Biaromatic ring compound as well as intermediate, preparation method and application thereof

Abstract

The invention discloses a biaromatic ring compound as well as an intermediate, a preparation method and application thereof. The invention provides a compound as shown in a formula I, and pharmaceutically acceptable salts or isotope compounds thereof. Compared with the prior art, the ATPase activity of the biaromatic ring compound provided by the invention and the inhibition effect on protein are greatly improved. # imgabs0 #

Description

[0001] This application claims the priority of 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. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The 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 chemotherapeutic drugs exert their anti-tumor effects. DNA double-strand breaks (DSBs) are one of the most common types of damage in cells, which can be directly caused by ionizing radiation or induced by ultraviolet rays, reactive oxygen species (ROS) or other mutagens, such as common chemotherapeutic drugs cisplatin, 5-FU, etoposide, etc. Unrepaired DNA damage can lead to functional blockade of cell transcription and replication, induce cell apoptosis or necrosis, and be cleared by immune cells. There are efficient damage repair or alternative repair pathways in tumor cells. Targeting the key proteins of the DNA damage repair pathway, causing the unrepaired DNA damage to continue to accumulate, and ultimately leading to cell death, is one of the important strategies for cancer treatment.

[0004] DNA double-strand breaks are usually repaired by three methods: non-homologous end joining (NHEJ), homologous recombination (HR), and alternative non-homologous end joining (Alt-NHEJ, also known as micro-homologous end joining MMEJ or TMEJ). Among them, the HR repair pathway only occurs in the G2 and S phases, and completes error-free repair in the presence of sister chromatids. In mammals, more than 90% of DSB damage is repaired by the NHEJ pathway. It is an error-prone repair that forms a deletion mutation of <30bp or an insertion mutation of <5bp or a micro-homology sequence of <2bp. The latest studies have shown that when HR and / or NHEJ are defective, cells are highly dependent on the third method, MMEJ, to repair broken DNA. Inhibition of MMEJ can lead to cell apoptosis. MMEJ is also an error-prone repair pathway that relies on DNA polymerase theta to connect micro-homologous end sequences (Theta mediated end joining, TMEJ) to complete the repair of 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 consisting of an N-terminal helicase domain, a central domain, and a C-terminal polymerase domain. Basic research has found that the polymerase domain is necessary for DNA extension at the DSB damage repair site, while the helicase domain and the central domain play a key role in the recognition and binding of Polθ to the substrate. Polθ can release the interaction between DNA and the damage repair complex (such as competitive binding with RAD51 to single-stranded DNA), inhibiting the HR repair pathway. In addition, the helicase domain of Polθ is also involved in DNA replication arrest, and its functional loss will lead to increased replication pressure of tumor cells and apoptosis.

[0006] Polθ is not expressed or expressed at a low level in normal tissue cells, but is highly expressed in a variety of tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, and colon cancer, and is associated with a poor prognosis. Among them, Polθ is overexpressed in more than 70% of breast cancers. These phenomena indicate that Polθ may play an important role in these cancers and is a potential tumor-specific target.

[0007] Studies that knock down or knock out Polθ in tumor cells have found that Polθ deficiency can sensitize these cells to radiation, induce the generation of DSBs, enhance replication fork instability, and make tumor cells sensitive to genotoxic agents, which may enhance the effects of radiotherapy and chemotherapy, and is 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 vivo and in vitro. In particular, in PARP inhibitor-resistant tumors (Olaparib, etc.) with HR defective reversion mutations, Polθ inhibitors can sensitize cells to PARPi again, providing valuable treatment opportunities. In addition, given that Polθ is a key protein in the MMEJ pathway, its functional defects can also lead to enhanced genomic instability in cancer cells, increase somatic mutations, and facilitate the production of tumor neoantigens. In addition, it has been reported 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 potential 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 lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, colon cancer, prostate cancer, pancreatic cancer and other tumors. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the relatively simple structure of polymerase theta inhibitor compounds in the prior art. To this end, the present invention provides a biaryl ring compound, an intermediate thereof, a preparation method and an application thereof. The ATPase activity and the inhibitory effect on proteins of the compounds are greatly improved compared with the prior art.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof or an isotope compound thereof,

[0012]

[0013] in,

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

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

[0016] X 2 and 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 or 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)2Rc 、-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 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;

[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, 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;

[0023] 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;

[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 hydroxyl 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 R3-2 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, 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. or

[0029] 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 C3-6 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 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

[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 3-1-3-1 Substituted 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, hydroxyl, cyano or halogen;

[0037] Each R 3-5-4 and R 3-7-3 Independently for 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 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;

[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 as shown in 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 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 R1-7 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 The alkyl group 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 In the above, 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 R1-3 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 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 or cyclobutyl.

[0057] In a preferred embodiment, R 1 wherein the 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.

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

[0059] In a preferred embodiment, R 1 wherein the unsubstituted or replaced by one or more R 1-6The number of heteroatoms of the 3-12-membered heterocycloalkyl group in the substituted 3-12-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 a monocyclic, bridged, fused or spirocyclic ring;

[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 ring 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 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;

[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 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

[0066] In a preferred embodiment, R 1 wherein the 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 the unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 C in aromatic groups6-12 Aryl is independently phenyl or naphthyl, for example phenyl.

[0068] In a preferred embodiment, R 1 wherein the 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 a monocyclic ring.

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

[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 , Rg , 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 ring, a bridged ring or a fused ring;

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

[0078] 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;

[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 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently a 4-8-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 heteroatom of the 3- to 12-membered heterocycloalkyl group in the substituted 3- to 12-membered heterocycloalkyl group is 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 of 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 , 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

[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 C6-12 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 in the substituted 5- to 12-membered heteroaryl 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, 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.

[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 Rm wherein the unsubstituted or replaced by one or more R 1-12 The number of heteroatoms of 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 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

[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 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.

[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 , R1-6 , 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.

[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 above-S(O)2C 1-6 The alkyl group is

[0094] 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 1-6 Alkyl)2 is

[0095] In a preferred embodiment, R 1 In the above, each 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 1-6Alkyl 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 the above, each 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 In the above, the halogen is independently fluorine, chlorine, bromine or iodine, for example fluorine.

[0101] In a preferred embodiment, each R 2 In the above, the one or more R 2-1 Substituted C 1-6 The alkyl group 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 1-6 Alkyl 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 in the substituted 4-12-membered heterocycloalkenyl is a monocyclic ring or a cyclic 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 4-12-membered heterocycloalkenyl in the substituted 4-12-membered heterocycloalkenyl is independently a 5-9-membered heterocycloalkenyl, for example a 5-6-membered heterocycloalkenyl.

[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 of 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 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

[0111] In a preferred embodiment, 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.

[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 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is independently a 6-8-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 of 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 ring or a fused ring,

[0121] The number of the rings to be combined 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 3wherein 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, 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 the above, each 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 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-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 in the substituted 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 3-1-1The 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

[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 group 1-6 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 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-membered heterocycloalkyl group.

[0137] In a preferred embodiment, each R 3-8 wherein the unsubstituted or replaced by one or more R 3-8-1The 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 of the 3-12-membered heterocycloalkyl group in the substituted 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 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

[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 3-12-membered heterocycloalkyl group in the substituted 3-12-membered heterocycloalkyl group is a 5-6-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 of the 3-12-membered heterocycloalkyl group in the substituted 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 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

[0145] In a preferred embodiment, each R 3-5-1 In the above, 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, the one or more R 3-5-1 Substituted C 1-6 The alkyl group is

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

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

[0149] In a preferred embodiment, C described in any one of the present invention 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 ring, a fused ring, a bridged ring or a spiro 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 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;

[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 group described in any one of the present invention is 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 embodiments of the present invention is independently fluorine, chlorine, bromine or iodine.

[0168] In a preferred embodiment, C described in any one of the present invention 1-6 The alkyl group 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 rings to be combined 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, C described in any one of the present invention 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 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.

[0180] In a preferred embodiment, 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.

[0181] In a preferred embodiment, 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 1-11 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-13Substituted C 1-6 alkyl.

[0182] In a preferred embodiment, 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.

[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 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.

[0186] In a preferred embodiment, R c is unsubstituted or substituted with 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 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.

[0189] In a preferred embodiment, R d is unsubstituted or substituted with 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 substituted with 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 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.

[0194] In a preferred embodiment, 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.

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

[0196] In a preferred embodiment, 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.

[0197] In a preferred embodiment, R g is unsubstituted or substituted with 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 substituted with one or more R 1-9Substituted 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 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.

[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 5-12 membered heteroaryl.

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

[0203] In a preferred embodiment, 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.

[0204] In a preferred embodiment, 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.

[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 substituted with one or more R 1-9 Substituted C3-10 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 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.

[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 substituted with 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.

[0210] In a preferred embodiment, 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.

[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 for 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 for 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 for 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 for 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 6-12Aryl 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 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.

[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 1-4Substituted 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 3-10 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.

[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 5-12 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 C6-12 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 or 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, 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 with 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 with 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, 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.

[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 or 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 R3-5-1 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 with 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 or unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

[0258] In a preferred embodiment, each R 3 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 for one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl.

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

[0261]

[0262] In a preferred embodiment, R 1 is hydrogen, methyl,

[0263] In a preferred embodiment, R 1 is hydrogen, deuterium, cyano, hydroxyl, fluorine, methyl,

[0264]

[0265] In a preferred embodiment, R 1 is hydrogen, methyl, In a preferred embodiment, for

[0266]

[0267] In a preferred embodiment, for

[0268] In a preferred embodiment, for

[0269]

[0270]

[0271] In a preferred embodiment, for

[0272]

[0273] In a preferred embodiment, for

[0274] Preferably,

[0275] In a preferred embodiment, R 2 for F or Cl.

[0276] In a preferred embodiment, R 2 for or Cl.

[0277] In a preferred embodiment, for

[0278] In a preferred embodiment, for In a preferred embodiment, R 3 Methyl,

[0279] In a preferred embodiment, R 3 for or methyl; preferably

[0280] In a preferred embodiment, m and n are independently 1, 2 or 3;

[0281] X 1 N or CH;

[0282] X 2 N or CH;

[0283] X 3 is N;

[0284] X 4 N or CH;

[0285] 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 C6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0286] 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;

[0287] 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;

[0288] 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;

[0289] Each R 2-1 and R 2-2 are independently halogen;

[0290] Each R 3 are independently unsubstituted or substituted with one or more R 3-1 Substituted C 1-6Alkyl, 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

[0291] Each R 3-1 Independently

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

[0293] Each R 3-5 is independently oxo or unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 alkyl;

[0294] Each R 3-6 is independently cyano or unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 alkyl;

[0295] 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;

[0296] Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 Substituted 3-12 membered heterocycloalkyl;

[0297] Each R 3-10 are independently hydroxyl groups;

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

[0299] Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl;

[0300] Each R 3-5-1 and R3-5-2 are independently deuterium, hydroxyl, cyano or halogen;

[0301] Each R 3-6-1 are independently hydroxy, cyano, halogen or C 1-6 Alkoxy;

[0302] Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0303] The heteroatoms in each of the 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.

[0304] In a preferred embodiment, m and n are independently 1, 2 or 3;

[0305] X 1 N or CH;

[0306] X 2 N or CH;

[0307] X 3 is N;

[0308] X 4 N or CH;

[0309] 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;

[0310] 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;

[0311] 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;

[0312] 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;

[0313] Each R 2-1 and R 2-2 are independently halogen;

[0314] 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 R3-5 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

[0315] Each R 3-1 Independently

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

[0317] Each R 3-5 is independently oxo or unsubstituted or substituted with one or more R 3-5-1 Substituted C 1-6 alkyl;

[0318] Each R 3-6 is independently cyano or unsubstituted or substituted with one or more R 3-6-1 Substituted C 1-6 alkyl;

[0319] 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;

[0320] Each R 3-8 are independently unsubstituted or substituted with one or more R 3-8-1 Substituted 3-12 membered heterocycloalkyl;

[0321] Each R 3-10 are independently hydroxyl groups;

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

[0323] Each R 3-1-3 are independently unsubstituted 3-12 membered heterocycloalkyl;

[0324] Each R 3-5-1 and R 3-5-2 are independently deuterium, hydroxyl, cyano or halogen;

[0325] Each R 3-6-1are independently hydroxy, cyano, halogen or C 1-6 Alkoxy;

[0326] Each R 3-8-1 are independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0327] The heteroatoms in each of the 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.

[0328] In a preferred embodiment, m is 1 or 2;

[0329] n is 1;

[0330] X 1 N or CH;

[0331] X 2 N or CH;

[0332] X 3 is N;

[0333] X 4 is N;

[0334] 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;

[0335] R b , Rc , 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;

[0336] 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;

[0337] 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;

[0338] Each R 2-1 and R 2-2 are independently halogen;

[0339] 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;

[0340] Each R 3-9 are independently oxo or halogen;

[0341] The heteroatoms in each of the 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.

[0342] In a preferred embodiment, m is 1 or 2;

[0343] n is 1;

[0344] X 1 N or CH;

[0345] X 2 , X 3 and X 4 is N;

[0346] 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;

[0347] Each R 1-3 and R 1-4 are independently halogen;

[0348] Each R 1-5 , R 1-6 , R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl;

[0349] R b For unsubstituted C 1-6 alkyl;

[0350] 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;

[0351] Each R 2-1and R 2-2 are independently halogen;

[0352] 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;

[0353] Each R 3-9 are independently oxo or halogen;

[0354] The heteroatoms in each of the 4- to 12-membered heterocycloalkenyl and 5- to 12-membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3.

[0355] In a preferred embodiment, m is 1 or 2;

[0356] n is 1;

[0357] X 1 N or CH;

[0358] X 2 , X 3 and X 4 is N;

[0359] 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;

[0360] Each R 1-3 and R 1-4 are independently halogen;

[0361] Each R 1-5 , R 1-7 and R 1-8 are independently halogen or C 1-6 alkyl;

[0362] 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 C1-6 Alkoxy;

[0363] Each R 2-1 and R 2-2 are independently halogen;

[0364] 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;

[0365] Each R 3-9 are independently oxo or halogen;

[0366] The heteroatoms in each of the 4- to 12-membered heterocycloalkenyl and 5- to 12-membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3.

[0367] In a preferred embodiment, m is 1 or 2;

[0368] n is 1;

[0369] X 1 N or CH;

[0370] X 2 , X 3 and X 4 is N;

[0371] 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;

[0372] Each R 1-8 Independently for C 1-6 alkyl;

[0373] 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;

[0374] Each R 2-1 and R 2-2 are independently halogen;

[0375] R 3is unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl;

[0376] Each R 3-9 are independently oxo or halogen;

[0377] The heteroatoms in each of the 4- to 12-membered heterocycloalkenyl and 5- to 12-membered heteroaryl are independently selected from one, two or three of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3.

[0378] In a preferred embodiment, m is 1 or 2;

[0379] n is 1;

[0380] X 2 and X 3 is N;

[0381] for

[0382] 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;

[0383] Each R 2-1 and R 2-2 are independently halogen;

[0384] R 3 is unsubstituted or substituted with one or more R 3-9 Substituted 4-12 membered heterocycloalkenyl;

[0385] Each R 3-9 are independently oxo or halogen;

[0386] 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.

[0387] In a preferred embodiment, the compound as shown in formula I is any of the following compounds:

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395] The present invention provides a pharmaceutical composition comprising:

[0396] (1) (therapeutically effective amount) 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 compound thereof; and

[0397] (2) Pharmaceutical excipients.

[0398] The present invention provides an application 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.

[0399] The present invention provides an application 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.

[0400] The present invention provides an application 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 as described in any one of the present invention, a pharmaceutically acceptable salt thereof, 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.

[0401] The present invention provides an application of a substance A in the preparation of a drug, wherein the substance A is a compound of formula I as described in any one of the present invention, 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.

[0402] 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 a disease associated with polymerase theta, wherein the substance A is a compound of formula I as described in any one of the present invention, a pharmaceutically acceptable salt or an 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.

[0403] 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.

[0404] 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.

[0405] 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 shown in formula I as described in 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.

[0406] The present invention provides a compound as shown in formula II or a salt thereof:

[0407]

[0408] R v It is a halogen.

[0409] In a preferred embodiment, the compound shown in formula II is

[0410]

[0411] Explanation of terms

[0412] 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.

[0413] 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 groups A appear at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. For example, "a group C substituted by 3 halogens" 6-10 "Aryl" refers to C 6-10 The aromatic 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.

[0414] The term "plurality" refers to 2 or more, such as 2, 3, 4, 5; preferably 2 or 3.

[0415] In the claims of this application, the term "multiple" in "satisfies one or more of the following conditions" means 2, 3, 4 or more, and the maximum value of "more" is the maximum value of the conditions recorded in each claim. For example, if a claim records 8 conditions, the term "one or more" in "satisfies one or more of the following conditions" in the claim is any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7 or 8.

[0416] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0417] 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, ammonium salts, and the like. 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, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0418] 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 N atom is attached to the rest of the molecule.

[0419] The term "halogen" refers to fluorine, chlorine, bromine or iodine. The 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 usually multiple substitutions occur on one carbon atom.

[0420] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, replacing a methylene group with a carbonyl group.

[0421] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., 1-6 ) is a linear or branched, saturated, monovalent hydrocarbon group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0422] 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.

[0423] 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.

[0424] The term "alkynyl" refers to a radical 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 groups include but are not limited to: ethynyl, wait.

[0425] 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. The monocyclic ring includes, but is not limited to: wait.

[0426] 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 a bond, and (at least one ring / each ring) is aromatic. 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.

[0427] 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 to 12 members), which is monocyclic or polycyclic (e.g., 2 or 3, bridged, spiro, and fused). 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.

[0428] Unless otherwise specified in the present invention, the term "heterocycloalkyl" refers to a monocyclic, bridged, spirocyclic, or fused ring having a specified number of ring atoms (e.g., 3 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one or more of N, O, and S). The monocyclic heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. The monocyclic heterocycloalkyl includes, but is not limited to: Spirocyclic heterocycloalkyl groups include but are not limited to:

[0429] etc. Bridged heterocycloalkyl groups include but are not limited to: Etc. Cycloheterocycloalkyl includes but is not limited to wait.

[0430] 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 heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic (e.g., 2 or 3, spirocyclic). Monocyclic heterocycloalkenyls include, but are not limited to: Spirocyclic heterocycloalkenyl groups include but are not limited to wait.

[0431] 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 to 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 a single ring or multiple rings, with two atoms and a bond shared between the single rings, and at least one ring having aromatic properties. The heteroaryl group is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected 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:

[0432] wait.

[0433] 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 has been replaced by an atom of a lower mass number that occurs naturally - a hydrogen atom in a compound has been replaced by deuterium, or a C has been replaced by 13 C replacement.

[0434] The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0435] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing 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.

[0436] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0437] The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or condition described herein when administered to a patient."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.

[0438] The term "patient" refers to any animal that is about to or has been administered the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human. 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, humans, etc., with humans being the most preferred.

[0439] In the present invention, "room temperature" means "20 to 40°C".

[0440] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0441] The reagents and raw materials used in the present invention are commercially available.

[0442] The positive improvement effect of the present invention is that the ATPase activity and the inhibitory effect on proteins of the compounds of the present invention are greatly improved compared with the prior art. DETAILED DESCRIPTION

[0443] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0444] All compounds of the present invention can be synthesized by different methods by those skilled in the art of organic chemistry. The following describes a general synthetic scheme for preparing the compounds of the present invention. These schemes are general, but are not meant to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. The 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 one or more compounds. The preparation and examples described below give examples of the preparation of the compounds of the present invention by the methods described in the general scheme. The preparation of compounds containing chiral center embodiments can be performed by techniques mastered by 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.

[0445] The chemical reactions and synthesis techniques described herein are carried out in the reagents and corresponding solvents described herein, and the corresponding reaction yields are also affected by the reagents and solvents used. In addition, it should be understood that in the synthetic method described below, all the reaction conditions mentioned, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and reaction feeding order, should be regarded as the operating condition standard of the reaction, which should be easily recognized by those skilled in the art. At the same time, it is also understandable to those skilled in the art in the field of organic synthesis. The functional groups present on each part of the molecule must be compatible with the reagents used and the reaction itself. For such restrictions that some functional groups present on each part of the molecule are incompatible with the reaction conditions, alternative methods must be used, which will be obvious to those skilled in the art. It is obvious that it is necessary to judge to adjust the order of the synthetic steps, or to select a specific synthetic process scheme to obtain the desired compound of the present invention. This is understandable and easily recognized by those skilled in the art in the field of organic synthesis. It should also be recognized that another major consideration for any synthetic route designed in this field is the reasonable selection of protecting groups for protecting the tolerance of reactive functional groups present in the compounds described in the present invention. 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)).

[0446] Example

[0447] 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 are meant to illustrate how to prepare the related compounds. The starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally available on the market, or reported in the relevant chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0448] 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 filtering and removing the solvent from the filtrate (generally under reduced pressure and at a temperature suitable for the stability of the prepared compound). Column chromatography generally uses conventional column chromatography or flash column chromatography for column separation and purification, or uses a medium pressure chromatograph (Biotage Isola One) pre-packed with silica gel columns and eluted in a specified solvent or solvent mixture. In some cases, the final product is quickly purified by preparative thin layer chromatography using 20cm x 20cm x 0.5mm or 20cm x 20cm x1mm silica gel plates in an appropriate solvent system. Preparative high performance liquid chromatography (HPLC) is performed using a reverse phase column (Waters Sunfire C18, Waters Xbridge C18 or similar reverse phase column) of a size appropriate to the amount of compound to be separated, typically using a gradient of methanol or acetonitrile concentration added to the aqueous phase, with the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid or 10 mM ammonium acetate, with an elution rate matched to the size of the reverse phase column used and the resolution of the preparation.

[0449] List of abbreviations

[0450] Table 1

[0451]

[0452]

[0453] 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

[0454]

[0455] Step 1: 6-Chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylic acid benzyl ester

[0456] Under nitrogen protection at room temperature, 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) were added to a mixed solution of 6-chloro-4-iodonicotinic acid benzyl ester (5.0 g, 13.40 mmol) in 1,4-dioxane (50 mL) and water (10 mL) in sequence. The reaction mixture was stirred at 90°C for 1.5 hours under nitrogen protection. After the reaction was complete, water was added, extracted with ethyl acetate, and 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 obtain the title compound (white solid, 3.06 g, yield 56.5%). LC / MS(ESI)m / z:405.1[M+H] + .

[0457] Step 2: 2"-Difluoromethyl-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxylic acid benzyl ester

[0458] Under nitrogen protection at room temperature, 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylic acid benzyl ester (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 for 1 hour under nitrogen protection. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate three times. 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] + .

[0459] Step 3: 2"-Difluoromethyl-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-tripyridine]-5'-carboxylic acid

[0460] Under nitrogen protection at room temperature, 10% palladium on carbon (300 mg) was added 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). The mixture was replaced with nitrogen three times and stirred at room temperature under 1 atmosphere of hydrogen for 3 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (brown solid, 1.01 g, yield 88.7%). LC / MS (ESI) m / z: 392.1 [M+H] + .

[0461] 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

[0462] At room temperature, 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-thiadiazole-5-amine (10.8 mg, 0.077 mmol) and 1-methylimidazole (16.80 mg, 0.21 mmol) were dissolved in acetonitrile (2 mL), and the mixture was stirred at 75°C for 5 minutes. Then N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (21.5 mg, 0.077 mmol) was added, and the mixture was stirred at 75°C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase preparation to obtain the title compound (white solid, 6 mg, yield 22.8%).

[0463] 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] + .

[0464] The compounds in Example 2 were synthesized using commercially available raw materials according to the synthesis steps of Example 1.

[0465] Table 2:

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472] Embodiment 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

[0473]

[0474] Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0475] Under nitrogen protection, 3-bromo-5-chloro-1,2,4-thiadiazole (500 mg, 2.51 mmol) was dissolved in anhydrous ethanol (5 mL), and then aqueous ammonia (0.34 mL, 5.01 mmol, 25% w / w) was slowly added dropwise, and then stirred at 70°C for 3 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (10 mL) was added to precipitate a white solid. The filter cake was filtered and concentrated under reduced pressure to obtain the title compound (white solid, 220 mg, yield 48.8%). LC / MS (ESI) m / z: 179.9 [M+H] + .

[0476] 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

[0477] 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), 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. Salt (215 mg, 0.77 mmol), the reaction solution turned from turbid to clear, and the reaction solution continued to stir at 70 ° C for 1 hour. LCMS detected that the reaction was complete. Ethyl acetate and water were added to the reaction solution, 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] + .

[0478] 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

[0479] 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)dichloropalladium(II) (5.3mg, 0.007mmol), the mixture was stirred at 90℃ for 16 hours. The reaction solution was cooled to room temperature, and 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 preparation to obtain the title compound (white solid, 1mg, yield 4.7%). 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] + .

[0480] Embodiment 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

[0481]

[0482] Step 1: 3-Bromo-1,2,4-thiadiazol-5-amine

[0483] Dissolve 3-bromo-5-chloro-1,2,4-thiadiazole (5.5 g, 27.6 mmol) in ethanol (16 mL), add ammonia water (4 mL), and stir the reaction solution 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, yield 80.6%). LC / MS (ESI) m / z: 182.0 [M+H] + .

[0484] Step 2: tert-Butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate

[0485] 3-Bromo-1,2,4-thiadiazole-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, and the reaction solution was stirred at 50°C for 3 hours. The mixed solution 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, yield 91.5%). LC / MS (ESI) m / z: 280.0 [M+H] + .

[0486] Step 3: tert-Butyl (3-morpholinyl-1,2,4-thiadiazol-5-yl)carbamate

[0487] 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 solution 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, yield 78.3%). LC / MS (ESI) m / z: 287.2 [M+H] + .

[0488] Step 4: 3-Morpholino-1,2,4-thiadiazole-5-amine hydrochloride

[0489] Dissolve tert-butyl (3-morpholinyl-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 0.279 mmol) in 4N hydrochloric acid / dioxane (3 mL) solution, and stir the reaction solution at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure to obtain the title compound (60 mg, white solid, yield 96.4%). LC / MS (ESI) m / z: 187.2 [M+H] + .

[0490] 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

[0491] 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-morpholine-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 then the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered and the title compound (8.16 mg, white solid, yield 28.5%) was obtained by HPLC. 1 H 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)+ .

[0492] Embodiment 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

[0493]

[0494] Step 1: tert-Butyl (3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0495] 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 solution at 100 ° C for 3 hours. Dilute the reaction solution with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30-50% ethyl acetate) to give the title compound (white solid, 20 mg, yield 37.6%). LC / MS (ESI) m / z: 299.2 [M+H] + .

[0496] Step 2: 3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-amine

[0497] 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) solution, add trifluoroacetic acid (0.2 mL) to the reaction solution, and stir the reaction solution at room temperature for 1 hour. Adjust the pH value of the reaction solution to 7-8 with sodium bicarbonate, and extract it three times with dichloromethane. Wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, and concentrate it under reduced pressure to give the title compound (10 mg, white solid, yield 75.3%). LC / MS(ESI)m / z:199.1[M+H] + .

[0498] Step 3: N-(3-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-1,2,4-thiadiazol-5-yl)-2"-(di fluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-bipyridine]-5'-carboxamide

[0499] 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 basically dissolved, and then the reaction solution was stirred at 70°C for 1 hour. The reaction solution was filtered and purified by preparative HPLC to obtain the title compound (1.29 mg, white solid, yield 4.4%). 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] + .

[0500] Embodiment 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

[0501]

[0502] Step 1: tert-Butyl 3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-ylcarbamate

[0503] Under nitrogen protection, 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), and the reaction solution was stirred at 90°C for 16 hours. The reaction solution 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, yield 94.9%). LC / MS (ESI) m / z: 296.2 [M+H] + .

[0504] Step 2: 3-(1,4-dimethyl-1H-pyrazol-5-yl)-1,2,4-thiadiazol-5-amine hydrochloride

[0505] 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 dioxane (5 mL) solution, and stir the reaction solution at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and slurried with ethyl acetate to obtain the title compound (70 mg, light yellow solid, yield 89.2%). LC / MS (ESI) m / z: 196.1 [M+H] + .

[0506] 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

[0507] At room temperature, 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-thiadiazole-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). 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 then 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 obtain the title compound (8.06 mg, white solid, yield 18.3%). 1H 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] + .

[0508] Embodiment 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

[0509]

[0510] Step 1: 3-(5-(2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyrrolidone tert-butyl 1,2,4-thiadiazol-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0511] 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-nitropropane were added to the reaction solution. -(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), the reaction solution was stirred at 130°C for 1 hour under nitrogen protection. The mixed solution 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, yield 19.3%). LC / MS(ESI)m / z:671.2[M+H] + .

[0512] Step 2: N-(3-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-1,2,4-thiadiazol-5-yl)-2"-(di Fluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0513] Under 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) solution, and then trifluoroacetic acid (0.5 mL) was added to the reaction solution. After the addition, the temperature was raised to room temperature and stirred for 16 hours. The residue was concentrated under reduced pressure and purified by preparative HPLC (YMC-Actus TriartC18 250*21 mm, 30-100% methanol in H2O solution and 0.1% FA) to give the title compound (13.42 mg, light yellow solid, yield 45.1%). 1 H 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] + .

[0514] Embodiment 28: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-2"-(difluoro methyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0515]

[0516] Step 1: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-thiadiazol-5-yl)-2"-(difluoromethane 1-(2 ...

[0517] 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 6mmol) 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) (4mg, 0.005mmol), the reaction solution was stirred at 110°C for 3 hours under nitrogen protection. The mixed solution was diluted with ethyl acetate, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*21mm, 30-100% methanol in H2O solution and 0.1% FA) to give the title compound (white solid, 1.52mg, yield 3.0%). 1 H NMR(400MHz,DMSO-d6)δ13.58(s,1H),9.00(s,1H),8.51(s,1H),8.07(s,1H),7.8 9-7.82(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),1.6 7-1.59(m,2H),0.75-0.66(m,1H),0.23-0.17(m,1H).LC / MS(ESI)(m / z):556[M+H] + .

[0518] Embodiment 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'-formyl amine

[0519]

[0520] 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

[0521] 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) solution, and then paraformaldehyde (2 mg, 0.067 mmol) and acetic acid (one drop) were added to the reaction solution, and the reaction was stirred at room temperature for 1 hour. Then, sodium acetate borohydride (3 mg, 0.048 mmol) was added to the reaction solution, and the reaction was continued to stir at 50°C for 16 hours after the addition. The reaction solution was filtered and purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O solution and 0.1% The title compound (3.60 mg, white solid, yield 35.1%) was obtained by purification of the product by FA. 1 H 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] + .

[0522] Embodiment 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

[0523]

[0524] Step 1: (5-(2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyrrolidone [(1,2,4-thiadiazol-3-yl)benzyl]-5'-carboxamido)-1,2,4-thiadiazole-3-yl)carbamate

[0525] 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), (5-amino-1,2,4-thiadiazol-3-yl)carbamic acid benzyl ester (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 then the reaction solution was stirred at 70°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (eluent: dichloromethane / methanol, gradient: 0-3% methanol) to obtain the title compound (white solid, 75 mg, yield 60%). LC / MS (ESI) m / z: 624.3 [M+H] + .

[0526] Step 2: N-(3-amino-1,2,4-thiadiazol-5-yl)-2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo Substituted-2H-[1,2':4',4"-terpyridine]-5'-carboxamide

[0527] Trifluoroacetic acid (2 mL) was added 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) at room temperature, and the reaction solution was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature and then concentrated under reduced pressure to remove trifluoroacetic acid. The residue was diluted with ethyl acetate and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 solution containing 0.1% FA) to give the title compound (white solid, 6 mg, yield 33%). 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] + 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

[0528]

[0529] 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

[0530] 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 250*21 mm, 10-95% acetonitrile in H2O solution containing 0.1% FA) to give 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] + .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

[0531]

[0532] Step 1: tert-Butyl (3-(methoxy(methyl)carbamoyl)-1,2,4-thiadiazol-5-yl)carbamate

[0533] At room temperature, 5-((tert-butyloxycarbonyl)amino)-1,2,4-thiadiazole-3-carboxylic acid (600 mg, 2.45 mmol, crude product), 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), and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701.6 mg, 3.67 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution, the layers were 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: 0-50% ethyl acetate) to give the title compound (white solid, 450 mg, yield 64%). LC / MS (ESI) (m / z): 289 [M+H] + .

[0534] Step 2: tert-Butyl (3-propionyl-1,2,4-thiadiazol-5-yl)carbamate

[0535] Under nitrogen protection, 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, 1.0 M ethylmagnesium bromide (2.0 mL, 2.03 mmol) was slowly added dropwise, and 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 chromatographed on a silica gel column (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to obtain the title compound (white solid, 160 mg, yield 40%). LC / MS (ESI) (m / z): 258 [M+H] + .

[0536] Step 3: tert-Butyl (Z)-(3-(2-(hydroxyimino)propionyl)-1,2,4-thiadiazol-5-yl)carbamate

[0537] Under nitrogen protection, 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 then isoamyl nitrite (136.6 mg, 1.17 mmol) was added. After the addition, the mixture was heated 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, yield 75%). LC / MS (ESI) m / z: 287.2 [M+H] + .

[0538] Step 4: 5-(5-((tert-Butyloxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-1,4-dimethyl-1H-imidazole-3-yl Oxide

[0539] 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), and then 1,3,5-trimethylhexahydro-1,3,5-triazine (67.6 mg, 0.524 mmol) was added at room temperature. The reaction solution was stirred under reflux for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (yellow solid, 50 mg, crude product, yield 100%). LC / MS(ESI)m / z:312[M+H] + .

[0540] Step 5: tert-Butyl (3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0541] 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 then 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 1 atmospheric pressure of hydrogen for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (brown oil, 26 mg, yield 55%). LC / MS(ESI)m / z:296.3[M+H] + .

[0542] Step 6: 3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-amine

[0543] 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 under an ice-water bath. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove 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, yield 87%). LC / MS (ESI) m / z: 196.3 [M+H] + .

[0544] Step 7: 2"-(difluoromethyl)-N-(3-(1,4-dimethyl-1H-imidazol-5-yl)-1,2,4-thiadiazole-5-yl) 1-(2 ...

[0545] 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-thiadiazole-5-amine (15 mg, 0.077 mmol) and N-methylimidazole (25 mg, 0.31 mmol) were dissolved in anhydrous acetonitrile (2 mL). After stirring at 70°C for five minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (32.3 mg, 0.12 mmol) was added to the reaction solution, and then 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 5um21.2*250mm, 30-95% methanol in H2O solution containing 0.1% TFA) to give the title compound (white solid, 0.4 mg, yield 0.92%). 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] + .

[0546] Embodiment 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

[0547]

[0548] Step 1: 3-cyclobutyl-1,2,4-thiadiazol-5-amine

[0549] At room temperature, sodium thiocyanate (196 mg, 2.41 mmol) was dissolved in methanol (30 mL), and then the mixture was cooled to -20 ° C, and triethylamine (0.31 mL, 2.23 mmol) and cyclobutanecarboximidamide hydrochloride (250 mg, 1.86 mmol) were added in sequence. After the addition, the mixture was stirred at -20 ° C for 45 minutes, triethylamine (0.26 mL, 1.86 mmol) was added, and 8% sodium hypochlorite aqueous solution (1.73 g, 1.86 mmol) was added dropwise. After the addition was completed, the mixture was stirred at -20 ° C for 2 hours, and then the mixture was warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the liquid was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine in sequence, 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 obtain the title compound (white solid, 50 mg, yield 17%). LC / MS(ESI)m / z:156.3[M+H] + .

[0550] 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

[0551] At room temperature, 3-cyclobutyl-1,2,4-thiadiazole-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 bottle. 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 then the reaction solution was stirred at 70°C for 1 hour. The mixture was filtered and purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 10-100% acetonitrile in H2O containing 0.1% The title compound (15 mg, white solid, yield 29%) was obtained by purification by FA. 1HNMR(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),7.0 1(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] + .

[0552] Effect Example

[0553] Experimental methods:

[0554] 1. Polθ inhibitor biochemical activity detection (ADP Glo assay)

[0555] The N-terminus of Polθ protein contains a helicase domain with ATPase activity, which can hydrolyze ATP into ADP. TM Kinase Assay, Promega, V9102) was used to analyze the ATPase activity of Polθ protein and the inhibitory effect of small molecule compounds on the protein. The specific detection method is as follows:

[0556] 1) Purify the helicase domain of Polθ protein using insect system to obtain protein with purity >90%. Order ssDNA (5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3', Hangzhou Youkang Biotechnology Co., Ltd.) as substrate of Polθ protein; prepare reaction buffer containing 10mM DTT (Dithiothreitol), 20mM MgCl2, Tris-HCl pH7.5;

[0557] 2) Prepare 2x ssDNA-Polθ premix, react in a 384-well plate, set up a control group with only buffer, and add the premix to the remaining groups. Use an automatic pipette (Thermo, Multidrop 8) to add the compound, starting at 10 μM, dilute at a 1 / 3 dilution ratio, set up 9 detection points in total, and 2 replicates per group;

[0558] 3) Prepare 2xATP solution, add equal volume of 2xATP solution to all wells, and let stand at room temperature for 60 minutes;

[0559] 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 min;

[0560] 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 an ELISA reader (Thermo, VarioskanLUX), and the reading interval for each well was set to 1000 ms;

[0561] Data analysis was performed on the measurement results: 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 value - experimental group) / (control group average value - buffer control group average value). 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.

[0562] 2. Polθ inhibitor cell viability assay

[0563] The in vitro effectiveness of the inhibitor was tested in a cell survival assay using the CellTiter Glo reagent (Promega, G7573), which is the commonly used CTG assay. The specific assay method is as follows:

[0564] 1) Culture DLD1 wild-type (ATCC, CCL-221) and DLD1 BRCA2- / - cells. Digest the cells with trypsin (0.025% Trypsin-EDTA, Hyclone) one day before the start of the test, centrifuge at 1000 rpm for 3 minutes, and collect the cells. Count the cells using a counter (Shanghai Mengwei Biomedical Technology Co., Ltd., SmartCell600A.SC1006) and inoculate them into 96-well white culture plates according to the appropriate inoculation ratio.

[0565] 2) 24 hours after cell plating, the drug treatment was performed, which was recorded as Day 0. An automatic pipette (Thermo, Multidrop8) was used to add the compound. The plate was set as a 96-well plate, the starting concentration was set to 30 μM, and the dilution ratio was 1 / 3. A total of 9 detection points were set, with 2 replicates in each group. The cells were cultured in a 37°C, 5% CO2 incubator;

[0566] 3) Change the medium twice on Day 3 and Day 7, and add compounds according to step 2);

[0567] 4) On Day 10, remove the cell culture plate and add an equal volume of CTG reagent (the CTG reagent needs to be restored to temperature in advance and premixed according to the reagent instructions), gently mix on a constant temperature mixer (Hangzhou Aosheng Instrument Co., Ltd., MSC-100) for 10 min (speed 300), and perform chemiluminescence detection using an enzyme reader (Thermo, VarioskanLUX);

[0568] 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. The data that meet the above quality control results are used to calculate cell survival (inhibition rate (%) = 100*(control group average value-experimental group) / (control group average value-culture solution control group average value). GraphPad Prism8 is used to perform nonlinear regression fitting of the inhibition rate curve of the compound and obtain the IC 50 The results are shown in Table 3.

[0569] The test showed that the example compounds of the present application had a strong proliferation inhibitory effect on DLD1 BRCA2- / - 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 for the proliferation inhibitory effect on the two types of cells.

[0570] Data list:

[0571] NT = not tested;

[0572] Table 3: Specific data of biochemical experiments and cell survival detection experiments:

[0573]

[0574]

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 is unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-11 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 substituted 5-12 membered heteroaryl or unsubstituted or 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 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, 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 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 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 methyl, e.g.

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

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