 3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-amine

[0511] At room temperature, tert-butyl (3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 0.161 mmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was slowly added dropwise in an ice-water bath. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the trifluoroacetic acid, then diluted with water, adjusted to pH ~8 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (yellow oil, 15 mg, 87% yield). LC / MS (ESI) m / z: 196.3 [M+H] + .

[0512] Step 7: 2"-(difluoromethyl)-N-(3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0513] Under nitrogen protection, 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (30 mg, 0.077 mmol), 3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-amine (15 mg, 0.077 mmol) and N-methylimidazole (25 mg, 0.31 mmol) were dissolved in anhydrous acetonitrile (2 mL) and stirred at 70°C for 5 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (32.3 mg, 0.12 mmol) was added to the reaction solution, and the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered and the filtrate was purified by preparative HPLC (Welch XBridge xb 5um The resulting suspension was purified by HPLC (21.2*250 mm, 30-95% methanol in H2O containing 0.1% TFA) to afford the title compound (white solid, 0.4 mg, 0.92% yield). 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.78(s,1H),8.53(s,1H),8.13(s,1H),7.88(d,J=7.1Hz,1H),7.79(s,1H),7.64-7. 54(m,1H),7.02(t,J=55.0Hz,1H),6.47-6.42(m,1H),4.09(s,3H),3.69(s,3H),2.63(s,3H).LC / MS(ESI)(m / z):569[M+H] + .

[0514] Example 33: N-(3-cyclobutyl-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-bipyridine]-5′-carboxamide

[0515] Step 1: 3-cyclobutyl-1,2,4-thiadiazol-5-amine

[0516] Sodium thiocyanate (196 mg, 2.41 mmol) was dissolved in methanol (30 mL) at room temperature. The mixture was then cooled to -20°C, and triethylamine (0.31 mL, 2.23 mmol) and cyclobutanecarboximidamide hydrochloride (250 mg, 1.86 mmol) were added sequentially. After the addition, the reaction was stirred at -20°C for 45 minutes. Triethylamine (0.26 mL, 1.86 mmol) was added, followed by the dropwise addition of 8% aqueous sodium hypochlorite (1.73 g, 1.86 mmol). After the addition, the reaction was stirred at -20°C for 2 hours, then warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 2-50% ethyl acetate) to afford the title compound (white solid, 50 mg, 17% yield). LC / MS(ESI)m / z:156.3[M+H] + .

[0517] Step 2: N-(3-cyclobutyl-1,2,4-thiadiazol-5-yl)-2″-(difluoromethyl)-3-fluoro-5″-methoxy-2-oxo-2H-[1,2′:4′,4″-terpyridine]-5′-carboxamide

[0518] At room temperature, 3-cyclobutyl-1,2,4-thiadiazol-5-amine (15 mg, 0.097 mmol), 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (38 mg, 0.097 mmol), N-methylimidazole (48 mg, 0.58 mmol) and acetonitrile (2 mL) were added to a reaction flask. After stirring at 70°C for one minute, a solution of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (54 mg, 0.19 mmol) in acetonitrile (1 mL) was added to the reaction solution, and the reaction solution was stirred at 70°C for 1 hour. The mixture was filtered and analyzed by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 10-100% acetonitrile in H2O containing 0.1% The residue was purified by FA to afford the title compound (15 mg, white solid, 29% yield). 1 H NMR (400MHz, DMSO-d6) δ13.76(s,1H),9.04(s,1H),8.51(s,1H),8.10(s,1H),7.87(d,J=7.0Hz,1H),7.76(s,1H),7.61-7.53(m,1H),7.01 (t,J=55.0Hz,1H),6.45-6.40(m,1H),3.77-3.71(m,1H),3.67(s,3H),2.40-2.31(m,4H),2.12-1.83(m,2H).LC / MS(ESI)(m / z):529[M+H] + .

[0519] Effect embodiment

[0520] Experimental methods:

[0521] 1. Polθ inhibitor biochemical activity detection (ADP Glo assay)

[0522] The N-terminus of the Polθ protein contains a helicase domain with ATPase activity, capable of hydrolyzing ATP to ADP. The ATPase activity of the Polθ protein and the inhibitory effect of small molecule compounds on the protein can be analyzed using the ADP-Glo ​​assay kit (ADP-GloTM Kinase Assay, Promega, V9102). The specific detection method is as follows:

[0523] 1) Purify the helicase domain of Polθ protein using an insect system to obtain a protein with a purity of >90%. Order ssDNA (5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3', Hangzhou Youkang Biotechnology Co., Ltd.) as a Polθ protein substrate; prepare the reaction buffer containing 10mM DTT (Dithiothreitol), 20mM MgCl2, and Tris-HCl pH 7.5.

[0524] 2) Prepare a 2x ssDNA-Polθ premix and perform the reaction in a 384-well plate. Set up a control group with only buffer, and add the premix to all other groups. Use an automated pipette (Thermo, Multidrop 8) to add the compound, starting at 10 μM and diluting it 1 / 3. Set up a total of 9 assay points, with 2 replicates per group.

[0525] 3) Prepare 2xATP solution, add equal volume of 2xATP solution to all wells, and let stand at room temperature for 60 minutes;

[0526] 4) According to the Promega reagent instructions, ADP-Glo ​​Detection Reagent was added to the reaction system and allowed to stand at room temperature for 60 minutes;

[0527] 5) According to the Promega reagent instructions, Kinase Detection Reagent was added to the reaction system, and the reaction was allowed to stand at room temperature for 60 min. The chemiluminescent signal was detected using a microplate reader (Thermo, VarioskanLUX), and the reading interval for each well was set to 1000 ms;

[0528] The measurement results were analyzed: the CV% of the control group test results should be less than 10%, and the z' value should be greater than 0.5. The data that met the above quality control results were used to calculate the inhibition rate of the compound (inhibition rate (%) = 100 * (control group average - experimental group) / (control group average - buffer control group average). GraphPad Prism8 was used to perform nonlinear regression fitting of the compound inhibition rate curve and obtain the IC 50 The results are shown in Table 3.

[0529] 2. Polθ inhibitor cell viability assay

[0530] The inhibitor's in vitro effectiveness was assessed by cell viability assay using CellTiter Glo reagent (Promega, G7573), also known as the commonly used CTG assay. The specific assay method is as follows:

[0531] 1) Culture DLD1 wild-type (ATCC, CCL-221) and DLD1BRCA2- / - cells. One day before the assay, digest the cells with trypsin (0.025% Trypsin-EDTA, Hyclone) and collect the cells by centrifugation at 1000 rpm for 3 minutes. Count the cells using a cell counter (Shanghai Mengwei Biomedical Technology Co., Ltd., SmartCell600A.SC1006) and inoculate them into 96-well white culture plates according to the appropriate inoculation ratio.

[0532] 2) 24 hours after cell plating, drug treatment was performed, designated as Day 0. Compound addition was performed using an automated pipette (Thermo, Multidrop 8) in a 96-well plate. The starting concentration was set at 30 μM, and dilution was performed at a 1 / 3 dilution ratio. A total of 9 assay points were set, with 2 replicates per group. Cells were cultured in a 37°C, 5% CO2 incubator.

[0533] 3) Change the medium twice on Day 3 and Day 7, and add the compound according to step 2);

[0534] 4) On Day 10, remove the cell culture plate and add an equal volume of CTG reagent (pre-mix the CTG reagent by returning it to its original temperature according to the reagent instructions). Gently mix the mixture on a thermomixer (Hangzhou Aosheng Instrument Co., Ltd., MSC-100) for 10 min (speed 300). Chemiluminescence detection is performed using a microplate reader (Thermo, VarioskanLUX).

[0535] 5) Data analysis of the measurement results: The CV% of the control group test results should be less than 20%, and the z' value should be greater than 0.5. Data that meet the above quality control results are used to calculate cell viability (inhibition rate (%) = 100 * (control group average - experimental group) / (control group average - culture medium control group average). Nonlinear regression fitting of the compound inhibition rate curve is performed using GraphPad Prism8 to obtain the IC 50 The results are shown in Table 3.

[0536] The test showed that the example compounds of the present application had a strong proliferation inhibitory effect on DLD1BRCA2- / - cells, and a very weak proliferation inhibitory effect on DLD1 wild-type cells, indicating that the example compounds of the present application had good selectivity in inhibiting the proliferation of the two cell types.

[0537] Data list:

[0538] NT = not tested;

[0539] Table 3: Specific data of biochemical experiments and cell survival assays:

Claims

1. A compound as shown in formula I, a pharmaceutically acceptable salt thereof or an isotope compound thereof, in, m and n are independently 0, 1, 2, 3 or 4; X 1 and X 4 N or CR independently a ; X 2 and X 3 are independently N or CH; Each R a are independently hydrogen, halogen, CN, OH, deuterium, cyano, -NHR f 、-C(O)NHR g , unsubstituted or replaced by one or more R 1-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 1-2 Substituted C 1-6 Alkoxy; Each R 1-1 and R 1-2 are independently halogen; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k 、-C(O)N(R m )2. unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 alkyl; Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently deuterium, halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2; Each R 2 are independently deuterium, halogen, cyano, amino, hydroxyl, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 2-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 2-3 Substituted C 2-6 Alkenyl, unsubstituted or substituted with one or more R 2-4 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 2-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 2-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 2-13 Substituted 4-12 membered heterocycloalkenyl, -COOR 2- 7 、-C(O)R 2-8 、-C(O)N(R 2-9 )2. or N(R 2-12 )2; Each R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-13 are independently deuterium, hydroxyl, cyano or halogen; Each R 2-7 , R 2-8 , R 2-9 and R 2-12 are independently hydrogen or C 1-6 alkyl; Each R 2-10 and R 2-11 are independently hydroxyl or C 1-6 alkyl; Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-2 Substituted C 2-6 Alkenyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-4 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, -O-5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl, -N(R 3-7 )2 or Each R 3-1 , R 3-2 and R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-1-2 Substituted 5-12 membered heteroaryl or Each R 3-4 , R 3-5 and R 3-9 are independently oxo, halogen, cyano, hydroxyl, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 3-5-5 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5-6 Substituted 3-12 membered heterocycloalkyl, -N(R 3-5-3 )2. Each R 3-6 and R 3-10 are independently oxo, halogen, cyano, hydroxyl, unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 3-5-5 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-6-2 Substituted 3-12 membered heterocycloalkyl, -N(R 3-6-3 )2. Each R 3-7 are independently hydrogen, unsubstituted or substituted with one or more R 3-7-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3- 8-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-7-2 Substituted 5-12 membered heteroaryl or Each R 3-8 are independently unsubstituted or substituted with one or more R 3-7-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-8-1 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-7-2 Substituted 5-12 membered heteroaryl or Each R 3-1-1 and R 3-1-2 are independently hydroxy, cyano, halogen or C 1-6 alkyl; Each R 3-1-3 are independently unsubstituted or substituted with one or more R 3-1-3-1 Substituted 3-12 membered heterocycloalkyl; Each R 3-1-3-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; Each R 3-4-1 , R 3-5-3 and R 3-6-3 are independently hydrogen or C 1-6 alkyl; Each R 3-5-1 , R 3-5-2 and R 3-7-1 are independently deuterium, hydroxyl, cyano or halogen; Each R 3-5-4 and R 3-7-3 Independently for C 1-6 Alkyl or C 3-6 Cycloalkyl; Each R 3-5-5 , R 3-5-6 and R 3-6-2 are independently hydroxy, cyano, halogen or C 1-6 alkyl; Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 Alkoxy; Each R 3-7-2 and R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, 5-12 membered heteroaryl and -O-5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt or its isotope compound, characterized in that: R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k 、-C(O)N(R m )2. unsubstituted or replaced by one or more R 1-3 Substituted C 1- 6 alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; and / or, each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2; Preferably, the compound as shown in Formula I satisfies one or more of the following conditions: (1) Each R a wherein the halogen is independently fluorine, chlorine, bromine or iodine; (2) Each R a wherein the unsubstituted or replaced by one or more R 1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) Each R a wherein the unsubstituted or replaced by one or more R 1-2 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (4) Each R 1-1 and R 1-2 wherein the halogen is independently fluorine, chlorine, bromine or iodine; (5)R 1 wherein the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine, and further such as fluorine; (6)R 1 wherein the unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl, n-propyl, isopropyl or tert-butyl, and further such as methyl, isopropyl or tert-butyl; (7)R 1 wherein the unsubstituted or replaced by one or more R 1-4 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; (8)R 1 wherein the unsubstituted or replaced by one or more R 1-5 Substituted C 3-10 C in cycloalkyl 3-10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl, for example cyclopropyl; (9)R 1 wherein the unsubstituted or replaced by one or more R 1-6 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a 5-8-membered heterocycloalkyl; (10)R 1 wherein the unsubstituted or replaced by one or more R 1-6 The heteroatoms of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl are independently N and / or O; (11)R 1 wherein the unsubstituted or replaced by one or more R 1-6 The number of heteroatoms of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently 1 or 2, for example 2; (12)R 1 wherein the unsubstituted or replaced by one or more R 1-6 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a monocyclic, bridged, fused or spirocyclic ring; The number of rings in the spiro ring, fused ring or bridged ring may be 2; The spiro ring may be a 3-membered spiro 5-membered heterocyclyl, a 3-membered spiro 6-membered heterocyclyl, a 4-membered spiro 4-membered heterocyclyl, a 4-membered spiro 5-membered heterocyclyl, a 4-membered spiro 6-membered heterocyclyl, a 4-membered spiro 7-membered heterocyclyl, a 5-membered spiro 4-membered heterocyclyl, a 5-membered spiro 5-membered heterocyclyl, a 5-membered spiro 6-membered heterocyclyl, a 5-membered spiro 7-membered heterocyclyl, a 6-membered spiro 4-membered heterocyclyl, a 6-membered spiro 5-membered heterocyclyl or a 6-membered spiro 6-membered heterocyclyl; for example, a 4-membered spiro 4-membered heterocyclyl; The cyclic ring may be the following scheme 1 or scheme 2, scheme 1: the cyclic ring is a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group or a 6-membered and 6-membered heterocyclic group; for example, a 5-membered and 5-membered heterocyclic group; scheme 2: the cyclic ring is a 3-membered and 5-membered heterocyclic group, a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group or a 6-membered and 6-membered heterocyclic group; for example, a 3-membered and 5-membered heterocyclic group or a 5-membered and 5-membered heterocyclic group; The bridged ring may be a 4-membered bridge 5-membered heterocyclic group, a 4-membered bridge 6-membered heterocyclic group, a 5-membered bridge 6-membered heterocyclic group or a 6-membered bridge 6-membered heterocyclic group; for example, a 4-membered bridge 6-membered heterocyclic group; (13)R 1 wherein the unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 C in aromatic groups 6-12 Aryl is independently phenyl or naphthyl, for example phenyl; (14)R 1 wherein the unsubstituted or replaced by one or more R 1-8 The 5-12 membered heteroaryl in the substituted 5-12 membered heteroaryl is a monocyclic ring; (15)R 1 wherein the unsubstituted or replaced by one or more R 1-8 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is independently a 5-6-membered heteroaryl; (16)R 1 wherein the unsubstituted or replaced by one or more R 1-8 The heteroatom of the 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is N and / or O, for example N; (17)R 1 wherein the unsubstituted or replaced by one or more R 1-8 The number of heteroatoms of the 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is 1 or 2; (18)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 9 Substituted C 3-10 C in cycloalkyl 3-10 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl; (19)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 10 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a monocyclic ring, a bridged ring or a fused ring; The number of rings in the fused ring or bridged ring may be 2; The cyclic ring may be a 4-membered and 5-membered heterocyclic group, a 4-membered and 6-membered heterocyclic group, a 5-membered and 5-membered heterocyclic group, a 5-membered and 6-membered heterocyclic group or a 6-membered and 6-membered heterocyclic group; for example, a 5-membered and 5-membered heterocyclic group; The bridged ring may be a 4-membered bridge 5-membered heterocyclic group, a 4-membered bridge 6-membered heterocyclic group, a 5-membered bridge 6-membered heterocyclic group or a 6-membered bridge 6-membered heterocyclic group; for example, a 4-membered bridge 6-membered heterocyclic group; (20)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 10 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a 4-8-membered heterocycloalkyl; (21)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 10 The heteroatoms of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl are independently N and / or O; (22)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 10 The number of heteroatoms of the 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently 1 or 2; (23)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 11 Substituted C 6-12 C in aromatic groups 6-12 Aryl is independently phenyl or naphthyl, for example phenyl; (24)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 12 The 5-12 membered heteroaryl in the substituted 5-12 membered heteroaryl is a monocyclic ring; (25)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 12 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is independently a 5-6-membered heteroaryl; (26)R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k wherein the unsubstituted or replaced by one or more R 1-12 The heteroatom of the 5- to 12-membered heteroaryl in the substituted 5- to 12-membered heteroaryl is N; (27)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 12 The number of heteroatoms of the 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is independently 1 or 2; (28)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1- 13 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (29) Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 wherein the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; (30) Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 In the C 1-6 Alkyl, the -S(O)2C 1-6 C in the alkyl group 1-6 The alkyl group and the -P(O)(C 1-6 Alkyl)2 in C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (31)R 1 , each plurality is 2 or 3, for example 2; (32) Each R 2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, fluorine or chlorine; (33) Each R 2 wherein the unsubstituted or replaced by one or more R 2-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (34) Each R 2 , each plurality is 2 or 3, for example 2; (35) Each R 2 wherein the unsubstituted or replaced by one or more R 2-2 Substituted C 1-6 C in alkoxy 1-6 Alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy; (36) Each R 2-1 and R 2-2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine; (37) Each R 3 wherein the unsubstituted or replaced by one or more R 3-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl; (38) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4-12-membered heterocycloalkenyl in the substituted 4-12-membered heterocycloalkenyl is a monocyclic ring or a cyclic ring; The number of rings in the ring combination may be 2; The cyclohexyl group may be a 4-membered and 5-membered heterocycloalkenyl group, a 4-membered and 6-membered heterocycloalkenyl group, a 5-membered and 5-membered heterocycloalkenyl group, a 5-membered and 6-membered heterocycloalkenyl group or a 6-membered and 6-membered heterocycloalkenyl group, for example, a 5-membered and 6-membered heterocycloalkenyl group; (39) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4-12-membered heterocycloalkenyl in the substituted 4-12-membered heterocycloalkenyl is independently a 5-9-membered heterocycloalkenyl, such as a 5-6-membered heterocycloalkenyl; (40) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The heteroatom of the 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is N; (41) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The number of heteroatoms of the 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is 1 or 2, for example, 1; (42) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The number of double bonds in the 4-12-membered heterocycloalkenyl group in the substituted 4-12-membered heterocycloalkenyl group is 1 or 2, for example 2; (43) Each R 3 wherein the unsubstituted or replaced by one or more R 3-3 Substituted C 2-6 C in alkynyl 2-6 Alkynyl is independently ethynyl, propynyl or propargyl, for example ethynyl; (44) Each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a bridged ring or a spiro ring; The number of rings in the spiro ring or bridge ring may be 2, and the spiro ring may be a 3-membered spiro 5-membered heterocyclyl, a 3-membered spiro 6-membered heterocyclyl, a 4-membered spiro 4-membered heterocyclyl, a 4-membered spiro 5-membered heterocyclyl, a 4-membered spiro 6-membered heterocyclyl, a 4-membered spiro 7-membered heterocyclyl, a 5-membered spiro 4-membered heterocyclyl, a 5-membered spiro 5-membered heterocyclyl, a 5-membered spiro 6-membered heterocyclyl, a 5-membered spiro 7-membered heterocyclyl, a 6-membered spiro 4-membered heterocyclyl, a 6-membered spiro 5-membered heterocyclyl or a 6-membered spiro 6-membered heterocyclyl; for example, a 3-membered spiro 6-membered heterocycloalkyl; The bridged ring may be a 4-membered bridge 5-membered heterocycloalkyl, a 4-membered bridge 6-membered heterocycloalkyl, a 5-membered bridge 6-membered heterocycloalkyl or a 6-membered bridge 6-membered heterocycloalkyl; for example, a 4-membered bridge 6-membered heterocycloalkyl; (45) Each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a 6-8-membered heterocycloalkyl; (46) Each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The heteroatom of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is N; (47) Each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The number of heteroatoms of the 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently 1 or 2; (48) Each R 3 wherein the unsubstituted or replaced by one or more R 3-5 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 6-8-membered heterocycloalkyl, the heteroatom of the 6-8-membered heterocycloalkyl is N, and the number of heteroatoms is 1 or 2; for example (49) Each R 3 wherein the unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 C in aromatic groups 6-12 Aryl is phenyl or naphthyl, for example phenyl; (50) Each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a monocyclic ring or a fused ring, The number of the rings in the ring combination may be 2; (51) Each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-9-membered heteroaryl; (52) Each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The heteroatom of the 5- to 12-membered heteroaryl in the substituted 5- to 12-membered heteroaryl is N and / or O; (53) Each R 3 , each plurality is 2 or 3, for example 2; (54) Each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is a monocyclic ring; (55) Each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl; (56) Each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The heteroatom of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is N and / or O, for example O; (57) Each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The number of heteroatoms of the 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is 1 or 2, for example, 1; (58) Each R 3-5 and R 3-9 wherein the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; (59) Each R 3-5 and R 3-9 wherein the unsubstituted or replaced by one or more R 3-5-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (60) Each R 3-5 and R 3-9 wherein the unsubstituted or replaced by one or more R 3-5-1 Substituted C 1-6 C in alkoxy 1-6 Alkyl is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, for example methoxy; (61) Each R 3-6 and R 3-10 wherein the unsubstituted or replaced by one or more R 3-6-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl; (62) Each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is a monocyclic ring; (63) Each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl; (64) Each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The heteroatom of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is N and / or O; (65) Each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The number of heteroatoms in the 3-12-membered heterocycloalkyl group of the substituted 3-12-membered heterocycloalkyl group is 1 or 2, for example, 2; (66) Each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3-12 membered heterocycloalkyl in the substituted 3-12 membered heterocycloalkyl is a monocyclic ring; (67) Each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl; (68) Each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The heteroatom of the 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is N and / or O; (69) Each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The number of heteroatoms in the 3-12-membered heterocycloalkyl group is 1 or 2, for example, 2; and (70) Each R 3-5-1 In the above, the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

3. The compound of formula I as claimed in claim 2, its pharmaceutically acceptable salt or its isotope compound, characterized in that: It meets one or more of the following conditions: (1)R 1 wherein the unsubstituted or replaced by one or more R 1-6 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a 5-8-membered heterocycloalkyl, the heteroatom of the 5-8-membered heterocycloalkyl is N and / or O, and the number of heteroatoms is 1 or 2; for example Another example (2)R 1 wherein the unsubstituted or replaced by one or more R 1-8 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl, wherein the heteroatom of the 5-6-membered heteroaryl is N and / or O, and the number of heteroatoms is 1 or 2, for example Preferably, R 1 wherein the unsubstituted or replaced by one or more R 1-8 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-6-membered heteroaryl, the heteroatom of the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2; for example (3)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1-10 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is independently a 4-8-membered heterocycloalkyl, the heteroatom of the 4-8-membered heterocycloalkyl is N and / or O, and the number of the heteroatoms is 1 or 2; for example (4)R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m wherein the unsubstituted or replaced by one or more R 1-12 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is independently a 5-6-membered heteroaryl, the heteroatom of the 5-6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2; for example (5) Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 In the above-S(O)2C 1-6 The alkyl group is (6) Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 In the 1-6 Alkyl)2 is (7) Each R 2 In the above, the one or more R 2-1 Substituted C 1-6 The alkyl group is (8) Each R 3 wherein the unsubstituted or replaced by one or more R 3-9 The 4-12-membered heterocycloalkenyl in the substituted 4-12-membered heterocycloalkenyl is independently a 5-9-membered heterocycloalkenyl, the heteroatom of the 5-9-membered heterocycloalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-9-membered heterocycloalkenyl is 1 or 2; for example (9) Each R 3 wherein the unsubstituted or replaced by one or more R 3-6 The 5-12-membered heteroaryl in the substituted 5-12-membered heteroaryl is a 5-9-membered heteroaryl, the heteroatoms of the 5-9-membered heteroaryl are N and / or O, and the number of heteroatoms is 1, 2 or 3; for example For example, (10) Each R 3-1 and R 3-3 wherein the unsubstituted or replaced by one or more R 3-1-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl, the heteroatom of the 5-6-membered heterocycloalkyl is N and / or O, and the number of heteroatoms is 1 or 2; for example (11) Each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl, the heteroatom of the 5-6-membered heterocycloalkyl is N and / or O, and the number of heteroatoms is 1 or 2; for example (12) Each R 3-1-3 wherein the unsubstituted or replaced by one or more R 3-1-3-1 The 3-12-membered heterocycloalkyl in the substituted 3-12-membered heterocycloalkyl is a 5-6-membered heterocycloalkyl, the heteroatom of the 5-6-membered heterocycloalkyl is N and / or O, and the number of heteroatoms is 1 or 2; for example and (13) Each R 3-5 and R 3-9 In the above, the one or more R 3-5-1 Substituted C 1-6 The alkyl group is 4. The compound of formula I according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its isotope compound, characterized in that: It meets one or more of the following conditions: (1)R a is hydrogen; (2)X 2 is N; (3)X 3 is N; (4)R b For the following scheme 1 or scheme 2, scheme 1: R b is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; preferably, R b is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-11 Substituted C 6-12 Aryl; more preferably, R b For unsubstituted C 3-10 Cycloalkyl or unsubstituted C 6-12 Aryl; Scheme 2: R b is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 Alkyl; preferably, R b for unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-13 Substituted C 1-6 Alkyl; more preferably, R b For unsubstituted C 3-10 Cycloalkyl, unsubstituted C 6-12 Aryl or unsubstituted C 1-6 Alkyl, preferably R b For unsubstituted C 1-6 alkyl; (5)R c is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl; preferably, R c is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl; more preferably, R c For unsubstituted C 3-10 Cycloalkyl; (6)R d is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl; preferably, R d is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl; more preferably, R d For unsubstituted C 3-10 Cycloalkyl; (7)R e is unsubstituted or substituted with one or more R 1-13 Substituted C 1-6 Alkyl; preferably, R e For unsubstituted C 1-6 alkyl; (8)R f is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; preferably, R f is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; more preferably, R f is an unsubstituted 3-12 membered heterocycloalkyl, an unsubstituted C 6-12 Aryl or unsubstituted 5-12 membered heteroaryl; (9)R g is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl; preferably, R g is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl; more preferably, R g For unsubstituted C 3-10 Cycloalkyl; (10)R h is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; preferably, R h For the following scheme 1 or scheme 2, scheme 1: R h is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; more preferably, R h is an unsubstituted 3-12 membered heterocycloalkyl, an unsubstituted C 6-12 Aryl or unsubstituted 5-12 membered heteroaryl; Scheme 2: R h For unsubstituted C 3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl or unsubstituted C 6-12 Aryl or unsubstituted 5-12 membered heteroaryl; (11)R i is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl or unsubstituted or with one or more R 1-11 Substituted C 6-12 Aryl; preferably, R i is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl or unsubstituted or with one or more R 1-11 Substituted C 6-12 Aryl; more preferably, R i is an unsubstituted 3-12 membered heterocycloalkyl or an unsubstituted C 6-12 Aryl; (12)R j is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl; preferably, R j is unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl or unsubstituted or with one or more R 1-12 substituted 5-12 membered heteroaryl; more preferably, R j is an unsubstituted 3-12 membered heterocycloalkyl or an unsubstituted 5-12 membered heteroaryl; (13)R k is unsubstituted or substituted with one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 Replaced 5- 12-membered heteroaryl or unsubstituted or substituted with one or more R 1-13 Substituted C 1-6 Alkyl; preferably, R k is unsubstituted or substituted with one or more R 1- 12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 Alkyl; more preferably, R k is an unsubstituted 5-12 membered heteroaryl or an unsubstituted C 1-6 alkyl; (14) Each R 1-3 are independently halogen; (15) Each R 1-4 are independently halogen; (16) Each R 1-5 are independently halogen or C 1-6 Alkyl; preferably, each R 1-5 Independently for C 1-6 alkyl; (17) Each R 1-6 are independently halogen or C 1-6 Alkyl; preferably, each R 1-6 Independently for C 1-6 alkyl; (18) Each R 1-7 are independently halogen or C 1-6 Alkyl; preferably, each R 1-7 are independently halogen; (19) Each R 1-8 Independently for C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Preferably, R 1-8 Independently for C 1- 6 alkyl; (20)R 1 For the following scheme 1 or scheme 2, scheme 1: R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1- 5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; Preferably, R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; More preferably, R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; Optimally, R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted C 6-12 Aryl or unsubstituted 5-12 membered heteroaryl; Option 2: R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; preferably, R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or One or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; more preferably, R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; most preferably, R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1- 6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; (21) m is 1, 2 or 3; preferably, m is 1 or 2; more preferably, m is 2 (22) n is 1, 2 or 3; preferably, n is 1; (23) Each R 2-1 and R 2-2 are independently halogen; (24) Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2-2 Substituted C 1-6 Alkoxy; preferably, each R 2 are independently halogen, 2-1 Substituted C 1-6 Alkyl or unsubstituted C 1-6 Alkoxy; (25) Each R 3-1 Independently (26) Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl; (27) Each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 substituted 3-12 membered heterocycloalkyl; preferably, each R 3- 3 are independently unsubstituted 3-12 membered heterocycloalkyl; (28) Each R 3-5 is independently oxo or unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl; preferably, each R 3-5 are independently oxo or unsubstituted C 1-6 alkyl; (29) Each R 3-6 is independently cyano or unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 Alkyl; preferably, each R 3- 6 are independently cyano or unsubstituted C 1-6 alkyl; (30) Each R 3-10 are independently hydroxyl groups; (31) Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 substituted 3-12 membered heterocycloalkyl; preferably, each R 3- 8 are independently unsubstituted 3-12 membered heterocycloalkyl; (32) Each R 3-9 are independently oxo, halogen, cyano, hydroxyl, unsubstituted or substituted with one or more R 3-5-1 Substituted C1-C6 alkyl or unsubstituted or with one or more R 3-5-2 Substituted C1-C6 alkoxy; Preferably, each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy; More preferably, each R 3-9 are independently oxo, halogen, or one or more R 3-5-1 Substituted C 1-6 Alkyl or unsubstituted C 1-6 Alkoxy; Optimally, each R 3-9 are independently oxo or halogen; (33) Each R 3-5-1 are independently halogen; (34) Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3- 3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or Preferably, each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-4 Substituted C 3-6 Cycloalkyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl or unsubstituted or with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; More preferably, each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Optimally, each R 3 independently unsubstituted C 1-6 Alkyl or one or more R 3-9 substituted 4-12 membered heterocycloalkenyl; for example, substituted by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl; and (35)X 4 is N.

5. The compound of formula I according to any one of claims 1 to 4, its pharmaceutically acceptable salt or its isotope compound, characterized in that: The compound as shown in Formula I is the following Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6 or Scheme 7: Scheme 1: m and n are independently 1, 2 or 3; X 1 N or CH; X 2 N or CH; X 3 is N; X 4 N or CH; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 alkyl; Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or Each R 3-1 Independently Each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 Substituted 3-12 membered heterocycloalkyl; Each R 3-5 is independently oxo or unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 alkyl; Each R 3-6 is independently cyano or unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 alkyl; Each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy; Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 Substituted 3-12 membered heterocycloalkyl; Each R 3-10 are independently hydroxyl groups; Each R 3-1-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl; Each R 3-5-1 and R 3-5-2 are independently deuterium, hydroxyl, cyano or halogen; Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 Alkoxy; Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Solution 2: m is 1 or 2; n is 1; X 1 N or CH; X 2 N or CH; X 3 is N; X 4 is N; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl or unsubstituted or By one or more R 1-8 substituted 5-12 membered heteroaryl; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 alkyl; Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 is independently unsubstituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Each R 3-9 are independently oxo or halogen; The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Solution 3: m is 1 or 2; n is 1; X 1 N or CH; X 2 , X 3 and X 4 is N; R 1 is hydrogen, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; Each R 1-3 and R 1-4 are independently halogen; Each R 1-5 , R 1-6 , R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 is independently unsubstituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Each R 3-9 are independently oxo or halogen; The heteroatoms in each 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 4: m and n are independently 1, 2 or 3; X 1 N or CH; X 2 N or CH; X 3 is N; X 4 N or CH; R 1 is hydrogen, deuterium, cyano, hydroxyl, halogen, amino, -NHC(O)R b 、-NHS(O)2R c 、-S(O)2NHR d , -NHR f 、-C(O)NHR g 、-OR h 、-SR i 、-C(O)R j 、-S(O)2R k , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3- 10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1-13 Substituted C 1-6 alkyl; Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 3-3 Substituted C 2-6 Alkynyl, unsubstituted or substituted with one or more R 3-5 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 3-9 substituted 4-12 membered heterocycloalkenyl, unsubstituted or replaced by one or more R 3-6 substituted 5-12 membered heteroaryl, unsubstituted or replaced by one or more R 3-10 Substituted C 6-12 Aryl or Each R 3-1 Independently Each R 3-3 are independently unsubstituted or substituted with one or more R 3-1-1 Substituted 3-12 membered heterocycloalkyl; Each R 3-5 is independently oxo or unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 alkyl; Each R 3-6 is independently cyano or unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 alkyl; Each R 3-9 are independently oxo, halogen, unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-5-2 Substituted C 1-6 Alkoxy; Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 Substituted 3-12 membered heterocycloalkyl; Each R 3-10 are independently hydroxyl groups; Each R 3-1-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl; Each R 3-5-1 and R 3-5-2 are independently deuterium, hydroxyl, cyano or halogen; Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 Alkoxy; Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl; The heteroatoms in each 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 5: m is 1 or 2; n is 1; X 1 N or CH; X 2 , X 3 and X 4 is N; R 1 is hydrogen, halogen, amino, -NHC(O)R b , unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; Each R 1-3 and R 1-4 are independently halogen; Each R 1-5 , R 1-6 , R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl; R b For unsubstituted C 1-6 alkyl; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 is independently unsubstituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Each R 3-9 are independently oxo or halogen; The heteroatoms in each 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 6: m is 1 or 2; n is 1; X 1 N or CH; X 2 , X 3 and X 4 is N; R 1 is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 Alkoxy, unsubstituted C 3-10 Cycloalkyl, unsubstituted 3-12 membered heterocycloalkyl, unsubstituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl; Each R 1-8 Independently for C 1-6 alkyl; Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; R 3 is unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Each R 3-9 are independently oxo or halogen; The heteroatoms in each 4-12 membered heterocycloalkenyl and 5-12 membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3; Scheme 7: m is 1 or 2; n is 1; X 2 and X 3 is N; for Each R 2 are independently halogen, unsubstituted or substituted with one or more R 2-1 Substituted C 1-6 Alkyl or unsubstituted or substituted with one or more R 2- 2 Substituted C 1-6 Alkoxy; Each R 2-1 and R 2-2 are independently halogen; R 3 is unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl; Each R 3-9 are independently oxo or halogen; The heteroatoms in each 4-12 membered heterocycloalkenyl group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2 or 3.

6. The compound of formula I according to any one of claims 1 to 5, its pharmaceutically acceptable salt or its isotope compound, characterized in that: It meets one or more of the following conditions: (1)R 1 For the following scheme 1 or scheme 2, scheme 1: R 1 is hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl, Preferably, R 1 is hydrogen, methyl, Option 2: R 1 is hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl, Preferably, R 1 is hydrogen, methyl, (2)R 2 for F or Cl; and (3)R 3 Methyl, Preferably, R 3 for or A Base, for example 7. The compound of formula I according to claim 6, its pharmaceutically acceptable salt or its isotope compound, characterized in that: It meets one or both of the following conditions: (1) It is the following plan 1 or plan 2, plan 1: for Preferably, for Scenario 2: for Preferably, for More preferably, for Best, for and (2) for Preferably, for 8. The compound of formula I according to claim 1, its pharmaceutically acceptable salt or its isotope compound, characterized in that: The compound as shown in formula I is any of the following compounds:

9. A pharmaceutical composition comprising: (1) substance A, wherein substance A is a compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or isotope compound thereof; and (2) Pharmaceutical excipients.

10. Use of a substance A or a pharmaceutical composition as claimed in claim 9 in the preparation of a polymerase theta inhibitor, wherein the substance A is a compound of formula I as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or isotope compound thereof.

11. Use of a substance A or a pharmaceutical composition as claimed in claim 9 in the preparation of a drug, wherein the substance A is a compound of formula I as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt or isotope compound thereof; the drug can be used to treat and / or prevent lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

12. Use of a substance A or a pharmaceutical composition as described in claim 9 in the preparation of a drug for treating and / or preventing diseases associated with polymerase theta, wherein the substance A is a compound of formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt or isotope compound thereof; and the disease associated with polymerase theta is lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

13. A compound of formula II or a salt thereof: R v is a halogen; Preferably, the compound as shown in formula II is 14. A method for treating a disease or a disease associated with polymerase theta, characterized in that: It includes the following steps: Substance A or the pharmaceutical composition as claimed in claim 9 administered to a subject, wherein substance A is a compound of formula I as claimed in any one of claims 1 to 8, a pharmaceutically acceptable salt or an isotope compound thereof; and the disease or the disease associated with polymerase theta is independently lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic cancer or colon cancer.

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