Biaryl compounds, their intermediates, preparation methods, and uses

Abstract

This invention discloses biaryl compounds, their intermediates, methods for preparation, and uses. The invention provides compounds represented by formula I, pharmaceutically acceptable salts thereof, or their isotopic compounds. The ATPase activity and protein inhibitory effects of the biaryl compounds provided by this invention can be significantly improved compared to the prior art. [C1] TIFF2026527603000201.tif34156

Description

[Technical Field]

[0001] This application claims priority to Chinese patent application 202311124367X, filed on 2023 / 9 / 1; Chinese patent application 2023114104077, filed on 2023 / 10 / 27; and Chinese patent application 2023118384594, filed on 2023 / 12 / 28. This application incorporates the full text of the aforementioned Chinese patent applications.

[0002] Technical field This invention relates to biaryl compounds, their intermediates, methods for their preparation, and their uses. [Background technology]

[0003] DNA damage is a crucial mechanism by which many chemotherapy drugs exert their antitumor effects. Double-strand breaks (DSBs) are one of the most common types of damage in cells, and can be caused directly by ionizing radiation, ultraviolet light, reactive oxygen species (ROS), or other mutagenic substances. Common chemotherapy drugs that cause DSBs include cisplatin, 5-FU, and etoposide. Unrepaired DNA damage causes functional blockages in cells, such as transcription and replication, inducing apoptosis or necrosis, which are then removed by immune cells. Tumor cells have efficient or alternative repair pathways, and by targeting key proteins in these DNA repair pathways, unrepaired DNA damage accumulates, ultimately leading to cell death. This is one of the important policies in cancer treatment.

[0004] DNA double-strand breaks are generally repaired by three mechanisms: non-homologous end joining (NHEJ), homologous recombination (HR), and alternative non-homologous end joining (Alt-NHEJ, also called microhomology-mediated end joining (MMEJ) or TMEJ). Of these, the HR repair pathway occurs only in the G2 and S phases and is error-free in the presence of sister chromatids. In mammals, more than 90% of DSB damage is repaired by the NHEJ pathway. This is an error-prone repair, resulting in deletion mutations less than 30 bp, insertion mutations less than 5 bp, or microhomology sequences less than 2 bp. Recent studies have shown that when HR and / or NHEJ are defective, cells become highly dependent on a third mechanism, namely MMEJ-mediated DNA repair. Inhibition of MMEJ leads to apoptosis. MMEJ is another DNA repair pathway that repairs double-strand breaks via theta-mediated end joining (TMEJ) of DNA polymerase, and is prone to errors.

[0005] DNA polymerase theta (Pol theta or Polθ) is a unique multifunctional polymerase that serves as a major protein in the MMEJ repair pathway. It consists of an N-terminal helicase domain, a central domain, and a single C-terminal polymerase domain. Basic research has revealed that the polymerase structural domain is necessary for DNA elongation at DSB damage repair sites, while the helicase domain and central domain play crucial roles in Polθ's recognition and binding to its substrate. Polθ disrupts the interaction between DNA and the damage repair complex (such as single-stranded DNA that competitively binds to RAD51), thereby inhibiting the HR repair pathway. Furthermore, the helicase domain of Polθ is involved in DNA replication blocking, and loss of its function leads to increased replication pressure in tumor cells and subsequent apoptosis.

[0006] Polθ is either not expressed or expressed at low levels in normal tissue cells, but is highly expressed in various tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, and colon cancer, and is associated with poor prognosis. Among these, Polθ is overexpressed in over 70% of breast cancers. These phenomena suggest that Polθ plays an important role in these cancers and may be a tumor-specific target.

[0007] Studies on Polθ knockdown or knockout in tumor cells have revealed that Polθ deficiency may sensitize these cells to radiation, induce DSB production, increase replication fork instability, sensitize tumor cells to mutagenic substances (genotoxic substances), and enhance the effects of radiotherapy and chemotherapy, making it a potential drug target. Furthermore, it has been found that Polθ and HR deficiency have a combined lethal effect, and that small molecule inhibitors of Polθ can kill HR-deficient tumor cells in vitro and in vivo. In particular, in PARP inhibitor (olaparib, etc.) resistant tumors with HR-deficient reverse mutations, Polθ inhibitors can resensitize cells to PARPi, providing a valuable therapeutic opportunity. Moreover, given that Polθ is a key protein in the MMEJ pathway, its dysfunction increases genomic instability in cancer cells, increases somatic mutations, and promotes the generation of tumor neoantigens. Additionally, since Polθ has been reported to be involved in cGAS-STING-mediated immune activation, targeting Polθ may enhance immunotherapy.

[0008] As described above, Polθ is a promising target for cancer treatment. By designing ATPase activity inhibitors that target the Polθ protein, which inhibits intracellular MMEJ, and testing them as monotherapy or in combination with other chemotherapy, radiotherapy, antibody therapy, or immunotherapy, it is possible to achieve the goal of killing tumor cells. This holds great promise for the treatment of tumors such as lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, colon cancer, prostate cancer, and pancreatic adenocarcinoma.

Summary of the Invention

Problems to be Solved by the Invention

[0009] The technical problem to be solved by the present invention is to overcome the relatively single structure of polymerase theta inhibitor compounds in the prior art. For this purpose, the present invention provides biaryl compounds, their intermediates, preparation methods and uses. The ATPase activity and protein inhibition effects of these compounds are significantly improved compared to the prior art.

Means for Solving the Problems

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

[0011] The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof or an isotope compound thereof,

Chemical formula

Chem.

[0012] In certain preferred embodiments, in the compound represented by formula I, its pharmaceutically acceptable salt, or isotope, certain groups may be defined as described below, and other groups may be defined as described in any of the embodiments described above (hereinafter referred to as "in certain preferred embodiments").

[0013] In certain preferred embodiments, R 1 This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -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 one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 A 5-12 member heteroaryl group substituted by, Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R1-10 , R 1-11 , R 1-12 and R 1-13 These are, independently, halogen, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl alkyl group, or -P(O)(C 1-6 It is alkyl group 2.

[0014] In a particular preferred embodiment, each R a In this, the halogen is independently fluorine, chlorine, bromine, or iodine.

[0015] In a particular preferred embodiment, each R a In this case, the unsubstituted or one or more R 1-1 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl groups are independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0016] In a particular preferred embodiment, each R a In this case, the unsubstituted or one or more R 1-2 C is replaced by 1-6 C in alkoxy groups 1-6 The alkoxy groups are independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0017] In a particular preferred embodiment, each R 1-1 and R 1-2 In this, the halogen is independently fluorine, chlorine, bromine, or iodine.

[0018] In certain preferred embodiments, R 1 In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0019] In certain preferred embodiments, R 1 In this, the halogen is independently fluorine or chlorine.

[0020] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-3 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group, an isopropyl group, or a tert-butyl group.

[0021] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-3 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an n-propyl group, an isopropyl group, or a tert-butyl group.

[0022] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-4 C is replaced by 1-6 C in alkoxy groups 1-6 The alkoxy group is independently a methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, or tert-butoxy group, for example, a methoxy group.

[0023] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-5 C is replaced by 3-10 C in cycloalkyl groups 3-10 The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group.

[0024] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-5 C is replaced by 3-10 C in cycloalkyl groups 3-10 The cycloalkyl group is independently either a cyclopropyl group or a cyclobutyl group.

[0025] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-6 The 3-12 member heterocycloalkyl groups substituted by are independently 5-8 member heterocycloalkyl groups.

[0026] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-6 In the 3-12 member heterocycloalkyl groups substituted by , the heteroatoms of the 3-12 member heterocycloalkyl groups are independently N and / or O.

[0027] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-6 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is independently one or two, for example, two.

[0028] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-6 In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently monocyclic, crosslinked, fused, or spirocyclic rings. The number of rings in the spiro ring, fused ring, or bridging ring may be two. The spiro ring may be a 3-membered spiro-5-membered heterocyclyl group, a 3-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-4-membered heterocyclyl group, a 4-membered spiro-5-membered heterocyclyl group, a 4-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-7-membered heterocyclyl group, a 5-membered spiro-4-membered heterocyclyl group, a 5-membered spiro-5-membered heterocyclyl group, a 5-membered spiro-6-membered heterocyclyl group, a 5-membered spiro-7-membered heterocyclyl group, a 6-membered spiro-4-membered heterocyclyl group, a 6-membered spiro-5-membered heterocyclyl group, or a 6-membered spiro-6-membered heterocyclyl group, for example, a 4-membered spiro-4-membered heterocyclyl group. The fused ring may be a 3-membered fused 5-membered heterocyclyl group, a 4-membered fused 5-membered heterocyclyl group, a 4-membered fused 6-membered heterocyclyl group, a 5-membered fused 5-membered heterocyclyl group, a 5-membered fused 6-membered heterocyclyl group, or a 6-membered fused 6-membered heterocyclyl group, for example, a 3-membered fused 5-membered heterocyclyl group or a 5-membered fused 5-membered heterocyclyl group, preferably the fused ring may be a 4-membered fused 5-membered heterocyclyl group, a 4-membered fused 6-membered heterocyclyl group, a 5-membered fused 5-membered heterocyclyl group, a 5-membered fused 6-membered heterocyclyl group, or a 6-membered fused 6-membered heterocyclyl group, for example, a 5-membered fused 5-membered heterocyclyl group. The crosslinking ring may be a 4-membered crosslinked 5-membered heterocyclyl group, a 4-membered crosslinked 6-membered heterocyclyl group, a 5-membered crosslinked 6-membered heterocyclyl group, or a 6-membered crosslinked 6-membered heterocyclyl group, for example, a 4-membered crosslinked 6-membered heterocyclyl group.

[0029] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-6 In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently 5-8 member heterocycloalkyl groups, the heteroatoms of the 5-8 member heterocycloalkyl groups are N and / or O, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0030] In certain preferred embodiments, R1 In this case, the unsubstituted or one or more R 1-6 In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl groups are independently, [ka] That is the case.

[0031] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-7 C is replaced by 6-12 C in aryl group 6-12 The aryl group is independently either a phenyl group or a naphthyl group, for example, a phenyl group.

[0032] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 The 5-12 membered heteroaryl group substituted by is a monocyclic group.

[0033] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 The 5-12 membered heteroaryl groups substituted by are independently 5-6 membered heteroaryl groups.

[0034] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 In the 5-12 membered heteroaryl group substituted by the substituted group, the heteroatoms of the 5-12 membered heteroaryl group are N and / or O.

[0035] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8In the 5-12 membered heteroaryl group substituted by the above, the heteroatom of the 5-12 membered heteroaryl group is N.

[0036] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 The number of heteroatoms in a 5-12 membered heteroaryl group substituted by is either one or two.

[0037] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 In a 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatoms of the 5-6 membered heteroaryl group are N and / or O, and the number of heteroatoms is one or two, for example, [ka] That is the case.

[0038] In certain preferred embodiments, R 1 In this case, the unsubstituted or one or more R 1-8 In a 5-12 membered heteroaryl group substituted by a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0039] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , Rk and R m In this case, the unsubstituted or one or more R 1-9 C is replaced by 3-10 C in cycloalkyl groups 3-10 The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group.

[0040] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-10 In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl groups are independently monocyclic, crosslinked, or fused rings. The number of rings in the aforementioned condensed ring or bridging ring may be two. The fused ring may be a 4-membered fused 5-membered heterocyclyl group, a 4-membered fused 6-membered heterocyclyl group, a 5-membered fused 5-membered heterocyclyl group, a 5-membered fused 6-membered heterocyclyl group, or a 6-membered fused 6-membered heterocyclyl group, for example, a 5-membered fused 5-membered heterocyclyl group. The aforementioned crosslinking ring may be a 4-membered crosslinked 5-membered heterocyclyl group, a 4-membered crosslinked 6-membered heterocyclyl group, a 5-membered crosslinked 6-membered heterocyclyl group, or a 6-membered crosslinked 6-membered heterocyclyl group, for example, a 4-membered crosslinked 6-membered heterocyclyl group.

[0041] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and Rm In this case, the unsubstituted or one or more R 1-10 The 3-12 member heterocycloalkyl groups substituted by are independently 4-8 member heterocycloalkyl groups.

[0042] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-10 In the 3-12 member heterocycloalkyl groups substituted by , the heteroatoms of the 3-12 member heterocycloalkyl groups are independently N and / or O.

[0043] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-10 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is independently either 1 or 2.

[0044] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and Rm In this case, the unsubstituted or one or more R 1-10 In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently 4-8 member heterocycloalkyl groups, the heteroatoms of the 4-8 member heterocycloalkyl groups are N and / or O, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0045] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-11 C is replaced by 6-12 C in aryl group 6-12 The aryl group is independently either a phenyl group or a naphthyl group, for example, a phenyl group.

[0046] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-12 The 5-12 membered heteroaryl group substituted by is a monocyclic group.

[0047] In certain preferred embodiments, R b , R c , Rd , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-12 The 5-12 membered heteroaryl groups substituted by are independently 5-6 membered heteroaryl groups.

[0048] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k In this case, the unsubstituted or one or more R 1-12 In the 5-12 membered heteroaryl group substituted by the above, the heteroatom of the 5-12 membered heteroaryl group is N.

[0049] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-12 The number of heteroatoms in a 5-12 membered heteroaryl group substituted by is either 1 or 2.

[0050] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g, R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-12 In the 5-12 membered heteroaryl group substituted by , the 5-12 membered heteroaryl group is independently a 5-6 membered heteroaryl group, the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0051] In certain preferred embodiments, R b , R c , R d , each R e , R f , R g , R h , R i , R j , R k and R m In this case, the unsubstituted or one or more R 1-13 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group.

[0052] In a particular 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 this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine.

[0053] In a particular 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 case of C 1-6 Alkyl alkyl group, the -S(O)2C 1-6 C in alkyl groups 1-6 Alkyl alkyl groups, and the -P(O)(C 1-6 C in alkyl group 2 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group.

[0054] In a particular 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-mentioned -S(O)2C 1-6 Alkyl groups are [ka] That is the case.

[0055] In a particular 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 -P(O)(C 1-6 Alkyl(alkyl)2 is, [ka] That is the case.

[0056] In certain preferred embodiments, R 1 In this case, each plurality is either two or three, for example, two.

[0057] In a particular preferred embodiment, each R 2 In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine.

[0058] In a particular preferred embodiment, each R 2 In this case, the unsubstituted or one or more R 2-1 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group.

[0059] In a particular preferred embodiment, each R 2 In this case, each plurality is either two or three, for example, two.

[0060] In a particular preferred embodiment, each R 2 In this case, the unsubstituted or one or more R 2-2 C is replaced by 1-6 C in alkoxy groups 1-6 The alkoxy group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, for example, a methoxy group.

[0061] In a particular preferred embodiment, each R 2-1 and R 2-2In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0062] In a particular preferred embodiment, each R 2 In this case, one or more R 2-1 C is replaced by 1-6 Alkyl groups are [ka] That is the case.

[0063] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-1 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group.

[0064] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9 The 4-12 member heterocycloalkenyl group substituted by is either a monocyclic or fused ring. The number of rings in the aforementioned fused ring may be two. The fused ring may be a 4-membered fused 5-membered heterocycloalkenyl group, a 4-membered fused 6-membered heterocycloalkenyl group, a 5-membered fused 5-membered heterocycloalkenyl group, a 5-membered fused 6-membered heterocycloalkenyl group, or a 6-membered fused 6-membered heterocycloalkenyl group, for example, a 5-membered fused 6-membered heterocycloalkenyl group.

[0065] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9The 4-12 member heterocycloalkenyl group substituted by is independently a 5-9 member heterocycloalkenyl group, for example, a 5-6 member heterocycloalkenyl group.

[0066] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9 In the 4-12 member heterocycloalkenyl group substituted by , the heteroatom of the 4-12 member heterocycloalkenyl group is N.

[0067] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9 The number of heteroatoms in a 4-12 member heterocycloalkenyl group substituted by is one or two, for example, one.

[0068] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9 The number of double bonds in the 4-12 member heterocycloalkenyl group substituted by is one or two, for example, two.

[0069] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-9 In the 4-12 member heterocycloalkenyl group substituted by , the 4-12 member heterocycloalkenyl group is independently a 5-9 member heterocycloalkenyl group, the heteroatom of the 5-9 member heterocycloalkenyl group is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-9 member heterocycloalkenyl group is 1 or 2, for example, [ka] That is the case.

[0070] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-3 C is replaced by 2-6 C in the alkynyl group 2-6 The alkynyl group is independently an ethynyl group, a propynyl group, or a propargyl group, for example, an ethynyl group.

[0071] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-5 In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl groups are independently either a crosslinking ring or a spiro ring. The number of rings in the spiro ring or crosslinking ring may be two, and the spiro ring may be a 3-membered spiro-5-membered heterocyclyl group, a 3-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-4-membered heterocyclyl group, a 4-membered spiro-5-membered heterocyclyl group, a 4-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-7-membered heterocyclyl group, a 5-membered spiro-4-membered heterocyclyl group, a 5-membered spiro-5-membered heterocyclyl group, a 5-membered spiro-6-membered heterocyclyl group, a 5-membered spiro-7-membered heterocyclyl group, a 6-membered spiro-4-membered heterocyclyl group, a 6-membered spiro-5-membered heterocyclyl group, or a 6-membered spiro-6-membered heterocyclyl group, for example, a 3-membered spiro-6-membered heterocycloalkyl group. The crosslinked ring may be a 4-membered crosslinked 5-membered heterocycloalkyl group, a 4-membered crosslinked 6-membered heterocycloalkyl group, a 5-membered crosslinked 6-membered heterocycloalkyl group, or a 6-membered crosslinked 6-membered heterocycloalkyl group, for example, a 4-membered crosslinked 6-membered heterocycloalkyl group.

[0072] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-5 The 3-12 member heterocycloalkyl groups substituted by are independently 6-8 member heterocycloalkyl groups.

[0073] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-5 In the 3-12 member heterocycloalkyl groups substituted by , the heteroatom of the 3-12 member heterocycloalkyl group is N.

[0074] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-5 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is independently either 1 or 2.

[0075] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-5 In the 3-12 member heterocycloalkyl group substituted by , the 3-12 member heterocycloalkyl group is a 6-8 member heterocycloalkyl group, the heteroatom of the 6-8 member heterocycloalkyl group is N, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0076] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-10 C is replaced by 6-12 C in aryl group 6-12 The aryl group is either a phenyl group or a naphthyl group, for example, a phenyl group.

[0077] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-6 The 5-12 membered heteroaryl group substituted by is either a monocyclic or fused ring. The number of rings in the fused ring may be two.

[0078] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-6 The 5-12 membered heteroaryl group substituted by is a 5-9 membered heteroaryl group.

[0079] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-6 In the 5-12 membered heteroaryl group substituted by the substituted group, the heteroatoms of the 5-12 membered heteroaryl group are N and / or O.

[0080] In a particular preferred embodiment, each R 3 In this case, the unsubstituted or one or more R 3-6 In a 5-12 membered heteroaryl group substituted by a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is a 5-9 membered heteroaryl group, the heteroatoms of the 5-9 membered heteroaryl group are N and / or O, and the number of heteroatoms is 1, 2, or 3, for example, [ka] And furthermore, for example, [ka] That is the case.

[0081] In a particular preferred embodiment, each R 3 In this case, each plurality is either two or three, for example, two.

[0082] In a particular preferred embodiment, each R 3-1 and R 3-3 In this case, the unsubstituted or one or more R 3-1-1 The 3-12 member heterocycloalkyl group in the substituted 3-12 member heterocycloalkyl group is monocyclic.

[0083] In a particular preferred embodiment, each R 3-1 and R 3-3 In this case, the unsubstituted or one or more R 3-1-1 The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group.

[0084] In a particular preferred embodiment, each R 3-1 and R 3-3 In this case, the unsubstituted or one or more R 3-1-1 In the 3-12 member heterocycloalkyl group substituted by , the heteroatom of the 3-12 member heterocycloalkyl group is N and / or O, for example, O.

[0085] In a particular preferred embodiment, each R 3-1 and R 3-3 In this case, the unsubstituted or one or more R 3-1-1 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is one or two, for example, one.

[0086] In a particular preferred embodiment, each R 3-1 and R 3-3 In this case, the unsubstituted or one or more R 3-1-1 In the 3-12 member heterocycloalkyl group substituted by , the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0087] In a particular preferred embodiment, each R 3-5 and R 3-9In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine.

[0088] In a particular preferred embodiment, each R 3-5 and R 3-9 In this case, the unsubstituted or one or more R 3-5-1 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, for example, a methyl group.

[0089] In a particular preferred embodiment, each R 3-5 and R 3-9 In this case, the unsubstituted or one or more R 3-5-1 C is replaced by 1-6 C in alkoxy groups 1-6 The alkyl group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, or a tert-butoxy group, for example, a methoxy group.

[0090] In a particular preferred embodiment, each R 3-6 and R 3-10 In this case, the unsubstituted or one or more R 3-6-1 C is replaced by 1-6 C in alkyl groups 1-6 The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, for example, a methyl group.

[0091] In a particular preferred embodiment, each R 3-8 In this case, the unsubstituted or one or more R 3-8-1The 3-12 member heterocycloalkyl group in the substituted 3-12 member heterocycloalkyl group is monocyclic.

[0092] In a particular preferred embodiment, each R 3-8 In this case, the unsubstituted or one or more R 3-8-1 The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group.

[0093] In a particular preferred embodiment, each R 3-8 In this case, the unsubstituted or one or more R 3-8-1 In the 3-12 member heterocycloalkyl groups substituted by the substituted 3-12 member heterocycloalkyl groups, the heteroatoms are N and / or O.

[0094] In a particular preferred embodiment, each R 3-8 In this case, the unsubstituted or one or more R 3-8-1 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is one or two, for example, two.

[0095] In a particular preferred embodiment, each R 3-8 In this case, the unsubstituted or one or more R 3-8-1 In the 3-12 member heterocycloalkyl group substituted by , the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0096] In a particular preferred embodiment, each R 3-1-3 In this case, the unsubstituted or one or more R 3-1-3-1The 3-12 member heterocycloalkyl group in the substituted 3-12 member heterocycloalkyl group is monocyclic.

[0097] In a particular preferred embodiment, each R 3-1-3 In this case, the unsubstituted or one or more R 3-1-3-1 The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group.

[0098] In a particular preferred embodiment, each R 3-1-3 In this case, the unsubstituted or one or more R 3-1-3-1 In the 3-12 member heterocycloalkyl groups substituted by the substituted 3-12 member heterocycloalkyl groups, the heteroatoms are N and / or O.

[0099] In a particular preferred embodiment, each R 3-1-3 In this case, the unsubstituted or one or more R 3-1-3-1 The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is one or two, for example, two.

[0100] In a particular preferred embodiment, each R 3-1-3 In this case, the unsubstituted or one or more R 3-1-3-1 In the 3-12 member heterocycloalkyl group substituted by , the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is 1 or 2, for example, [ka] That is the case.

[0101] In a particular preferred embodiment, each R 3-5-1In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine.

[0102] In a particular preferred embodiment, each R 3-5 and R 3-9 In this case, the one or more R 3-5-1 C is replaced by 1-6 Alkyl groups are [ka] That is the case.

[0103] In certain preferred embodiments, C as described in any one of the present invention 2-6 The alkenyl group is independently a vinyl group, a propenyl group, or an allyl group.

[0104] In certain preferred embodiments, C as described in any one of the present invention 2-6 The alkynyl group is independently an ethynyl group, a propynyl group, or a propargyl group.

[0105] In certain preferred embodiments, C as described in any one of the present invention 3-10 Cycloalkyl groups and C 3-6 The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0106] In certain preferred embodiments, the 3- to 12-membered heterocycloalkyl group described in any one of the present invention is a monocycle, a fused ring, a crosslinked ring, or a spirocycle. The number of rings in the spiro ring, fused ring, or bridging ring may be two. The spiro ring may be a 3-membered spiro-5-membered heterocyclyl group, a 3-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-4-membered heterocyclyl group, a 4-membered spiro-5-membered heterocyclyl group, a 4-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-7-membered heterocyclyl group, a 5-membered spiro-4-membered heterocyclyl group, a 5-membered spiro-5-membered heterocyclyl group, a 5-membered spiro-6-membered heterocyclyl group, a 5-membered spiro-7-membered heterocyclyl group, a 6-membered spiro-4-membered heterocyclyl group, a 6-membered spiro-5-membered heterocyclyl group, or a 6-membered spiro-6-membered heterocyclyl group. The condensed ring may be a 4-membered condensed 5-membered heterocyclyl group, a 4-membered condensed 6-membered heterocyclyl group, a 5-membered condensed 5-membered heterocyclyl group, a 5-membered condensed 6-membered heterocyclyl group, or a 6-membered condensed 6-membered heterocyclyl group. The crosslinking ring may be a 4-membered crosslinked 5-membered heterocyclyl group, a 4-membered crosslinked 6-membered heterocyclyl group, a 5-membered crosslinked 6-membered heterocyclyl group, or a 6-membered crosslinked 6-membered heterocyclyl group.

[0107] In certain preferred embodiments, the 3- to 12-membered heterocycloalkyl group described in any one of the present inventions is a 5- to 6-membered heterocycloalkyl group.

[0108] In certain preferred embodiments, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups described in any one of the present inventions are N and / or O.

[0109] In certain preferred embodiments, the number of heteroatoms in the 3- to 12-membered heterocycloalkyl group described in any one of the present inventions is one or two, for example, two.

[0110] In certain preferred embodiments, the 3- to 12-membered heterocycloalkyl groups described in any one of the present inventions are independently: [ka] That is the case.

[0111] In certain preferred embodiments, the 4- to 12-membered heterocycloalkenyl group described in any one of the present invention is a monocyclic or fused ring, The number of rings in the aforementioned fused ring may be two. The fused ring may be a 4-membered fused 5-membered heterocycloalkenyl group, a 4-membered fused 6-membered heterocycloalkenyl group, a 5-membered fused 5-membered heterocycloalkenyl group, a 5-membered fused 6-membered heterocycloalkenyl group, or a 6-membered fused 6-membered heterocycloalkenyl group.

[0112] In certain preferred embodiments, the 4- to 12-membered heterocycloalkenyl group described in any one of the present inventions is independently a 5- to 9-membered heterocycloalkenyl group.

[0113] In certain preferred embodiments, the heteroatom of the 4- to 12-membered heterocycloalkenyl group described in any one of the present inventions is N.

[0114] In certain preferred embodiments, the number of heteroatoms in the 4- to 12-membered heterocycloalkenyl group described in any one of the present inventions is one or two, for example, one.

[0115] In certain preferred embodiments, the number of double bonds in the 4- to 12-membered heterocycloalkenyl group described in any one of the present inventions is one or two, for example, two.

[0116] In certain preferred embodiments, the 4- to 12-membered heterocycloalkenyl group described in any one of the present inventions is independently, [ka] That is the case.

[0117] In certain preferred embodiments, the halogen described in any one of the present inventions is independently fluorine, chlorine, bromine, or iodine.

[0118] In certain preferred embodiments, C as described in any one of the present invention 1-6The alkyl groups are independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group.

[0119] In certain preferred embodiments, the 5- to 12-membered heteroaryl group described in any one of the present inventions is a monocyclic or fused ring, The number of rings in the fused ring may be two.

[0120] In certain preferred embodiments, the 5- to 12-membered heteroaryl group described in any one of the present inventions is a 5- to 9-membered heteroaryl group.

[0121] In certain preferred embodiments, the heteroatoms of the 5- to 12-membered heteroaryl group described in any one of the present inventions are N and / or O.

[0122] In certain preferred embodiments, the 5- to 12-membered heteroaryl group described in any one of the present inventions is independently, [ka] That is the case.

[0123] In certain preferred embodiments, C as described in any one of the present invention 1-6 The alkoxy groups are independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group.

[0124] In certain preferred embodiments, R a It is hydrogen.

[0125] In certain preferred embodiments, X 2 It is N.

[0126] In certain preferred embodiments, X 3 It is N.

[0127] In certain preferred embodiments, X 4 It is N.

[0128] In certain preferred embodiments, R b This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, unsubstituted or one or more R 1-12 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group.

[0129] In certain preferred embodiments, R b This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0130] In certain preferred embodiments, R b This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group.

[0131] In certain preferred embodiments, R b This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, or unsubstituted or one or more R groups 1-11 C is replaced by 6-12 It is an aryl group.

[0132] In certain preferred embodiments, R b is the unsubstituted C 3-10 Cycloalkyl groups, unsubstituted C 6-12 Aryl group or unsubstituted C 1-6 It is an alkyl group, preferably an unsubstituted C 1-6 It is an alkyl group.

[0133] In certain preferred embodiments, R b is the unsubstituted C 3-10 Cycloalkyl groups or unsubstituted C 6-12 It is an aryl group.

[0134] In certain preferred embodiments, R c This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, or unsubstituted or one or more R groups 1-10 It is a 3- to 12-membered heterocycloalkyl group that is substituted by [the specified agent].

[0135] In certain preferred embodiments, R c This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 It is a cycloalkyl group.

[0136] In certain preferred embodiments, R c is the unsubstituted C 3-10 It is a cycloalkyl group.

[0137] In certain preferred embodiments, R d This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, or unsubstituted or one or more R groups 1-10 It is a 3- to 12-membered heterocycloalkyl group that is substituted by [the specified agent].

[0138] In certain preferred embodiments, R d This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 It is a cycloalkyl group.

[0139] In certain preferred embodiments, R d is the unsubstituted C 3-10 It is a cycloalkyl group.

[0140] In certain preferred embodiments, R e This is either not substituted or has one or more R's. 1-13 C is replaced by 1-6 It is an alkyl group.

[0141] In certain preferred embodiments, R e is the unsubstituted C 1-6 It is an alkyl group.

[0142] In certain preferred embodiments, R f This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0143] In certain preferred embodiments, R f This is either not substituted or has one or more R's. 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0144] In certain preferred embodiments, R f This is an unsubstituted 3-12 member heterocycloalkyl group, and an unsubstituted C 6-12 It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group.

[0145] In certain preferred embodiments, R g This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, or unsubstituted or one or more R groups 1-10 It is a 3- to 12-membered heterocycloalkyl group that is substituted by [the specified agent].

[0146] In certain preferred embodiments, R g This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 It is a cycloalkyl group.

[0147] In certain preferred embodiments, R g is the unsubstituted C 3-10 It is a cycloalkyl group.

[0148] In certain preferred embodiments, R h This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0149] In certain preferred embodiments, R h This is either not substituted or has one or more R's. 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0150] In certain preferred embodiments, R h is the unsubstituted C 3-10 Cycloalkyl groups, unsubstituted 3-12 member heterocycloalkyl groups, unsubstituted C 6-12 It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group.

[0151] In certain preferred embodiments, R h This is an unsubstituted 3-12 member heterocycloalkyl group, and an unsubstituted C 6-12 It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group.

[0152] In certain preferred embodiments, R i This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or one or more R 1-11 C is replaced by 6-12 It is an aryl group.

[0153] In certain preferred embodiments, R i This is either not substituted or has one or more R's. 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or one or more R 1-11 C is replaced by 6-12 It is an aryl group.

[0154] In certain preferred embodiments, R i This is an unsubstituted 3- to 12-membered heterocycloalkyl group, or an unsubstituted C 6-12 It is an aryl group.

[0155] In certain preferred embodiments, R j This is either not substituted or has one or more R's. 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0156] In certain preferred embodiments, R j This is either not substituted or has one or more R's. 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or one or more R 1-12 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0157] In certain preferred embodiments, R j This is an unsubstituted 3- to 12-membered heterocycloalkyl group or an unsubstituted 5- to 12-membered heteroaryl group.

[0158] In certain preferred embodiments, R k This is either not substituted or has one or more R's. 1-11 C is replaced by 6-12 Aryl group, unsubstituted or one or more R 1-12 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group.

[0159] In certain preferred embodiments, R k This is either not substituted or has one or more R's. 1-12 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group.

[0160] In certain preferred embodiments, R k This is an unsubstituted 5-12 member heteroaryl group, or an unsubstituted C 1-6 It is an alkyl group.

[0161] In a particular preferred embodiment, each R 1-3 It is, independently, a halogen.

[0162] In a particular preferred embodiment, each R 1-4 It is, independently, a halogen.

[0163] In a particular preferred embodiment, each R 1-5 These are, independently, halogen or C 1-6 It is an alkyl group.

[0164] In a particular preferred embodiment, each R 1-5 Independently, C 1-6 It is an alkyl group.

[0165] In a particular preferred embodiment, each R 1-5 It is, independently, a halogen.

[0166] In a particular preferred embodiment, each R 1-6 These are, independently, halogen or C 1-6 It is an alkyl group.

[0167] In a particular preferred embodiment, each R 1-6 Independently, C 1-6 It is an alkyl group.

[0168] In a particular preferred embodiment, each R 1-7 These are, independently, halogen or C 1-6 It is an alkyl group.

[0169] In a particular preferred embodiment, each R 1-7 It is, independently, a halogen.

[0170] In a particular preferred embodiment, each R 1-8 Independently, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl alkyl group, or -P(O)(C 1-6 It is alkyl group 2.

[0171] In a particular preferred embodiment, each R 1-8 Independently, C 1-6 It is an alkyl group.

[0172] In certain preferred embodiments, R 1 This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, amino group, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -NHR f -C(O)NHR g , -OR h , -SR i , -C(O)R j -S(O)2R k , either not substituted or one or more R1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0173] In certain preferred embodiments, R 1 This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -NHR f -C(O)NHR g , -OR h , -SR i , -C(O)R j -S(O)2R k , either not substituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0174] In certain preferred embodiments, R 1 It consists of hydrogen, halogen, amino group, and -NHC(O)R b , either not substituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0175] In certain preferred embodiments, R 1 is hydrogen, unsubstituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0176] In certain preferred embodiments, R 1 is hydrogen, unsubstituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0177] In certain preferred embodiments, R 1 It consists of hydrogen, halogen, amino group, and -NHC(O)R b , unsubstituted C 1-6 Alkyl alkyl group, unsubstituted C 1-6 Alkoxy group, unsubstituted C 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0178] In certain preferred embodiments, R 1 is hydrogen, unsubstituted C 1-6 Alkyl alkyl group, unsubstituted C 1-6 Alkoxy group, unsubstituted C 3-10 Cycloalkyl groups, unsubstituted C 6-12 It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group.

[0179] In certain preferred embodiments, R 1 is hydrogen, unsubstituted C 1-6 Alkyl alkyl group, unsubstituted C 1-6 Alkoxy group, unsubstituted C 3-10 Cycloalkyl groups, unsubstituted 3-12 member heterocycloalkyl groups, unsubstituted C 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 It is a 5- to 12-membered heteroaryl group that is substituted by [the specified group].

[0180] In certain preferred embodiments, m is 1, 2, or 3.

[0181] In certain preferred embodiments, m is 1 or 2.

[0182] In a particular preferred embodiment, m is 2.

[0183] In certain preferred embodiments, n is 1, 2, or 3.

[0184] In a particular preferred embodiment, n is 1.

[0185] In a particular preferred embodiment, each R 2-1 and R 2-2 It is, independently, a halogen.

[0186] In a particular preferred embodiment, each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group.

[0187] In a particular preferred embodiment, each R 2 These are, independently, halogen, one or more R 2-1 C is replaced by 1-6Alkyl alkyl groups, or unsubstituted C 1-6 It is an alkoxy group.

[0188] In a particular preferred embodiment, each R 3-1 Independently, [ka] That is the case.

[0189] In a particular preferred embodiment, each R 3-1-3 These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups.

[0190] In a particular preferred embodiment, each R 3-3 These are independently, unsubstituted or one or more R 3-1-1 It is a 3- to 12-membered heterocycloalkyl group that is substituted by [the specified agent].

[0191] In a particular preferred embodiment, each R 3-3 These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups.

[0192] In a particular preferred embodiment, each R 3-5 These are independently oxo groups, or unsubstituted or one or more R groups. 3-5-1 C is replaced by 1-6 It is an alkyl group.

[0193] In a particular preferred embodiment, each R 3-5 These are, independently, an oxo group or an unsubstituted C 1-6 It is an alkyl group.

[0194] In a particular preferred embodiment, each R 3-6 These are independently cyano groups, or unsubstituted or one or more R groups. 3-6-1 C is replaced by 1-6 It is an alkyl group.

[0195] In a particular preferred embodiment, each R3-6 is, independently, a cyano group or an unsubstituted C 1-6 alkyl group.

[0196] In certain preferred embodiments, each R 3-10 is, independently, a hydroxy group.

[0197] In certain preferred embodiments, each R 3-8 is, independently, an unsubstituted or substituted by one or more R 3-8-1 3- to 12-member heterocycloalkyl group.

[0198] In certain preferred embodiments, each R 3-8 is, independently, an unsubstituted 3- to 12-member heterocycloalkyl group.

[0199] In certain preferred embodiments, each R 3-9 is, independently, an oxo group, a halogen, a cyano group, a hydroxy group, an unsubstituted or substituted by one or more R 3-5-1 C1-C6 alkyl group, or an unsubstituted or substituted by one or more R 3-5-2 C1-C6 alkoxy group.

[0200] In certain preferred embodiments, each R 3-9 is, independently, an oxo group, a halogen, an unsubstituted or substituted by one or more R 3-5-1 C 1-6 alkyl group, or an unsubstituted or substituted by one or more R 3-5-2 C 1-6 alkoxy group.

[0201] In certain preferred embodiments, each R 3-9 is, independently, an oxo group, a halogen, one or more R 3-5-1 substituted C 1-6 alkyl group, or an unsubstituted C 1-6 alkoxy group.

[0202] In certain preferred embodiments, each R 3-9 is, independently, an oxo group or a halogen.

[0203] In certain preferred embodiments, each R 3-5-1 is, independently, a halogen.

[0204] In certain preferred embodiments, each R 3 is, independently, an unsubstituted or one or more R 3-1 substituted C 1-6 alkyl group, an unsubstituted or one or more R 3-3 substituted C 2-6 alkynyl group, an unsubstituted or one or more R 3-5 substituted 3- to 12-member heterocycloalkyl group, an unsubstituted or one or more R 3-9 substituted 4- to 12-member heterocycloalkenyl group, an unsubstituted or one or more R 3-6 substituted 5- to 12-member heteroaryl group, an unsubstituted or one or more R 3-10 substituted C 6-12 aryl group, or

Chemical formula

[0205] In certain preferred embodiments, each R 3 is, independently, an unsubstituted or one or more R 3-1 substituted C 1-6 alkyl group, an unsubstituted or one or more R 3-4 substituted C 3-6 cycloalkyl group, an unsubstituted or one or more R 3-5 substituted 3- to 12-member heterocycloalkyl group, or an unsubstituted or one or more R 3-9 substituted 4- to 12-member heterocycloalkenyl group.

[0206] In a particular preferred embodiment, each R 3 These are independently, unsubstituted or one or more R 3-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-9 These are 4- to 12-membered heterocycloalkenyl groups that are substituted by [the specified group].

[0207] In a particular preferred embodiment, each R 3 This is an independent, unsubstituted C 1-6 Alkyl group, or one or more R 3-9 These are 4- to 12-membered heterocycloalkenyl groups that are substituted by [the specified group].

[0208] In a particular preferred embodiment, each R 3 These are, independently, one or more R 3-9 These are 4- to 12-membered heterocycloalkenyl groups that are substituted by [the specified group].

[0209] In certain preferred embodiments, R 1 These are hydrogen, deuterium, cyano group, hydroxyl group, fluorine, methyl group, [ka] That is the case.

[0210] In certain preferred embodiments, R 1 is hydrogen, methyl group, [ka] That is the case.

[0211] In certain preferred embodiments, R 1 These are hydrogen, deuterium, cyano group, hydroxyl group, fluorine, methyl group, [ka] That is the case.

[0212] In certain preferred embodiments, R 1 is hydrogen, methyl group, [ka] That is the case.

[0213] In certain preferred embodiments, [ka] teeth, [ka] [ka] That is the case.

[0214] In certain preferred embodiments, [ka] teeth, [ka] That is the case.

[0215] In certain preferred embodiments, [ka] teeth, [ka] [ka] That is the case.

[0216] In certain preferred embodiments, [ka] teeth, [ka] That is the case.

[0217] In certain preferred embodiments, [ka] teeth, [ka] And, Preferably, [ka] teeth, [ka] That is the case.

[0218] In certain preferred embodiments, R 2 teeth, [ka] It is either F or Cl.

[0219] In certain preferred embodiments, R 2 teeth, [ka] , or Cl.

[0220] In certain preferred embodiments, [ka] teeth, [ka] That is the case.

[0221] In certain preferred embodiments, [ka] teeth, [ka] That is the case.

[0222] In certain preferred embodiments, R 3 is a methyl group, [ka] That is the case.

[0223] In certain preferred embodiments, R 3 teeth, [ka] , or a methyl group, preferably, [ka] That is the case.

[0224] In certain preferred embodiments, m and n are independently 1, 2, or 3. X 1 is N or CH, X 2 is N or CH, X 3 N is, X 4 is N or CH, R 1 This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, amino group, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -NHR f -C(O)NHR g , -OR h , -SR i , -C(O)R j -S(O)2R k , either not substituted or one or more R 1-3C replaced by 1-6 an alkyl group, an unsubstituted or one or more Rs 1-4 C replaced by 1-6 an alkoxy group, an unsubstituted or one or more Rs 1-5 C replaced by 3-10 a cycloalkyl group, an unsubstituted or one or more Rs 1-6 a 3- to 12-member heterocycloalkyl group replaced by one or more Rs, an unsubstituted or one or more Rs 1-7 C replaced by 6-12 an aryl group, or an unsubstituted or one or more Rs 1-8 a 5- to 12-member heteroaryl group replaced by one or more Rs, R b R <00009​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​These are, independently, halogen, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl alkyl group, or -P(O)(C 1-6 (alkyl group)2, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, Each R 3 These are independently, unsubstituted or one or more R 3-1 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 3-3 C is replaced by 2-6 Alkynyl group, unsubstituted or one or more R 3-5 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 3-9 A 4-12 member heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups 3-6 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 3-10 C is replaced by 6-12 aryl group, or [ka] And, Each R 3-1 However, each is independent of the others. [ka] And, Each R 3-3 These are independently, unsubstituted or one or more R 3-1-1A 3-12 member heterocycloalkyl group substituted by, Each R 3-5 These are independently oxo groups, or unsubstituted or one or more R groups. 3-5-1 C is replaced by 1-6 It is an alkyl group, Each R 3-6 These are independently cyano groups, or unsubstituted or one or more R groups. 3-6-1 C is replaced by 1-6 It is an alkyl group, Each R 3-9 These are independently oxo groups, halogens, and unsubstituted or one or more R groups. 3-5-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-5-2 C is replaced by 1-6 It is an alkoxy group, Each R 3-8 These are independently, unsubstituted or one or more R 3-8-1 A 3-12 member heterocycloalkyl group substituted by, Each R 3-10 It is independently a hydroxyl group, Each R 3-1-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkyl group, Each R 3-1-3 These are independently unsubstituted 3-12 member heterocycloalkyl groups. Each R 3-5-1 and R 3-5-2 These are independently deuterium, a hydroxyl group, a cyano group, or a halogen. Each R 3-6-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkoxy group, Each R 3-8-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkyl group, In each of the 3-12 member heterocycloalkyl groups, 4-12 member heterocycloalkenyl groups, and 5-12 member heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0225] In certain preferred embodiments, m and n are independently 1, 2, or 3. X 1 is N or CH, X 2 is N or CH, X 3 N is, X 4 is N or CH, R 1 This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -NHR f -C(O)NHR g , -OR h , -SR i , -C(O)R j -S(O)2R k , either not substituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8A 5-12 member heteroaryl group substituted by, R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k These are independently, unsubstituted or one or more R 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12 Aryl group, unsubstituted or one or more R 1-12 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group, 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 These are, independently, halogen, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl alkyl group, or -P(O)(C 1-6 (alkyl group)2, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2It is, independently, a halogen, Each R 3 These are independently, unsubstituted or one or more R 3-1 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 3-3 C is replaced by 2-6 Alkynyl group, unsubstituted or one or more R 3-5 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 3-9 A 4-12 member heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups 3-6 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 3-10 C is replaced by 6-12 aryl group, or [ka] And, Each R 3-1 However, each is independent of the others. [ka] And, Each R 3-3 These are independently, unsubstituted or one or more R 3-1-1 A 3-12 member heterocycloalkyl group substituted by, Each R 3-5 These are independently oxo groups, or unsubstituted or one or more R groups. 3-5-1 C is replaced by 1-6 It is an alkyl group, Each R 3-6 These are independently cyano groups, or unsubstituted or one or more R groups. 3-6-1 C is replaced by 1-6 It is an alkyl group, Each R 3-9 These are independently oxo groups, halogens, and unsubstituted or one or more R groups. 3-5-1 C is replaced by1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-5-2 C is replaced by 1-6 It is an alkoxy group, Each R 3-8 These are independently, unsubstituted or one or more R 3-8-1 A 3-12 member heterocycloalkyl group substituted by, Each R 3-10 It is independently a hydroxyl group, Each R 3-1-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkyl group, Each R 3-1-3 These are independently unsubstituted 3-12 member heterocycloalkyl groups. Each R 3-5-1 and R 3-5-2 These are independently deuterium, a hydroxyl group, a cyano group, or a halogen. Each R 3-6-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkoxy group, Each R 3-8-1 These are independently a hydroxyl group, a cyano group, a halogen, or C 1-6 It is an alkyl group, In each of the 3-12 member heterocycloalkyl groups, 4-12 member heterocycloalkenyl groups, and 5-12 member heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0226] In certain preferred embodiments, m is 1 or 2, n is 1, X 1 is N or CH, X 2 is N or CH, X 3 N is, X 4 N is, R 1This includes hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R b , -NHS(O)2R c -S(O)2NHR d , [ka] , -NHR f -C(O)NHR g , -OR h , -SR i , -C(O)R j -S(O)2R k , either not substituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 A 5-12 member heteroaryl group substituted by, R b , R c , R d , each R e , R f , R g , R h , R i , R j and R k These are independently, unsubstituted or one or more R 1-9 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-10 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-11 C is replaced by 6-12Aryl group, unsubstituted or one or more R 1-12 A 5-12 member heteroaryl group substituted by, or an unsubstituted or one or more R groups 1-13 C is replaced by 1-6 It is an alkyl group, 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 These are, independently, halogen, C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl alkyl group, or -P(O)(C 1-6 (alkyl group)2, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, Each R 3 This is an independent, unsubstituted C 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-9 A 4-12 member heterocycloalkenyl group substituted by, Each R 3-9 These are independently oxo groups or halogens. In each of the 3-12 member heterocycloalkyl groups, 4-12 member heterocycloalkenyl groups, and 5-12 member heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0227] In certain preferred embodiments, m is 1 or 2, n is 1, X 1 is N or CH, X 2 , X 3 and X 4 N is, R 1 It consists of hydrogen, halogen, amino group, and -NHC(O)R b , either not substituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-6 A 3-12 member heterocycloalkyl group substituted by, or unsubstituted or with one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 A 5-12 member heteroaryl group substituted by, Each R 1-3 and R 1-4 It is, independently, a halogen, Each R 1-5 , R 1-6 , R 1-7 and R 1-8 These are, independently, halogen, or C 1-6 It is an alkyl group, R b is the unsubstituted C 1-6 It is an alkyl group, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, Each R 3 This is an independent, unsubstituted C 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-9 A 4-12 member heterocycloalkenyl group substituted by, Each R 3-9 These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0228] In certain preferred embodiments, m is 1 or 2, n is 1, X 1 is N or CH, X 2 , X 3 and X 4 N is, R 1 is hydrogen, unsubstituted or one or more R 1-3 C is replaced by 1-6 Alkyl alkyl groups, unsubstituted or one or more R 1-4 C is replaced by 1-6 Alkoxy group, unsubstituted or one or more R 1-5 C is replaced by 3-10 Cycloalkyl groups, unsubstituted or one or more R 1-7 C is replaced by 6-12 Aryl group, or unsubstituted or one or more R groups 1-8 A 5-12 member heteroaryl group substituted by, Each R 1-3 and R 1-4 It is, independently, a halogen, Each R 1-5 , R 1-7and R 1-8 These are, independently, halogen, or C 1-6 It is an alkyl group, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, Each R 3 This is an independent, unsubstituted C 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 3-9 A 4-12 member heterocycloalkenyl group substituted by, Each R 3-9 These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0229] In certain preferred embodiments, m is 1 or 2, n is 1, X 1 is N or CH, X 2 , X 3 and X 4 N is, R 1 is hydrogen, unsubstituted C 1-6 Alkyl alkyl group, unsubstituted C 1-6 Alkoxy group, unsubstituted C 3-10 Cycloalkyl groups, unsubstituted 3-12 member heterocycloalkyl groups, unsubstituted C 6-12 Aryl group, or unsubstituted or one or more R groups 1-8A 5-12 member heteroaryl group substituted by, Each R 1-8 Independently, C 1-6 It is an alkyl group, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2 C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, R 3 This is either not substituted or has one or more R's. 3-9 A 4-12 member heterocycloalkenyl group substituted by, Each R 3-9 These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0230] In certain preferred embodiments, m is 1 or 2, n is 1, X 2 and X 3 N is, [ka] teeth, [ka] And, Each R 2 These are, independently, halogens, unsubstituted or one or more R 2-1 C is replaced by 1-6 Alkyl alkyl groups, or unsubstituted or one or more R 2-2C is replaced by 1-6 It is an alkoxy group, Each R 2-1 and R 2-2 It is, independently, a halogen, R 3 This is either not substituted or has one or more R's. 3-9 A 4-12 member heterocycloalkenyl group substituted by, Each R 3-9 These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three.

[0231] In certain preferred embodiments, the compound represented by formula I is one of the following compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0232] The present invention (1) Substance A (in a therapeutically effective amount) is a compound represented by formula I as described in any one of the present inventions, a pharmaceutically acceptable salt or isotope thereof, (2) Pharmaceutical additives, The present invention provides a pharmaceutical composition containing the following:

[0233] The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt or isotope thereof, or a pharmaceutical composition for the preparation of a polymerase theta inhibitor.

[0234] The present invention provides for the use of substance A, which is a compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotope compound, in the preparation of polymerase theta inhibitors.

[0235] The present invention provides the use of a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, an isotope compound thereof, or substance A, or said pharmaceutical composition, in the preparation of a drug for treating and / or preventing lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

[0236] The present invention provides for the use of substance A, which is a compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotope compound, as described in any one of the present invention, in the preparation of agents for treating and / or preventing lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

[0237] The present invention provides the use of a compound represented by formula I as described in any one of the present invention, substance A which is a pharmaceutically acceptable salt or isotope thereof, or the pharmaceutical composition, in the preparation of a drug for treating and / or preventing polymerase theta-related diseases, which are lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

[0238] The present invention provides, as a pharmaceutical agent, substance A which is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt or isotope compound thereof, or the pharmaceutical composition thereof.

[0239] The present invention provides a compound represented by formula I as described in any one of the present invention, substance A which is a pharmaceutically acceptable salt or isotope compound thereof, or a pharmaceutical composition used for the treatment and / or prevention of lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

[0240] The present invention provides a treatment for a disease which is lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer, comprising the procedure of administering to a subject substance A which is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt or isotope thereof, or the pharmaceutical composition (in a therapeutically effective amount).

[0241] The present invention provides a compound represented by formula II or a salt thereof: [ka] R v It is a halogen.

[0242] In certain preferred embodiments, the compound represented by formula II is [ka] That is the case.

[0243] Glossary Those skilled in the art will use the following when describing the basic structural formula of the present invention, in accordance with the conventions used in the art. [ka] It should be understood that this indicates that the corresponding group is linked to other fragments or groups within the compound via that site.

[0244] The term "unsubstituted or substituted by one or more groups A" refers to a situation where one or more hydrogen atoms in group B are independently substituted by group A, or where B is unsubstituted. Simultaneously, when multiple A groups appear, their definitions are independent of each other and do not influence one another unless otherwise specified. For example, "C substituted by three halogens" 6-10 The term "aryl group" is C 6-10 This refers to the substitution of an aryl group with three halogens. The definitions of the three halogens are independent and do not influence each other. [ka] This includes, but is not limited to, the following.

[0245] The term "multiple items" refers to two or more items, for example, two, three, four, or five items, and preferably two or three.

[0246] In the claims of this application, the phrase “satisfying any one or more of the conditions” means two, three, four, or more, where “more” is the maximum number of conditions stated in each claim. For example, if a particular claim states eight conditions, then “satisfying any one or more of the conditions” in that claim means any integer from 1 to 8, for example, 1, 2, 3, 4, 5, 6, 7, or 8.

[0247] The term "pharmaceutically acceptable" refers to a substance that is relatively non-toxic, safe, and suitable for patient use.

[0248] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. If the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, and ammonium salts. If 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, hydrochloride salts, sulfate salts, formate salts, and methanesulfonate salts. For specifics, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0249] The "-" sign in a group indicates that the group is bonded to another part of the molecule via that site. For example, -NHC(O)R b This refers to the fact that the N atom within the molecule is bonded to the rest of the molecule.

[0250] The term "halogen" refers to fluorine, chlorine, bromine, or iodine. In this invention, halogen substitution includes, but is not limited to, substitution by one halogen, substitution by two halogens, or substitution by three halogens; typically, multiple substitutions occur on the same carbon atom.

[0251] The term "oxo" refers to =O, meaning that two hydrogen atoms on the same carbon atom are substituted by oxygen atoms, i.e., a carbonyl group is substituted by a methylene group.

[0252] The term "alkyl group" refers to a specified number of carbon atoms (for example, C 1-6 This refers to a linear or branched saturated monovalent hydrocarbon group having ) ). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl groups.

[0253] The term "alkoxy group" is R X -O- refers to Ill, R X The definition is the same as the term "alkyl group." The groups in an alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy groups.

[0254] The term "alkenyl group" refers to one or more (e.g., one, two, or three) carbon-carbon sp² groups. 2 A specified number of carbon atoms having a double bond (for example, C 2-6 This refers to a linear or branched unsaturated monovalent hydrocarbon group having a vinyl group. [ka] This includes, but is not limited to, these examples.

[0255] The term "alkynyl group" refers to one or more (e.g., one, two, or three) carbon-carbon sp² groups. 3 A specified number of carbon atoms having a triple bond (for example, C 2-6 This refers to a linear or branched unsaturated monovalent hydrocarbon group having an ethynyl group. [ka] This includes, but is not limited to, these examples.

[0256] In this invention, unless otherwise specified, the term "cycloalkyl group" refers to a cyclic saturated and monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 3 to 10 members), which is a monocycle. A monocycle includes, [ka] This includes, but is not limited to, these examples.

[0257] In this invention, unless otherwise specified, the term "aryl group" refers to a cyclic saturated and monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 6 to 12 members), which may be monocyclic or multicyclic (e.g., 2 or 3 rings), where, in the case of multicyclic groups, the monocyclic rings share 2 carbon atoms and 1 bond, and (at least one ring / each ring) is aromatic. The aryl group is bonded to the rest of the molecule via aromatic or non-aromatic rings. Examples of aryl groups include phenyl groups, naphthalene groups, [ka] This includes, but is not limited to, these examples.

[0258] In this invention, unless otherwise specified, the term "cycloalkenyl group" refers to a cyclic unsaturated and monovalent hydrocarbon group having a specified number of carbon atoms (e.g., 4 to 12 members), which may be monocyclic or multicyclic (e.g., 2 or 3 members, bridging ring, spirocycle, fused ring). Monocyclic cycloalkenyl groups include: [ka] These include, but are not limited to, the cycloalkenyl group of the crosslinking ring. [ka] This includes, but is not limited to, the spirocyclic cycloalkenyl group. [ka] These include, but are not limited to, condensed ring cycloalkenyl groups. [ka] This includes, but is not limited to, these examples.

[0259] In this invention, unless otherwise specified, "heterocycloalkyl group" refers to a monocyclic, bridging, 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), or a specified type of heteroatom (one or more of N, O, and S). Monocyclic heterocycloalkyl groups are bonded to other parts of the molecule via carbon atoms or heteroatoms. Monocyclic heterocycloalkyl groups include: [ka] These include, but are not limited to, spirocyclic heterocycloalkyl groups. [ka] These include, but are not limited to, crosslinked ring heterocycloalkyl groups. [ka] This includes, but is not limited to, fused ring heterocycloalkyl groups. [ka] This includes, but is not limited to, these examples.

[0260] In this invention, unless otherwise specified, the term "heterocycloalkenyl group" refers to a cyclic unsaturated monovalent group having a specified number of ring atoms (e.g., 4 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and heteroatoms of a specified type (one or more of N, O, and S), which may be monocyclic or multicyclic (e.g., 2 or 3, spirocyclic). Monocyclic heterocycloalkenyl groups include: [ka] These include, but are not limited to, the spiro ring heterocycloalkenyl group. [ka] This includes, but is not limited to, these examples.

[0261] In this invention, unless otherwise specified, the term “heteroaryl group” means a cyclic unsaturated and monovalent group having a specified number of ring atoms (e.g., 5 to 12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), or a specified type of heteroatom (one or more of N, O, and S), which may be monocyclic or polycyclic, where monocyclic rings share two carbon atoms and one bond, and at least one ring is aromatic. Heteroaryl groups may be bonded to other parts of a molecule via carbon atoms or heteroatoms, or via rings having heteroatoms or not having heteroatoms, or via aromatic or non-aromatic rings. Heteroaryl groups include: [ka] This includes, but is not limited to, these examples.

[0262] The term "isotope compound" refers to a compound in which the isotopic abundance of one or more atoms differs from their natural abundance. For example, a hydrogen atom in a compound may be substituted with deuterium, or C may be substituted with deuterium. 13 One or more atoms in the compound are substituted with naturally occurring atoms with lower mass numbers, such as by substitution with carbon.

[0263] The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture and preparation of pharmaceuticals, encompassing all substances in a pharmaceutical preparation excluding the active ingredient. See Part IV of the Chinese Pharmacopoeia (2015 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0264] The term “treatment” refers to therapeutic therapy. When relating to a specific medical condition, the term treatment means (1) alleviating one or more biological symptoms of a disease or condition; (2) (a) inhibiting one or more points in a biological cascade that causes or promotes a disease, or (b) inhibiting one or more biological symptoms of a disease; (3) improving one or more symptoms, effects, or side effects associated with a disease, or one or more symptoms, effects, or side effects associated with the disease or its treatment; or (4) delaying the onset of one or more biological symptoms of a disease or condition.

[0265] The term "prevention" refers to reducing the risk of contracting or developing a disease or disorder.

[0266] The term "therapeutic dose" refers to the amount of a compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The therapeutic dose varies depending on the compound, the symptoms and their severity, and the age of the patient being treated, but can be adjusted as needed by those skilled in the art.

[0267] The term "patient" refers to any animal, preferably a mammal, most preferably a human, that is to be administered or has already been administered a compound or pharmaceutical composition according to embodiments of the present invention. The term "mammal" refers to any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, most preferably humans.

[0268] In this invention, "room temperature" refers to "20 to 40°C".

[0269] Each of the above preferred conditions can be combined in any way that is in line with the common sense of those skilled in the art to obtain each preferred embodiment of the present invention.

[0270] The reagents and raw materials used in this invention can be obtained from commercially available sources.

[0271] Positive and progressive effects of the present invention: The ATPase activity and protein inhibitory effect of the compounds of the present invention are significantly improved compared to conventional techniques. [Modes for carrying out the invention]

[0272] Specific Embodiments The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of these examples. Experimental methods for which specific conditions are not given in the following examples should be selected according to conventional methods and conditions or in accordance with the product instruction manual.

[0273] All compounds of the present invention can be synthesized by various methods by those skilled in the art of organic chemistry. General synthetic embodiments for preparing the compounds of the present invention are described below. These methods are essentially general but do not limit the techniques that those skilled in the art can use to prepare the compounds disclosed herein. Different methods for preparing the compounds of the present invention will be obvious to those skilled in the art. Furthermore, the individual steps in the synthesis can be performed alternately to obtain one or more desired compounds. The following sections on preparation and examples show examples of the preparation of the compounds of the present invention by the methods of the general embodiments. The preparation of compounds in embodiments containing a chiral center can be carried out by techniques known to those skilled in the art. For example, chiral compounds can be prepared by separating racemic products by chiral resolution using HPLC, or exemplary compounds can be prepared by known methods to obtain chiral compounds.

[0274] 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. Furthermore, it should be understood that in the synthesis methods described below, all mentioned reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experiment duration, and reaction input sequence, should be considered as criteria for the operation of the reaction, as can be easily conceived by those skilled in the art. At the same time, it can also be conceived by those skilled in the field of organic synthesis. The functional groups present in each part of the molecule must be compatible with the reagents used and the reaction itself. It should be easily conceived by those skilled in the art that alternative methods will be necessary in the event that some functional groups present in each part of the molecule are not compatible with the reaction conditions. It is obvious that judgment is required to adjust the sequence of synthesis steps or select a particular embodiment of the synthesis steps in order to obtain the desired compound of the present invention. This is understandable and easily recognized by those skilled in the field of organic synthesis. It should also be recognized that the rational selection of protecting groups to protect the resistance of the reactive functional groups present in the compounds described herein is another major consideration in any synthesis route devised in this art. For specifics, please refer to "Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)" by Greene et al., authorities in the field of chemistry.

[0275] Example The preparation of compounds and intermediates used in compound preparation can be prepared using the steps shown in the following examples and related steps. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not limiting but are illustrative of methods for preparing relevant compounds. If the starting materials and reagents used in these examples are not prepared by the steps described herein, they are usually commercially available, reported in relevant chemical literature, or can be prepared by steps described in chemical literature.

[0276] In the examples described herein, the term “drying and concentration” typically refers to adding a dry solution of anhydrous sodium sulfate or magnesium sulfate to an organic solvent, then filtering and removing the solvent from the filtrate (usually under reduced pressure and at a temperature suitable for the stability of the prepared compound). Columnar chromatography typically involves column separation and purification using conventional column chromatography or flash column chromatography, or elution with a specified solvent or solvent mixture using a medium-pressure chromatograph (Biotage Isola One) pre-loaded with silica gel columns. In some cases, the final product is rapidly purified by preparative thin-layer chromatography using 20cm x 20cm x 0.5mm or 20cm x 20cm x 1mm silica gel plates in a suitable solvent system. Preparative high-performance liquid chromatography (HPLC) is performed using a reversed-phase column (Waters Sunfire C18, Waters Xbridge C18, or equivalent) sized appropriately for the amount of compound to be separated. Elution is typically performed by adding a methanol or acetonitrile concentration gradient to the aqueous phase. Eluting agents include 0.05% or 0.1% formic acid, trifluoroacetic acid, or 10 mM ammonium acetate, and the elution rate depends on the size of the reversed-phase column used and the degree of separation of the preparation.

[0277] List of Abbreviations [Table 1]

[0278] Example 1: N-(3-cyclopropyl-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide [ka]

[0279] Step 1: 6-Chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylate benzyl ester At room temperature and under nitrogen protection, a mixed solution of 6-chloro-4-iodonicotinate benzyl ester (5.0 g, 13.40 mmol) in 1,4-dioxane (50 mL) and water (10 mL) was sequentially mixed with 2-difluoromethyl-5-methoxy-4-boronyl ester pyridine (4.58 g, 16.08 mmol), potassium phosphate (8.53 g, 40.21 mmol), and (1,1'-bis(di-tert-butylphosphine)ferrocene) palladium dichloride (865 mg, 0.294 mmol). The reaction mixture was stirred under nitrogen gas protection at 90°C for 1.5 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated and saline solutions, 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] + .

[0280] Step 2: 2''-Difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-Tripyridine]-5'-Benzyl Carboxylate At room temperature and under nitrogen protection, 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylate benzyl ester (3.0 g, 7.42 mmol), 3-fluoropyridine-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 purged three times with nitrogen gas, and the mixture was reacted under nitrogen protection at 100°C with stirring for 1 hour. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 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]+ .

[0281] Step 3: 2''-Difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-carboxylic acid At room temperature and under nitrogen protection, 10% palladium-carbon (300 mg) was added to a methanol (14 mL) solution of 2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-benzyl carboxylate (1.4 g, 2.91 mmol). The mixture was purged three times with nitrogen gas, and the mixture was reacted at 1 atm under a hydrogen atmosphere at room temperature with stirring 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] + .

[0282] Step 4: N-(3-cyclopropyl-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide At room temperature, 2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-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 reacted at 75°C with stirring for 5 minutes. Next, N,N,N',N'-tetramethylformamidinium hexafluorophosphate (21.5 mg, 0.077 mmol) was added, and the mixture was reacted at 75°C with further stirring for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase fractionation to obtain the title compound (white solid, 6 mg, yield 22.8%). 1H NMR (400 MHz, DMSO-d6) δ 13.85 - 13.53 (m, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.73 (s, 1H), 7.62 - 7.48 (m, 1H), 7.00 (t, J = 55.1 Hz, 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] + .

[0283] The compounds in the examples shown in Table 2 were synthesized using commercially available raw materials, following the synthesis procedure of Example 1.

[0284] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0285] Example 23: N-(3-(4-chlorophenyl)-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide [ka]

[0286] Step 1: 3-bromo-1,2,4-thiadiazole-5-amine Under nitrogen protection, 3-bromo-5-chloro-1,2,4-thiadiazole (500 mg, 2.51 mmol) was dissolved in anhydrous ethanol (5 mL), and aqueous ammonia (0.34 mL, 5.01 mmol, 25% w / w) was slowly added dropwise. The reaction was carried out at 70°C with stirring for 3 hours. The reaction mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution (10 mL) was added, causing a white solid to precipitate. The mixture was filtered, and the filter cake was 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] + .

[0287] Step 2: N-(3-bromo-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide At room temperature, 2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-carboxylic acid (200 mg, 0.511 mmol), 3-bromo-1,2,4-thiadiazole-5-amine (92.01 mg, 0.511 mmol), and N-methylimidazole (168 mg, 2.04 mmol) were added to acetonitrile (3 mL) and N,N-dimethylformamide (1 mL). The mixture was stirred at 70°C for 5 minutes. Then, N,N,N',N'-tetramethylformamidinium hexafluorophosphate (215 mg, 0.77 mmol) was added to the reaction mixture. The reaction solution changed from turbid to clear, and the mixture was allowed to react for 1 hour with further stirring at 70°C. The completion of the reaction was confirmed by LC-MS. Ethyl acetate and water were added to the reaction mixture, 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] + .

[0288] Step 3: N-(3-(4-chlorophenyl)-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazole-5-yl)-2''-difluoromethyl-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-tripyridine]-5'-formamide (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). Under nitrogen protection, 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (5.3 mg, 0.007 mmol) was added, and the mixture was reacted at 90°C with stirring for 16 hours. The reaction mixture was cooled to room temperature, 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 preparative chromatography to obtain the title compound (white solid, 1 mg, yield 4.7%). 1 H NMR (400 MHz, DMSO-d6) δ 14.01 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 8.11 - 7.97 (m, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.73 (s, 1H), 7.60 - 7.54 (m, 3H), 7.00 (t, J = 55.1 Hz, 1H), 6.45 - 6.40 (m, 1H), 3.68 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -113.43 (s), -132.05 (s). LC / MS (ESI) m / z: 585.3 [M+H] + .

[0289] Example 24: 2''-(difluoromethyl)-3-fluoro-5''-methoxy-N-(3-mololinyl-1,2,4-thiadiazole-5-yl)-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0290] Step 1: 3-bromo-1,2,4-thiadiazole-5-amine 3-Bromo-5-chloro-1,2,4-thiadiazole (5.5 g, 27.6 mmol) was dissolved in ethanol (16 mL), and aqueous ammonia (4 mL) was added. The reaction mixture was allowed to proceed at 70°C with stirring for 3 hours. Saturated ammonium chloride solution was added to the mixture, and the mixture was filtered. The filter cake was dried under reduced pressure to obtain the title compound (white solid, 4 g, yield 80.6%). LC / MS (ESI) m / z: 182.0 [M+H] + .

[0291] Step 2: (3-bromo-1,2,4-thiadiazole-5-yl)tert-butylcarbamate 3-Bromo-1,2,4-thiadiazole-5-amine (300 mg, 1.67 mmol) was dissolved in tetrahydrofuran (10 mL), and 4-dimethylaminopyridine (10 mg, 0.082 mmol) and di-tert-butyl dicarbonate (436 mg, 2.0 mmol) were added. The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-20% ethyl acetate) to obtain the title compound (white solid, 430 mg, yield 91.5%). LC / MS (ESI) m / z: 280.0 [M+H] + .

[0292] Step 3: (3-mololinyl-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (3-bromo-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (100 mg, 0.357 mmol) was dissolved in morpholine (1 mL), and the reaction mixture was stirred at 120°C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 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] + .

[0293] Step 4: 3-Mololinyl-1,2,4-thiadiazole-5-amine hydrochloride (3-Mololinyl-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (80 mg, 0.279 mmol) was dissolved in 4N hydrochloric acid / dioxane (3 mL) solution, and the reaction mixture was allowed to react at room temperature with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (60 mg, white solid, yield 96.4%). LC / MS (ESI) m / z: 187.2 [M+H] + .

[0294] Step 5: 2''-(difluoromethyl)-3-fluoro-5''-methoxy-N-(3-mololinyl-1,2,4-thiadiazole-5-yl)-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (20 mg, 0.051 mmol), 3-mololinyl-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), and the mixture was stirred at 70°C for 5 minutes. Then, N,N,N',N'-tetramethylformamidinium hexafluorophosphate (22 mg, 0.078 mmol) was added to the reaction mixture, and the mixture was reacted at 70°C for 1 hour. The reaction mixture was filtered and separated by HPLC to obtain the title compound (8.16 mg, white solid, yield 28.5%). 1 H NMR (400 MHz, DMSO-d6) δ 13.60 (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 LC / MS (ESI) m / z: 560.2 [M+H] + .

[0295] Example 25: N-(3-(2-oxo-6-azaspiro[3,3]heptan-6-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-bipyridine]-5'-formamide [ka]

[0296] Step 1: (3-(2-oxo-6-azaspiro[3,3]heptan-6-yl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (3-bromo-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (50 mg, 0.178 mmol) was dissolved in 2-oxo-6-azaspiro[3.3]heptane (0.5 mL), and the reaction mixture was stirred at 100°C for 3 hours. The reaction mixture was diluted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30-50% ethyl acetate) to obtain the title compound (white solid, 20 mg, yield 37.6%). LC / MS(ESI) m / z: 299.2[M+H] + .

[0297] Step 2: 3-(2-oxo-6-azaspiro[3,3]heptan-6-yl)-1,2,4-thiadiazole-5-amine (3-(2-oxo-6-azaspiro[3,3]heptan-6-yl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (20 mg, 0.067 mmol) was dissolved in dichloromethane (2 mL) solution. Trifluoroacetic acid (0.2 mL) was added to the reaction mixture, and the mixture was reacted at room temperature with stirring for 1 hour. The reaction mixture was adjusted to pH = 7-8 with sodium bicarbonate and extracted three times with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (10 mg, white solid, yield 75.3%). LC / MS (ESI) m / z: 199.1 [M+H] + .

[0298] Step 3: N-(3-(2-oxo-6-azaspiro[3,3]heptan-6-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-bipyridine]-5'-formamide At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (20 mg, 0.051 mmol), 3-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-1,2,4-thiadiazole-5-amine (10 mg, 0.050 mmol), and N-methylimidazole (17 mg, 0.207 mmol) were dissolved in acetonitrile (3 mL), stirred at 70°C for 5 minutes, and then N,N,N',N'-tetramethylformamidinium hexafluorophosphate (22 mg, 0.078 mmol) was added to the reaction mixture to dissolve it completely, and then the reaction mixture was allowed to react at 70°C for 1 hour. The reaction mixture was filtered and purified by preparative HPLC to obtain the title compound (1.29 mg, white solid, yield 4.4%). 1 H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 9.00 (s, 1H), 8.51 (s, 1H), 8.07 (s, 1H), 7.86 (m, 1H), 7.73 (s, 1H), 7.61 - 7.52 (m, 1H), 7.00 (t, J = 55.1 Hz, 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] + .

[0299] Example 26: 2''-Chloro-N-(3-(1,4-dimethyl-1H-pyrazole-5-yl)-1,2,4-thiadiazole-5-yl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0300] Procedure 1: 3-(1,4-dimethyl-1H-pyrazole-5-yl)-1,2,4-thiadiazole-5-yl tert-butylcarbamate Under nitrogen protection, (3-bromo-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (100 mg, 0.357 mmol), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-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 mixture was allowed to react for 16 hours with stirring at 90°C. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10-20% ethyl acetate) to obtain the title compound (white solid, 100 mg, yield 94.9%). LC / MS (ESI) m / z: 296.2 [M+H] + .

[0301] Step 2: 3-(1,4-dimethyl-1H-pyrazole-5-yl)-1,2,4-thiadiazole-5-amine hydrochloride 3-(1,4-dimethyl-1H-pyrazole-5-yl)-1,2,4-thiadiazole-5-yl tert-butylcarbamate (100 mg, 0.339 mmol) was dissolved in 4N dioxane hydrochloride solution (5 mL), and the reaction mixture was allowed to react at room temperature with stirring for 16 hours. The reaction mixture was concentrated under reduced pressure and slurryed with ethyl acetate to obtain the title compound (70 mg, pale yellow solid, yield 89.2%). LC / MS (ESI) m / z: 196.1 [M+H] + .

[0302] Step 3: 2''-Chloro-N-(3-(1,4-dimethyl-1H-pyrazole-5-yl)-1,2,4-thiadiazole-5-yl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide At room temperature, 2''-chloro-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (30 mg, 0.080 mmol), 3-(1,4-dimethyl-1H-pyrazole-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). The mixture was stirred at 70°C for 5 minutes, and then N,N,N',N'-tetramethylformamidinium hexafluorophosphate (45 mg, 0.160 mmol) was added to the reaction mixture. The reaction mixture was then allowed to react at 70°C for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to obtain the title compound (8.06 mg, white solid, yield 18.3%). 1 H NMR (400 MHz, DMSO-d6) δ 13.98 (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] + .

[0303] Example 27: N-(3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0304] Procedure 1: 3-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide)-1,2,4-thiadiazole-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate tert-butyl ester Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide (150 mg, 0.271 mmol) was dissolved in a solution of anhydrous 1,4-dioxane (5 mL), and 3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester was added to the reaction mixture. Ter (108 mg, 0.545 mmol), cesium carbonate (353 mg, 1.08 mmol), and [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (12 mg, 0.014 mmol) were added, and the reaction mixture was reacted under nitrogen protection at 130°C for 1 hour. After filtering the mixture, it was 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] + .

[0305] Step 2: N-(3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide Under ice water bath, 3-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide)-1,2,4-thiadiazole-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (35 mg, 0.052 mmol) was dissolved in dichloromethane (2.5 mL) solution, and trifluoroacetic acid (0.5 mL) was added to the reaction mixture. The mixture was then heated to room temperature and reacted with stirring for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O solution and 0.1% FA) to obtain the title compound (13.42 mg, pale yellow solid, yield 45.1%). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (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 = 55.1 Hz, 1H), 6.47 - 6.39 (m, 1H), 4.35 (d, J = 6.3 Hz, 2H), 3.97 - 3.88 (m, 4H), 3.69 (s, 3H), 2.88 - 2.79 (m, 1H), 1.84 (d, J = 10.0 Hz, 1H).LC / MS (ESI) (m / z): 571 [M+H] + .

[0306] Example 28: N-(3-(3-azabicyclo[3.1.0]hexa-3-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka] Procedure 1: N-(3-(3-azabicyclo[3.1.0]hexa-3-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide Under nitrogen protection, N-(3-bromo-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide (50 mg, 0.09 mmol) was dissolved in anhydrous dioxane (3 mL) solution, and 3-azabicyclo[3.1.0]hexane hydrochloride (22 mg, 0.18 mL) was sequentially added to the reaction mixture. Adding 118 mg, 0.36 mmol of palladium(II) palladium(II) methanesulfonate (2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl) to 4 mg, 0.005 mmol of palladium(II) palladium(II) methanesulfonate, the reaction mixture was allowed to react under nitrogen protection at 110°C with stirring for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 30-100% methanol in H2O solution and 0.1% FA) to obtain the title compound (white solid, 1.52 mg, yield 3.0%). 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.00 (s, 1H), 8.51 (s, 1H), 8.07 (s, 1H), 7.89 - 7.82 (m, 1H), 7.73 (s, 1H), 7.60 - 7.53 (m, 1H), 7.00 (t, J = 55.0 Hz, 1H), 6.46 - 6.38 (m, 1H), 3.73 - 3.70 (m, 1H), 3.69 (s, 3H), 3.68 - 3.66 (m, 1H), 3.49 - 3.45 (m, 2H), 1.67 - 1.59 (m, 2H), 0.75 - 0.66 (m, 1H), 0.23 - 0.17 (m, 1H). LC / MS (ESI) (m / z): 556 [M+H] + .

[0307] Example 29: 2''-(difluoromethyl)-3-fluoro-5''-methoxy-N-(3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,2,4-thiadiazole-5-yl)-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0308] Procedure 1: 2''-(difluoromethyl)-3-fluoro-5''-methoxy-N-(3-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,2,4-thiadiazole-5-yl)-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide At room temperature, N-(3-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide (10 mg, 0.018 mmol) was dissolved in methanol (3 mL), polyacetal (2 mg, 0.067 mmol) and acetic acid (1 drop) were added to the reaction mixture, and the mixture was reacted at room temperature with stirring for 1 hour. Then, sodium triacetoxyborohydride (3 mg, 0.048 mmol) was added to the reaction mixture, and the mixture was reacted at 50°C with stirring for a further 16 hours. After filtering the reaction mixture, it was purified by preparative HPLC (YMC-Actus Triart C18 250*21mm, 30-100% methanol-based H2O solution and 0.1% FA) to obtain the title compound (3.60 mg, white solid, yield 35.1%). 1 H NMR (400 MHz, CDCl3) δ 10.93 (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 = 55.5 Hz, 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 = 10.0 Hz, 1H). LC / MS (ESI) (m / z): 585 [M+H] + .

[0309] Example 30: N-(3-amino-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0310] Step 1: (5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide)-1,2,4-thiadiazole-3-yl)benzylcarbamate Under nitrogen protection, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (78.2 mg, 0.20 mmol), (5-amino-1,2,4-thiadiazole-3-yl)benzylcarbamate (50 mg, 0.20 mmol), and N-methylimidazole (65.6 mg, 0.78 mmol) were dissolved in anhydrous acetonitrile (2 mL), stirred at 70°C for 5 minutes, and then N,N,N',N'-tetramethylformamidinium hexafluorophosphate (84.1 mg, 0.30 mmol) was added to the reaction mixture, and the reaction mixture was allowed to react at 70°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-3% methanol) to obtain the title compound (white solid, 75 mg, yield 60%). LC / MS(ESI) m / z: 624.3[M+H] + .

[0311] Step 2: N-(3-amino-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide At room temperature, trifluoroacetic acid (2 mL) was added to a flask containing (5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide)-1,2,4-thiadiazole-3-yl)benzylcarbamate (70 mg, 0.11 mmol), and the reaction mixture was allowed to react at 80°C with stirring for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the trifluoroacetic acid was removed. The residue was diluted with ethyl acetate, and the saturated sodium bicarbonate aqueous solution was adjusted to pH=8. Next, the aqueous phase was extracted with ethyl acetate, the organic phase was 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 solution containing 0.1% FA in H2O) to obtain the title compound (white solid, 6 mg, yield 33%). 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.74 (s, 1H), 7.62 - 7.46 (m, 1H), 7.00 (t, J = 55.0 Hz, 1H), 6.48 - 6.29 (m, 3H), 3.70 (s, 3H). LC / MS (ESI) (m / z): 490 [M+H] + .

[0312] Example 31: N-(3-acetamido-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0313] Step 1: N-(3-acetamido-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide Under nitrogen protection, N-(3-amino-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide (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 2-(7-azabenzotriazole)-N,N,N'',N''-tetramethyluronium hexafluorophosphate (17.5 mg, 0.046 mmol) was added. The reaction mixture was allowed to react for 1 hour with stirring at room temperature. The reaction mixture was filtered, and the filtrate was separated and purified by HPLC (Welch XBridge C18 250*21mm, 10-95% acetonitrile solution containing 0.1% FA in H2O) to obtain the title compound (white solid, 7 mg, yield 43%). 1 H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 10.88 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.60 - 7.52 (m, 1H), 7.01 (t, J = 55.1 Hz, 1H), 6.45 - 6.40 (m, 1H), 3.68 (s, 3H), 2.12 (s, 3H). LC / MS (ESI) (m / z): 532 [M+H] + .

[0314] Example 32: 2''-(difluoromethyl)-N-(3-(1,4-dimethyl-1H-imidazo-5-yl)-1,2,4-thiadiazole-5-yl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide [ka]

[0315] Step 1: (3-(methoxy(methyl)carbamoyl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate At room temperature, 5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazole-3-carboxylic acid (600 mg, 2.45 mmol, crude product), dimethylhydroxylamine (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). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (701.6 mg, 3.67 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the mixture was stratified. 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 obtain the title compound (white solid, 450 mg, yield 64%). LC / MS(ESI)(m / z):289[M+H] + .

[0316] Step 2: (3-propionyl-1,2,4-thiadiazole-5-yl)tert-butylcarbamate Under nitrogen protection, (3-(methoxy(methyl)carbamoyl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (450 mg, 1.56 mmol) was dissolved in tetrahydrofuran (5 mL). The reaction mixture was cooled to -78°C, and 1.0 M ethylmagnesium bromide (2.0 mL, 2.03 mmol) was slowly added dropwise. The reaction mixture was continued at -78°C with stirring for 1 hour. The reaction mixture was quenched at 0°C with saturated ammonium chloride aqueous solution and extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0-50% ethyl acetate) to obtain the title compound (white solid, 160 mg, yield 40%). LC / MS(ESI)(m / z):258[M+H] + .

[0317] Step 3: (Z)-(3-(2-(hydroxyimino)propionyl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate Under nitrogen protection, (3-propionyl-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (250 mg, 0.97 mmol) and trimethylchlorosilane (126.7 mg, 1.17 mmol) were dissolved in anhydrous dichloromethane (5 mL). The reaction mixture was cooled to -20°C, amyl nitrite (136.6 mg, 1.17 mmol) was added, and the mixture was heated to room temperature and reacted with stirring for 16 hours. Dichloromethane and water were added to the reaction mixture to separate the organic phase. The mixture was 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] + .

[0318] Step 4: 5-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazole-3-yl)-1,4-dimethyl-1H-imidazolium 3-oxide At room temperature, (Z)-(3-(2-(hydroxyimino)propionyl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (50 mg, 0.175 mmol) was added to a flask containing anhydrous ethanol (3 mL), and 1,3,5-trimethylhexahydro-1,3,5-triazine (67.6 mg, 0.524 mmol) was added at room temperature. The reaction mixture was allowed to react under reflux with stirring for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (yellow solid, 50 mg, crude product, 100% yield). LC / MS (ESI) m / z: 312 [M+H] + .

[0319] Step 5: (3-(1,4-dimethyl-1H-imidazo-5-yl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate Under nitrogen protection, 5-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazole-3-yl)-1,4-dimethyl-1H-imidazolium 3-oxide (50 mg, 0.161 mmol) was dissolved in anhydrous methanol (1 mL), and Raney nickel (10 mg) was added under nitrogen protection. The reaction mixture was purged three times with nitrogen gas and reacted at room temperature under a hydrogen atmosphere of 1 atm for 1 hour with stirring. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (brown oily substance, 26 mg, yield 55%). LC / MS (ESI) m / z: 296.3 [M+H] + .

[0320] Step 6: 3-(1,4-dimethyl-1H-imidazo-5-yl)-1,2,4-thiadiazole-5-amine At room temperature, (3-(1,4-dimethyl-1H-imidazo-5-yl)-1,2,4-thiadiazole-5-yl)tert-butylcarbamate (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 bath. The reaction mixture was allowed to react for 1 hour with stirring at room temperature. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid was removed, diluted with water, and the pH was adjusted to 8 using saturated sodium bicarbonate aqueous solution. The mixture was then 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 oily substance, 15 mg, yield 87%). LC / MS(ESI) m / z: 196.3[M+H] + .

[0321] Procedure 7: 2''-(difluoromethyl)-N-(3-(1,4-dimethyl-1H-imidazo-5-yl)-1,2,4-thiadiazole-5-yl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide Under nitrogen protection, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (30 mg, 0.077 mmol), 3-(1,4-dimethyl-1H-imidazo-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), stirred at 70°C for 5 minutes, and then N,N,N',N'-tetramethylformamidinium hexafluorophosphate (32.3 mg, 0.12 mmol) was added to the reaction mixture, and the reaction mixture was allowed to react at 70°C for 1 hour. The reaction mixture was filtered, and the filtrate was separated and purified by HPLC (Welch XBridge xb 5um 21.2*250mm, H2O solution of 30-95% methanol containing 0.1% TFA) to obtain the title compound (white solid, 0.4 mg, yield 0.92%). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 8.13 (s, 1H), 7.88 (d, J = 7.1 Hz, 1H), 7.79 (s, 1H), 7.64 - 7.54 LC / MS (ESI) (m / z): 569 [M+H] + .

[0322] Example 33: N-(3-cyclobutyl-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-bipyridine]-5'-formamide [ka]

[0323] Step 1: 3-Cyclobutyl-1,2,4-thiadiazole-5-amine At room temperature, sodium thiocyanate (196 mg, 2.41 mmol) was dissolved in methanol (30 mL). The mixture was cooled to -20°C, and triethylamine (0.31 mL, 2.23 mmol) and cyclobutamethaneamide hydrochloride (250 mg, 1.86 mmol) were added sequentially. The mixture was then reacted at -20°C with stirring for 45 minutes, and triethylamine (0.26 mL, 1.86 mmol) was added, followed by the dropwise addition of 8% sodium hypochlorite aqueous solution (1.73 g, 1.86 mmol). The mixture was then reacted at -20°C with stirring for another 2 hours, after which it was raised to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined and sequentially washed with water and saturated brine. The mixture was concentrated under reduced pressure, and 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] + .

[0324] Step 2: N-(3-cyclobutyl-1,2,4-thiadiazole-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-formamide At room temperature, 3-cyclobutyl-1,2,4-thiadiazole-5-amine (15 mg, 0.097 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (38 mg, 0.097 mmol), N-methylimidazole (48 mg, 0.58 mmol), and acetonitrile (2 mL) were added to a reaction flask and stirred at 70°C for 1 minute. Then, a solution of N,N,N',N'-tetramethylformamidinium hexafluorophosphate (54 mg, 0.19 mmol) in acetonitrile (1 mL) was added to the reaction mixture, and the mixture was reacted at 70°C for 1 hour. After filtering the mixture, it was purified by preparative HPLC (YMC-Actus Triart C18 250*21mm, 10-100% acetonitrile H2O solution containing 0.1% FA) to obtain the title compound (15 mg, white solid, yield 29%). 1 H NMR (400 MHz, DMSO-d6) δ 13.76 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.76 (s, 1H), 7.61 - 7.53 (m, 1H), 7.01 (t, J = 55.0 Hz, 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] + .

[0325] Examples of effects Test method: 1. Polθ inhibitor biochemical activity assay (ADP Glo assay) The N-terminus of the Polθ protein contains a deconjugase structure domain with ATPase activity that hydrolyzes ATP to ADP, and is used in the ADP-Glo ​​assay kit (ADP-Glo TMThe kinase assay (Promega, V9102) allows for the analysis of the ATPase activity of Polθ protein and the inhibitory effects of small molecule compounds on the protein. The specific assay procedure is as follows: 1) The deconjugase structural domain of the Polθ protein was purified using an insect system to obtain a protein with a purity of over 90%. ssDNA (5'-CCAGTGAATTGTTGCTCGGTACCTGCTAAC-3', Hangzhou Youkang Biotechnology Co., Ltd.) was purchased as the substrate for the Polθ protein. A reaction buffer containing 10 mM DTT (Dithiothreitol), 20 mM MgCl2, and Tris-HCl pH 7.5 was prepared. 2) A 2xssDNA-Polθ premix was prepared, and the reaction was carried out in a 384-well plate. A control group containing only buffer was prepared, and the premix was added to each of the other groups. The compounds were added using an automated pipette (Thermo, Multidrop 8), with a starting concentration of 10 μM. The mixture was diluted to a 1 / 3 dilution ratio, and nine assay points were set. Two of these points were repeated for each group. 3) Prepare a 2x ATP solution, add an equal volume of the 2x ATP solution to all wells, and let stand at room temperature for 60 minutes. 4) Following the instructions for the Promega reagent, the ADP-Glo ​​detection reagent was added to the reaction system and allowed to stand at room temperature for 60 minutes. 5) Following the instructions for the Promega reagent, the kinase detection reagent was added to the reaction system and allowed to stand at room temperature for 60 minutes. The chemiluminescence signal was detected using a microplate reader (Thermo, Varioskan LUX), and the time interval for readings in each well was set to 1000 ms.

[0326] Data analysis of the measurement results was performed. The CV% of the assay results for the control group was defined as less than 10%, and the z' value was defined as greater than 0.5. Using the data that met the above quality control criteria, the inhibition rate of the compound was calculated (inhibition rate (%) = 100 * (mean value of control group - test group) / (mean value of control group - mean value of buffer control group)). The inhibition rate curve of the compound was fitted using nonlinear regression with GraphPad Prism8, and IC was calculated. 50 Values ​​were obtained. The results are shown in Table 3.

[0327] 2. Polθ inhibitor cell viability assay The in vitro efficacy of the inhibitor was evaluated using a cell viability assay, specifically a CTG assay, using CellTiter Glo reagent (Promega, G7573). The specific assay procedure is as follows: 1) DLD1 wild-type (ATCC, CCL-221) and DLD1 BRCA2- / - cells were cultured. One day before the start of the assay, the cells were digested with trypsin (0.025% Trypsin-EDTA, Hyclone), centrifuged at 1000 rpm for 3 minutes, and then harvested. The cells were counted using a counter (Shanghai Mengwei Biomedical Technology Co., Ltd., SmartCell600A.SC1006) and inoculated into 96-well white culture plates at the appropriate inoculation ratio. 2) 24 hours after plating the cells, the drug was added, marking Day 0. The compound was added using an automated pipette (Thermo, Multidrop 8), the plate was set to a 96-well plate, the starting concentration was 30 μM, diluted to a 1 / 3 dilution ratio, nine assay points were set, and two points were repeated for each group. The cells were incubated at 37°C in a 5% CO2 incubator. 3) The solution was changed twice on Day 3 and Day 7, and the compound was added according to Procedure 2. 4) On Day 10, the cell culture plate was removed, an equal volume of CTG reagent (pre-mixed according to the reagent instructions, after returning the CTG reagent to its original temperature), and the mixture was homogenized for 10 minutes (speed 300) in a constant temperature homogenizer (Hangzhou Aoseng Instruments Co., Ltd., MSC-100). The chemiluminescence signal was detected using a microplate reader (Thermo, Varioskan LUX). 5) Data analysis of the measurement results was performed. The CV% of the assay results for the control group was defined as less than 20%, and the z' value was defined as greater than 0.5. Using the data that met the above quality control criteria, cell viability was calculated (inhibition rate (%) = 100 * (mean value of control group - test group) / (mean value of control group - mean value of culture medium control group)). The inhibition rate curves of the compounds were fitted using nonlinear regression with GraphPad Prism8, and IC was obtained. 50 Values ​​were obtained. The results are shown in Table 3.

[0328] Assays showed that the compounds in the examples of the present application had a strong inhibitory effect on the proliferation of DLD1 BRCA2- / - cells, but a very weak inhibitory effect on the proliferation of DLD1 wild-type cells, demonstrating that the compounds in the examples of the present application have excellent selectivity in inhibiting the proliferation of these two types of cells.

[0329] Data list: NT=Not detected [Table 3]

Claims

1. A compound represented by formula I, a pharmaceutically acceptable salt thereof, or an isotopic compound thereof, 【Chemistry 1】 Here, m and n are independently 0, 1, 2, 3, or 4. X １ and X ４ Independently, N or CR ａ And, X ２ and X ３ These are independently N or CH, Each R ａ is, independently, hydrogen, halogen, CN, OH, deuterium, cyano group, -NHR ｆ , -C(O)NHR ｇ , an unsubstituted or one or more R １－１ substituted C １－６ alkyl group, or an unsubstituted or one or more R １－２ substituted C １－６ alkoxy group, and Each R １－１ and R １－２ It is, independently, a halogen, R １ It contains deuterium, cyano group, hydroxyl group, halogen, amino group, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 2】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , -C(O)N(R ｍ ) ２ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, R ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ and R ｍ These are independently, unsubstituted or one or more R １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, 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 These are independently deuterium, halogen, and C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And, Each R ２ is independently deuterium, a halogen, a cyano group, an amino group, a hydroxy group, unsubstituted or substituted by one or more R ２－１ substituted C １－６ alkyl group, unsubstituted or substituted by one or more R ２－２ substituted C １－６ alkoxy group, unsubstituted or substituted by one or more R ２－３ substituted C ２－６ alkenyl group, unsubstituted or substituted by one or more R ２－４ substituted C ２－６ alkynyl group, unsubstituted or substituted by one or more R ２－５ substituted C ３－１０ cycloalkyl group, unsubstituted or substituted by one or more R ２－６ substituted 3- to 12-member heterocycloalkyl group, unsubstituted or substituted by one or more R ２－１３ substituted 4- to 12-member heterocycloalkenyl group, -COOR ２－７ , -C(O)R ２－８ , -C(O)N(R ２－９ ) ２ , 【Transformation 3】 , or N(R ２－１２ ) ２ And, Each R ２－１ , R ２－２ , R ２－３ , R ２－４ , R ２－５ , R ２－６ and R ２－１３ is independently deuterium, a hydroxy group, a cyano group, or a halogen, Each R ２－７ , R ２－８ , R ２－９ and R ２－１２ These are, independently, hydrogen, or C １－６ It is an alkyl group, Each R ２－１０ and R ２－１１ These are independently a hydroxyl group, or C １－６ It is an alkyl group, Each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－２ C is replaced by ２－６ Alkenyl group, unsubstituted or one or more R ３－３ C is replaced by ２－６ Alkynyl group, unsubstituted or one or more R ３－４ C is replaced by ３－６ Cycloalkyl groups, unsubstituted or one or more R groups ３－５ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups ３－６ A 5- to 12-membered heteroaryl group substituted by, an -O-5 to 12-membered heteroaryl group, or an unsubstituted or one or more R groups ３－１０ C is replaced by ６－１２ Aryl group, -N(R ３－７ ) ２ ,or 【Chemistry 4】 And, Each R ３－１ , R ３－２ and R ３－３ These are independently, unsubstituted or one or more R ３－１－１ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－１－２ A 5- to 12-membered heteroaryl group substituted by, 【Transformation 5】 And, Each R ３－４ , R ３－５ and R ３－９ These are independently oxo groups, halogens, cyano groups, hydroxyl groups, and unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－５－２ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R ３－５－５ C is replaced by ３－６ Cycloalkyl groups, unsubstituted or one or more R groups ３－５－６ 3- to 12-membered heterocycloalkyl groups substituted by -N(R ３－５－３ ) ２ , 【Transformation 6】 And, Each R ３－６ and R ３－１０ These are independently oxo groups, halogens, cyano groups, hydroxyl groups, and unsubstituted or one or more R groups. ３－６－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－５－２ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R ３－５－５ C is replaced by ３－６ Cycloalkyl groups, unsubstituted or one or more R groups ３－６－２ 3- to 12-membered heterocycloalkyl groups substituted by -N(R ３－６－３ ) ２ , 【Transformation 7】 And, Each R ３－７ These are independently hydrogen, unsubstituted or one or more R atoms. ３－７－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－８－１ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－７－２ A 5- to 12-membered heteroaryl group substituted by, 【Transformation 8】 And, Each R ３－８ These are independently, unsubstituted or one or more R ３－７－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－８－１ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－７－２ A 5- to 12-membered heteroaryl group substituted by, 【Chemistry 9】 And, Each R ３－１－１ and R ３－１－２ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, Each R ３－１－３ These are independently, unsubstituted or one or more R ３－１－３－１ A 3- to 12-membered heterocycloalkyl group substituted by, Each R ３－１－３－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, Each R ３－４－１ , R ３－５－３ and R ３－６－３ These are, independently, hydrogen, or C １－６ It is an alkyl group, Each R ３－５－１ , R ３－５－２ and R ３－７－１ These are independently deuterium, a hydroxyl group, a cyano group, or a halogen. Each R ３－５－４ and R ３－７－３ Independently, C １－６ alkyl group, or C ３－６ It is a cycloalkyl group, Each R ３－５－５ , R ３－５－６ and R ３－６－２ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, Each R ３－６－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkoxy group, Each R ３－７－２ and R ３－８－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, In each of the 3-12 member heterocycloalkyl groups, 4-12 member heterocycloalkenyl groups, 5-12 member heteroaryl groups, and -O-5-12 member heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. A compound, its pharmaceutically acceptable salt, or its isotopic compounds.

2. R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 10】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , -C(O)N(R ｍ ) ２ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, 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 These are, independently, halogen, C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And, Preferably, the compound represented by formula I is (1) Each R ａ In this, the halogen is independently fluorine, chlorine, bromine, or iodine. (2) Each R ａ In this case, the unsubstituted or one or more R １－１ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. (3) Each R ａ In this case, the unsubstituted or one or more R １－２ C is replaced by １－６ C in an alkoxy group １－６ The alkoxy group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group. (4) Each R １－１ and R １－２ In this, the halogen is independently fluorine, chlorine, bromine, or iodine. (5) Caution １ In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine, and more specifically, fluorine. (6) R １ In this case, the unsubstituted or one or more R １－３ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example a methyl group, an n-propyl group, an isopropyl group, or a tert-butyl group, and further for example a methyl group, an isopropyl group, or a tert-butyl group. (7) R １ In this case, the unsubstituted or one or more R １－４ C is replaced by １－６ C in an alkoxy group １－６ The alkoxy group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, for example, a methoxy group. (8) R １ In this case, the unsubstituted or one or more R １－５ C is replaced by ３－１０ C in cycloalkyl groups ３－１０ The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group or a cyclobutyl group, and more specifically, a cyclopropyl group. (9) Caution １ In this case, the unsubstituted or one or more R １－６ The 3-12 member heterocycloalkyl groups substituted by are independently 5-8 member heterocycloalkyl groups. (10) R １ In this case, the unsubstituted or one or more R １－６ In the 3- to 12-membered heterocycloalkyl groups substituted by, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups are independently N and / or O. (11) R １ In this case, the unsubstituted or one or more R １－６ The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is independently one or two, for example, two. (12) R １ In this case, the unsubstituted or one or more R １－６ In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently monocyclic, crosslinked, fused, or spirocyclic rings. The number of rings in the spiro ring, fused ring, or bridging ring may be two. The spiro ring may be a 3-membered spiro-5-membered heterocyclyl group, a 3-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-4-membered heterocyclyl group, a 4-membered spiro-5-membered heterocyclyl group, a 4-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-7-membered heterocyclyl group, a 5-membered spiro-4-membered heterocyclyl group, a 5-membered spiro-5-membered heterocyclyl group, a 5-membered spiro-6-membered heterocyclyl group, a 5-membered spiro-7-membered heterocyclyl group, a 6-membered spiro-4-membered heterocyclyl group, a 6-membered spiro-5-membered heterocyclyl group, or a 6-membered spiro-6-membered heterocyclyl group, for example, a 4-membered spiro-4-membered heterocyclyl group. The condensed ring may be in the following scheme 1 or scheme 2: Scheme 1: The condensed ring is a 4-membered condensed 5-membered heterocyclyl group, a 4-membered condensed 6-membered heterocyclyl group, a 5-membered condensed 5-membered heterocyclyl group, a 5-membered condensed 6-membered heterocyclyl group, or a 6-membered condensed 6-membered heterocyclyl group, for example, a 5-membered condensed 5-membered heterocyclyl group. Scheme 2: The condensed ring is a 3-membered condensed 5-membered heterocyclyl group, a 4-membered condensed 5-membered heterocyclyl group, a 4-membered condensed 6-membered heterocyclyl group, a 5-membered condensed 5-membered heterocyclyl group, a 5-membered condensed 6-membered heterocyclyl group, or a 6-membered condensed 6-membered heterocyclyl group, for example, a 3-membered condensed 5-membered heterocyclyl group or a 5-membered condensed 5-membered heterocyclyl group. The aforementioned crosslinking ring may be a 4-membered crosslinked 5-membered heterocyclyl group, a 4-membered crosslinked 6-membered heterocyclyl group, a 5-membered crosslinked 6-membered heterocyclyl group, or a 6-membered crosslinked 6-membered heterocyclyl group, for example, a 4-membered crosslinked 6-membered heterocyclyl group. (13) R １ In this case, the unsubstituted or one or more R １－７ C is replaced by ６－１２ C in aryl group ６－１２ The aryl group is independently a phenyl group or a naphthyl group; for example, it is a phenyl group. (14) R １ In this case, the unsubstituted or one or more R １－８ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is monocyclic. (15) R １ In this case, the unsubstituted or one or more R １－８ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is independently a 5-6 membered heteroaryl group. (16) R １ In this case, the unsubstituted or one or more R １－８ In a 5-12 membered heteroaryl group substituted by, the heteroatom of the 5-12 membered heteroaryl group is N and / or O, for example, N. (17) R １ In this case, the unsubstituted or one or more R １－８ The number of heteroatoms in the 5-12 membered heteroaryl group substituted by is one or two. (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 In this case, the unsubstituted or one or more R １－９ C is replaced by ３－１０ C in cycloalkyl groups ３－１０ The cycloalkyl group is independently a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, for example, a cyclopropyl group. (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 In this case, the unsubstituted or one or more R １－１０ In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl groups are independently monocyclic, crosslinked, or fused rings. The number of rings in the aforementioned condensed ring or bridging ring may be two. The fused ring may be a 4-membered fused 5-membered heterocyclyl group, a 4-membered fused 6-membered heterocyclyl group, a 5-membered fused 5-membered heterocyclyl group, a 5-membered fused 6-membered heterocyclyl group, or a 6-membered fused 6-membered heterocyclyl group, for example, a 5-membered fused 5-membered heterocyclyl group. The aforementioned crosslinking ring may be a 4-membered crosslinked 5-membered heterocyclyl group, a 4-membered crosslinked 6-membered heterocyclyl group, a 5-membered crosslinked 6-membered heterocyclyl group, or a 6-membered crosslinked 6-membered heterocyclyl group, for example, a 4-membered crosslinked 6-membered heterocyclyl 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 In this case, the unsubstituted or one or more R １－１０ The 3-12 member heterocycloalkyl groups substituted by are independently 4-8 member heterocycloalkyl groups. (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 In this case, the unsubstituted or one or more R １－１０ In the 3- to 12-membered heterocycloalkyl groups substituted by, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups 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 In this case, the unsubstituted or one or more R １－１０ The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group substituted by is independently one or two. (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 In this case, the unsubstituted or one or more R １－１１ C is replaced by ６－１２ C in aryl group ６－１２ The aryl group is independently a phenyl group or a naphthyl group; for example, it is a phenyl group. (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 In this case, the unsubstituted or one or more R １－１２ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is monocyclic. (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 In this case, the unsubstituted or one or more R １－１２ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is independently a 5-6 membered heteroaryl group. (26) R ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ and R ｋ In this case, the unsubstituted or one or more R １－１２ In the 5-12 membered heteroaryl group substituted by the above, the heteroatom of the 5-12 membered heteroaryl group is nitrogen. (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 In this case, the unsubstituted or one or more R １－１２ The number of heteroatoms in the 5-12 membered heteroaryl group substituted by is either 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 In this case, the unsubstituted or one or more R １－１３ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group. (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 In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, 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 case of C １－６ Alkyl alkyl group, the aforementioned -S(O) ２ C １－６ C in alkyl groups １－６ Alkyl alkyl groups and the -P(O)(C １－６ (Alkyl group) ２ C in １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group. (31) R １ In this case, each plurality is either two or three, for example, two. (32) Each R ２ In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. (33) Each R ２ In this case, the unsubstituted or one or more R ２－１ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group. (34) Each R ２ In this case, each plurality is either two or three, for example, two. (35) Each R ２ In this case, the unsubstituted or one or more R ２－２ C is replaced by １－６ C in an alkoxy group １－６ The alkoxy group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, or a tert-butoxy group, for example, a methoxy group. (36) Each R ２－１ and R ２－２ In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine. (37) Each R ３ In this case, the unsubstituted or one or more R ３－１ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group, for example, a methyl group. (38) Each R ３ In this case, the unsubstituted or one or more R ３－９ The 4-12 member heterocycloalkenyl group substituted by is either a monocyclic or fused ring. The number of rings in the aforementioned fused ring may be two. The fused ring may be a 4-membered fused 5-membered heterocycloalkenyl group, a 4-membered fused 6-membered heterocycloalkenyl group, a 5-membered fused 5-membered heterocycloalkenyl group, a 5-membered fused 6-membered heterocycloalkenyl group, or a 6-membered fused 6-membered heterocycloalkenyl group, for example, a 5-membered fused 6-membered heterocycloalkenyl group. (39) Each R ３ In this case, the unsubstituted or one or more R ３－９ The 4-12 member heterocycloalkenyl group substituted by is independently a 5-9 member heterocycloalkenyl group, for example, a 5-6 member heterocycloalkenyl group. (40) Each R ３ In this case, the unsubstituted or one or more R ３－９ In the 4-12 member heterocycloalkenyl group substituted by the above, the heteroatom of the 4-12 member heterocycloalkenyl group is N. (41) Each R ３ In this case, the unsubstituted or one or more R ３－９ The number of heteroatoms in a 4- to 12-membered heterocycloalkenyl group substituted by is one or two, for example, one. (42) Each R ３ In this case, the unsubstituted or one or more R ３－９ The number of double bonds in the 4-12 member heterocycloalkenyl group substituted by is one or two, for example, two. (43) Each R ３ In this case, the unsubstituted or one or more R ３－３ C is replaced by ２－６ C in the alkynyl group ２－６ The alkynyl group is independently an ethynyl group, a propynyl group, or a propargyl group; for example, it is an ethynyl group. (44) Each R ３ In this case, the unsubstituted or one or more R ３－５ In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl groups are independently either a crosslinking ring or a spiro ring. The number of rings in the spiro ring or crosslinking ring may be two, and the spiro ring may be a 3-membered spiro-5-membered heterocyclyl group, a 3-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-4-membered heterocyclyl group, a 4-membered spiro-5-membered heterocyclyl group, a 4-membered spiro-6-membered heterocyclyl group, a 4-membered spiro-7-membered heterocyclyl group, a 5-membered spiro-4-membered heterocyclyl group, a 5-membered spiro-5-membered heterocyclyl group, a 5-membered spiro-6-membered heterocyclyl group, a 5-membered spiro-7-membered heterocyclyl group, a 6-membered spiro-4-membered heterocyclyl group, a 6-membered spiro-5-membered heterocyclyl group, or a 6-membered spiro-6-membered heterocyclyl group, for example, a 3-membered spiro-6-membered heterocycloalkyl group. The aforementioned crosslinking ring may be a 4-membered crosslinked 5-membered heterocycloalkyl group, a 4-membered crosslinked 6-membered heterocycloalkyl group, a 5-membered crosslinked 6-membered heterocycloalkyl group, or a 6-membered crosslinked 6-membered heterocycloalkyl group, for example, a 4-membered crosslinked 6-membered heterocycloalkyl group. (45) Each R ３ In this case, the unsubstituted or one or more R ３－５ The 3-12 member heterocycloalkyl groups substituted by are independently 6-8 member heterocycloalkyl groups. (46) Each R ３ In this case, the unsubstituted or one or more R ３－５ In the 3- to 12-membered heterocycloalkyl groups substituted by the above, the heteroatom of the 3- to 12-membered heterocycloalkyl group is nitrogen. (47) Each R ３ In this case, the unsubstituted or one or more R ３－５ The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group substituted by is independently one or two. (48) Each R ３ In this case, the unsubstituted or one or more R ３－５ In the 3-12 member heterocycloalkyl group substituted by, the 3-12 member heterocycloalkyl group is a 6-8 member heterocycloalkyl group, the heteroatom of the 6-8 member heterocycloalkyl group is N, and the number of heteroatoms is one or two, for example, 【Chemistry 11】 Being (49) Each R ３ In this case, the unsubstituted or one or more R ３－１０ C is replaced by ６－１２ C in aryl group ６－１２ The aryl group is either a phenyl group or a naphthyl group; for example, it is a phenyl group. (50) Each R ３ In this case, the unsubstituted or one or more R ３－６ The 5-12 membered heteroaryl group substituted by is either a monocyclic or fused ring. The number of rings in the aforementioned fused ring may be two. (51) Each R ３ In this case, the unsubstituted or one or more R ３－６ The 5-12 membered heteroaryl group substituted by is a 5-9 membered heteroaryl group. (52) Each R ３ In this case, the unsubstituted or one or more R ３－６ In the 5-12 membered heteroaryl group substituted by, the heteroatoms of the 5-12 membered heteroaryl group are N and / or O. (53) Each R ３ In this case, each plurality is either two or three, for example, two. (54) Each R ３－１ and R ３－３ In this case, the unsubstituted or one or more R ３－１－１ The 3-12 member heterocycloalkyl group substituted by is monocyclic. (55) Each R ３－１ and R ３－３ In this case, the unsubstituted or one or more R ３－１－１ The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group. (56) Each R ３－１ and R ３－３ In this case, the unsubstituted or one or more R ３－１－１ In the 3- to 12-membered heterocycloalkyl groups substituted by, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups are N and / or O, for example, O. (57) Each R ３－１ and R ３－３ In this case, the unsubstituted or one or more R ３－１－１ The number of heteroatoms in the 3- to 12-membered heterocycloalkyl group substituted by is one or two, for example, one. (58) Each R ３－５ and R ３－９ In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine or chlorine. (59) Each R ３－５ and R ３－９ In this case, the unsubstituted or one or more R ３－５－１ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, for example, a methyl group. (60) Each R ３－５ and R ３－９ In this case, the unsubstituted or one or more R ３－５－１ C is replaced by １－６ C in an alkoxy group １－６ The alkyl group is independently a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, an isobutoxy group, or a tert-butoxy group, for example, a methoxy group. (61) Each R ３－６ and R ３－１０ In this case, the unsubstituted or one or more R ３－６－１ C is replaced by １－６ C in alkyl groups １－６ The alkyl group is independently a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, for example, a methyl group. (62) Each R ３－８ In this case, the unsubstituted or one or more R ３－８－１ The 3-12 member heterocycloalkyl group substituted by is monocyclic. (63) Each R ３－８ In this case, the unsubstituted or one or more R ３－８－１ The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group. (64) Each R ３－８ In this case, the unsubstituted or one or more R ３－８－１ In the 3- to 12-membered heterocycloalkyl groups substituted by, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups are N and / or O. (65) Each R ３－８ In this case, the unsubstituted or one or more R ３－８－１ The number of heteroatoms in a 3- to 12-membered heterocycloalkyl group substituted by is one or two, for example, two. (66) Each R ３－１－３ In this case, the unsubstituted or one or more R ３－１－３－１ In the 3-12 member heterocycloalkyl groups substituted by, the 3-12 member heterocycloalkyl group is monocyclic, (67) Each R ３－１－３ In this case, the unsubstituted or one or more R ３－１－３－１ The 3-12 member heterocycloalkyl group substituted by is a 5-6 member heterocycloalkyl group. (68) Each R ３－１－３ In this case, the unsubstituted or one or more R ３－１－３－１ In the 3- to 12-membered heterocycloalkyl groups substituted by, the heteroatoms of the 3- to 12-membered heterocycloalkyl groups are N and / or O. (69) Each R ３－１－３ In this case, the unsubstituted or one or more R ３－１－３－１ The number of heteroatoms in the 3-12 member heterocycloalkyl group substituted by is one or two, for example, two and (70) Each R ３－５－１ In this, the halogen is independently fluorine, chlorine, bromine, or iodine, for example, fluorine. A compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, or an isotope compound thereof, characterized in that it satisfies one or more of the following conditions.

3. (1) R １ In this case, the unsubstituted or one or more R １－６ In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently 5-8 member heterocycloalkyl groups, the heteroatoms of the 5-8 member heterocycloalkyl groups are N and / or O, and the number of heteroatoms is 1 or 2, for example, 【Chemistry 12】 And furthermore, for example, 【Chemistry 13】 Being (2) R １ In this case, the unsubstituted or one or more R １－８ In a 5-12 membered heteroaryl group substituted by a 5-12 membered heteroaryl group, the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatoms of the 5-6 membered heteroaryl group are N and / or O, and the number of heteroatoms is one or two, for example, 【Chemistry 14】 And preferably, R １ In this case, the unsubstituted or one or more R １－８ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is a 5-6 membered heteroaryl group, the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is one or two, for example, 【Chemistry 15】 Being (3) Caution ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ and R ｍ In this case, the unsubstituted or one or more R １－１０ In the 3-12 member heterocycloalkyl groups substituted by , the 3-12 member heterocycloalkyl groups are independently 4-8 member heterocycloalkyl groups, the heteroatoms of the 4-8 member heterocycloalkyl groups are N and / or O, and the number of heteroatoms is one or two, for example, 【Chemistry 16】 Being (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 In this case, the unsubstituted or one or more R １－１２ In the 5-12 membered heteroaryl group substituted by, the 5-12 membered heteroaryl group is independently a 5-6 membered heteroaryl group, the heteroatom of the 5-6 membered heteroaryl group is N, and the number of heteroatoms is one or two, for example, 【Chemistry 17】 Being (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-mentioned -S(O) ２ C １－６ Alkyl groups are [Chemistry 18] Being (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 -P(O)(C １－６ (Alkyl group) ２ teeth, 【Chemistry 19】 Being (7) Each R ２ In this case, the one or more R ２－１ C is replaced by １－６ Alkyl groups are 【Chemistry 20】 Being (8) Each R ３ In this case, the unsubstituted or one or more R ３－９ In the 4-12 member heterocycloalkenyl group substituted by , the 4-12 member heterocycloalkenyl group is independently a 5-9 member heterocycloalkenyl group, the heteroatom of the 5-9 member heterocycloalkenyl group is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-9 member heterocycloalkenyl group is 1 or 2, for example, 【Chemistry 21】 Being (9) Each R ３ In this case, the unsubstituted or one or more R ３－６ In a 5-12 membered heteroaryl group substituted by , the 5-12 membered heteroaryl group is a 5-9 membered heteroaryl group, the heteroatoms of the 5-9 membered heteroaryl group are N and / or O, and the number of heteroatoms is 1, 2, or 3, for example, 【Chemistry 22】 And furthermore, for example, 【Chemistry 23】 Being (10) Each R ３－１ and R ３－３ In this case, the unsubstituted or one or more R ３－１－１ In the 3-12 member heterocycloalkyl group substituted by, the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is one or two, for example, 【Chemistry 24】 Being (11) Each R ３－８ In this case, the unsubstituted or one or more R ３－８－１ In the 3-12 member heterocycloalkyl group substituted by, the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is one or two, for example, 【Chemistry 25】 Being (12) Each R ３－１－３ In this case, the unsubstituted or one or more R ３－１－３－１ In the 3-12 member heterocycloalkyl group substituted by, the 3-12 member heterocycloalkyl group is a 5-6 member heterocycloalkyl group, the heteroatoms of the 5-6 member heterocycloalkyl group are N and / or O, and the number of heteroatoms is one or two, for example, 【Chemistry 26】 Being, and (13) Each R ３－５ and R ３－９ In this case, the one or more R ３－５－１ C is replaced by １－６ Alkyl groups are 【Chemistry 27】 Being A compound represented by formula I according to claim 2, a pharmaceutically acceptable salt thereof, or an isotope compound thereof, characterized in that it satisfies one or more of the following conditions.

4. (1) R ａ It is hydrogen. (2) X ２ This means that N (3) X ３ This means that N (4) R ｂ This is either scheme 1 or scheme 2 below, Scheme 1: R ｂ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, preferably R ｂ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, or unsubstituted or one or more R groups １－１１ C is replaced by ６－１２ It is an aryl group, more preferably R ｂ is the unsubstituted C ３－１０ Cycloalkyl groups or unsubstituted C ６－１２ It is an aryl group, Scheme 2: R ｂ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, preferably R ｂ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１３ C is replaced by １－６ It is an alkyl group, more preferably R ｂ is the unsubstituted C ３－１０ Cycloalkyl groups, unsubstituted C ６－１２ Aryl group or unsubstituted carbon １－６ It is an alkyl group, most preferably R ｂ is the unsubstituted C １－６ Being an alkyl group, (5) Caution ｃ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, or unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, preferably R ｃ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ It is a cycloalkyl group, more preferably R ｃ is the unsubstituted C ３－１０ Being a cycloalkyl group, (6) R ｄ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, or unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, preferably R ｄ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ It is a cycloalkyl group, more preferably R ｄ is the unsubstituted C ３－１０ Being a cycloalkyl group, (7) R ｅ This is either not substituted or has one or more R's. １－１３ C is replaced by １－６ It is an alkyl group, preferably R ｅ is the unsubstituted C １－６ Being an alkyl group, (8) R ｆ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, preferably R ｆ This is either not substituted or has one or more R's. １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, more preferably R ｆ These are unsubstituted 3- to 12-membered heterocycloalkyl groups and unsubstituted C ６－１２ It is an aryl group, or an unsubstituted 5- to 12-membered heteroaryl group. (9) Caution ｇ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, or unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, preferably R ｇ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ It is a cycloalkyl group, more preferably R ｇ is the unsubstituted C ３－１０ Being a cycloalkyl group, (10) R ｈ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, preferably R ｈ This is either Scheme 1 or Scheme 2 below, and Scheme 1: R ｈ This is either not substituted or has one or more R's. １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, more preferably R ｈ These are unsubstituted 3- to 12-membered heterocycloalkyl groups and unsubstituted C ６－１２ It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group, Scheme 2: R ｈ is the unsubstituted C ３－１０ Cycloalkyl groups, unsubstituted 3- to 12-membered heterocycloalkyl groups, or unsubstituted C ６－１２ It is an aryl group or an unsubstituted 5- to 12-membered heteroaryl group. (11) R ｉ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or one or more R １－１１ C is replaced by ６－１２ It is an aryl group, preferably R ｉ This is either not substituted or has one or more R's. １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or one or more R １－１１ C is replaced by ６－１２ It is an aryl group, more preferably R ｉ This is an unsubstituted 3- to 12-membered heterocycloalkyl group, or an unsubstituted C ６－１２ It is an aryl group, (12) R ｊ This is either not substituted or has one or more R's. １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－１２ A 5- to 12-membered heteroaryl group substituted by, preferably R ｊ This is either not substituted or has one or more R's. １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, more preferably R ｊ This is an unsubstituted 3- to 12-membered heterocycloalkyl group, or an unsubstituted 5- to 12-membered heteroaryl group. (13) R ｋ This is either not substituted or has one or more R's. １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, preferably R ｋ This is either not substituted or has one or more R's. １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, more preferably R ｋ This is an unsubstituted 5- to 12-membered heteroaryl group, or an unsubstituted C １－６ Being an alkyl group, (14) Each R １－３ It is, independently, a halogen. (15) Each R １－４ It is, independently, a halogen. (16) Each R １－５ These are, independently, halogen, or C １－６ They are alkyl groups, preferably each R １－５ Independently, C １－６ Being an alkyl group, (17) Each R １－６ These are, independently, halogen, or C １－６ They are alkyl groups, preferably each R １－６ Independently, C １－６ Being an alkyl group, (18) Each R １－７ These are, independently, halogen, or C １－６ They are alkyl groups, preferably each R １－７ It is, independently, a halogen. (19) Each R １－８ Independently, C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And preferably, R １－８ Independently, C １－６ Being an alkyl group, (20) R １ This is either scheme 1 or scheme 2 below, Scheme 1: R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 28】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, Preferably, R １ is hydrogen, unsubstituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, More specifically, R １ is hydrogen, unsubstituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, Most preferably, R １ is hydrogen, unsubstituted C １－６ Alkyl alkyl group, unsubstituted C １－６ Alkoxy group, unsubstituted carbon ３－１０ Cycloalkyl groups, unsubstituted C ６－１２ It is an aryl group, or an unsubstituted 5- to 12-membered heteroaryl group. Scheme 2: R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, amino group, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 29】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5- to 12-membered heteroaryl group substituted by, preferably R １ It consists of hydrogen, halogen, amino group, and -NHC(O)R. ｂ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5- to 12-membered heteroaryl group substituted by, more preferably R １ It consists of hydrogen, halogen, amino group, and -NHC(O)R. ｂ , unsubstituted C １－６ Alkyl alkyl group, unsubstituted C １－６ Alkoxy group, unsubstituted carbon ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5- to 12-membered heteroaryl group substituted by, most preferably R １ is hydrogen, unsubstituted C １－６ Alkyl alkyl group, unsubstituted C １－６ Alkoxy group, unsubstituted carbon ３－１０ Cycloalkyl groups, unsubstituted 3- to 12-membered heterocycloalkyl groups, unsubstituted C ６－１２ An aryl group, or one or more unsubstituted R groups １－８ It is a 5- to 12-membered heteroaryl group substituted by (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 It is, independently, a halogen. (24) Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, preferably each R ２ These are, independently, halogen, one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups or unsubstituted C １－６ It is an alkoxy group. (25) Each R ３－１ Each of them operates independently. 【Transformation 30】 Being (26) Each R ３－１－３ These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups. (27) Each R ３－３ These are independently, unsubstituted or one or more R ３－１－１ A 3- to 12-membered heterocycloalkyl group substituted by, preferably each R ３－３ These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups. (28) Each R ３－５ These are independently oxo groups or unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ They are alkyl groups, preferably each R ３－５ These are, independently, an oxo group or an unsubstituted C １－６ Being an alkyl group, (29) Each R ３－６ These are independently cyano groups or unsubstituted or one or more R groups. ３－６－１ C is replaced by １－６ They are alkyl groups, preferably each R ３－６ These are independently cyano groups or unsubstituted C １－６ Being an alkyl group, (30) Each R ３－１０ is independently a hydroxy group, (31) Each R ３－８ These are independently, unsubstituted or one or more R ３－８－１ A 3- to 12-membered heterocycloalkyl group substituted by, preferably each R ３－８ These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups. (32) Each R ３－９ is independently an oxo group, a halogen, a cyano group, a hydroxy group, an unsubstituted or substituted C ３－５－１ by one or more R １ -C ６ alkyl group, or an unsubstituted or substituted C ３－５－２ by one or more R １ -C ６ alkoxy group, and Preferably, each R ３－９ These are independently oxo groups, halogens, and unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－５－２ C is replaced by １－６ It is an alkoxy group, More precisely, each R ３－９ These are independently an oxo group, a halogen, and one or more R groups. ３－５－１ C is replaced by １－６ Alkyl alkyl groups or unsubstituted C １－６ It is an alkoxy group, Most preferably, each R ３－９ These are, independently, oxo groups or halogens. (33) Each R ３－５－１ However, each is independently a halogen, (34) Each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－３ C is replaced by ２－６ Alkynyl group, unsubstituted or one or more R ３－５ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups ３－６ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups ３－１０ C is replaced by ６－１２ aryl group, or 【Chemistry 31】 And, Preferably, each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－４ C is replaced by ３－６ Cycloalkyl groups, unsubstituted or one or more R groups ３－５ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, More precisely, each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Most preferably, each R ３ This is an independent, unsubstituted C １－６ Alkyl alkyl group, or one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, for example, one or more R ３－９ It is a 4- to 12-membered heterocycloalkenyl group substituted by, and (35) X ４ This means that N A compound represented by formula I according to any one of claims 1 to 3, a pharmaceutically acceptable salt thereof, or an isotope compound thereof, characterized in that it satisfies one or more of the following conditions.

5. The compound represented by the above formula I is one of the following schemes 1, 2, 3, 4, 5, 6, or 7: Scheme 1: m and n are independently 1, 2, or 3. X １ is N or CH, X ２ is N or CH, X ３ N is, X ４ is N or CH, R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 32】 , -NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , an unsubstituted or one or more R １－３ -substituted C １－６ alkyl group, an unsubstituted or one or more R １－４ -substituted C １－６ alkoxy group, an unsubstituted or one or more R １－５ -substituted C ３－１０ cycloalkyl group, an unsubstituted or one or more R １－６ -substituted 3- to 12-membered heterocycloalkyl group, an unsubstituted or one or more R １－７ -substituted C ６－１２ aryl group, or an unsubstituted or one or more R １－８ -substituted 5- to 12-membered heteroaryl group, and R ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ and R ｋ These are independently, unsubstituted or one or more R １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, 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 These are, independently, halogen, C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, Each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－３ C is replaced by ２－６ Alkynyl group, unsubstituted or one or more R ３－５ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups ３－６ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups ３－１０ C is replaced by ６－１２ aryl group, or 【Transformation 33】 And, Each R ３－１ However, each is independent of the others. 【Transformation 34】 And, Each R ３－３ These are independently, unsubstituted or one or more R ３－１－１ A 3- to 12-membered heterocycloalkyl group substituted by, Each R ３－５ These are independently oxo groups, or unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ It is an alkyl group, Each R ３－６ These are independently cyano groups, or unsubstituted or one or more R groups. ３－６－１ C is replaced by １－６ It is an alkyl group, Each R ３－９ These are independently oxo groups, halogens, and unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－５－２ C is replaced by １－６ It is an alkoxy group, Each R ３－８ These are independently, unsubstituted or one or more R ３－８－１ A 3- to 12-membered heterocycloalkyl group substituted by, Each R ３－１０ These are independently hydroxyl groups, Each R ３－１－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, Each R ３－１－３ These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups. Each R ３－５－１ and R ３－５－２ These are independently deuterium, a hydroxyl group, a cyano group, or a halogen. Each R ３－６－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkoxy group, Each R ３－８－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, In each of the 3- to 12-membered heterocycloalkyl groups, 4- to 12-membered heterocycloalkenyl groups, and 5- to 12-membered heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 2: m is 1 or 2, n is 1, X １ is N or CH, X ２ is N or CH, X ３ N is, X ４ N is, R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Chemistry 35】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, R ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ and R ｋ These are independently, unsubstituted or one or more R １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, 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 These are, independently, halogen, C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, Each R ３ This is an independent, unsubstituted C １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Each R ３－９ These are independently oxo groups or halogens. In each of the 3- to 12-membered heterocycloalkyl groups, 4- to 12-membered heterocycloalkenyl groups, and 5- to 12-membered heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 3: m is 1 or 2, n is 1, X １ is N or CH, X ２ , X ３ and X ４ N is, R １ is hydrogen, unsubstituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, Each R １－３ and R １－４ It is, independently, a halogen, Each R １－５ , R １－６ , R １－７ and R １－８ These are, independently, halogen, or C １－６ It is an alkyl group, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, Each R ３ This is an independent, unsubstituted C １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Each R ３－９ These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 4: m and n are independently 1, 2, or 3. X １ is N or CH, X ２ is N or CH, X ３ N is, X ４ is N or CH, R １ It consists of hydrogen, deuterium, cyano group, hydroxyl group, halogen, amino group, and -NHC(O)R. ｂ , -NHS(O) ２ R ｃ , -S(O) ２ NHR ｄ , 【Transformation 36】 , - NHR ｆ , -C(O)NHR ｇ , -OR ｈ , -SR ｉ , -C(O)R ｊ , -S(O) ２ R ｋ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, R ｂ , R ｃ , R ｄ , each R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ and R ｋ These are independently, unsubstituted or one or more R １－９ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－１０ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－１１ C is replaced by ６－１２ Aryl group, unsubstituted or one or more R １－１２ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups １－１３ C is replaced by １－６ It is an alkyl group, 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 These are, independently, halogen, C １－６ Alkyl alkyl group, -S(O) ２ C １－６ Alkyl alkyl group, or -P(O)(C １－６ (Alkyl group) ２ And, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, Each R ３ These are independently, unsubstituted or one or more R ３－１ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R ３－３ C is replaced by ２－６ Alkynyl group, unsubstituted or one or more R ３－５ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, or an unsubstituted or one or more R groups ３－６ A 5- to 12-membered heteroaryl group substituted by, or an unsubstituted or one or more R groups ３－１０ C is replaced by ６－１２ aryl group, or 【Chemistry 37】 And, Each R ３－１ However, each is independent of the others. 【Transformation 38】 And, Each R ３－３ These are independently, unsubstituted or one or more R ３－１－１ A 3- to 12-membered heterocycloalkyl group substituted by, Each R ３－５ These are independently oxo groups, or unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ It is an alkyl group, Each R ３－６ These are independently cyano groups, or unsubstituted or one or more R groups. ３－６－１ C is replaced by １－６ It is an alkyl group, Each R ３－９ These are independently oxo groups, halogens, and unsubstituted or one or more R groups. ３－５－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－５－２ C is replaced by １－６ It is an alkoxy group, Each R ３－８ These are independently, unsubstituted or one or more R ３－８－１ A 3- to 12-membered heterocycloalkyl group substituted by, Each R ３－１０ These are independently hydroxyl groups, Each R ３－１－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, Each R ３－１－３ These are independently unsubstituted 3- to 12-membered heterocycloalkyl groups. Each R ３－５－１ and R ３－５－２ These are independently deuterium, a hydroxyl group, a cyano group, or a halogen. Each R ３－６－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkoxy group, Each R ３－８－１ These are independently a hydroxyl group, a cyano group, a halogen, or C １－６ It is an alkyl group, In each of the 3- to 12-membered heterocycloalkyl groups, 4- to 12-membered heterocycloalkenyl groups, and 5- to 12-membered heteroaryl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 5: m is 1 or 2, n is 1, X １ is N or CH, X ２ , X ３ and X ４ N is, R １ It consists of hydrogen, halogen, amino group, and -NHC(O)R. ｂ , either not substituted or one or more R １－３ C is replaced by １－６ Alkyl alkyl group, unsubstituted or one or more R １－４ C is replaced by １－６ Alkoxy group, unsubstituted or one or more R １－５ C is replaced by ３－１０ Cycloalkyl groups, unsubstituted or one or more R groups １－６ A 3- to 12-membered heterocycloalkyl group substituted by, or unsubstituted or with one or more R １－７ C is replaced by ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, Each R １－３ and R １－４ It is, independently, a halogen, Each R １－５ , R １－６ , R １－７ and R １－８ These are, independently, halogen, or C １－６ It is an alkyl group, R ｂ is the unsubstituted C １－６ It is an alkyl group, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, Each R ３ This is an independent, unsubstituted C １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Each R ３－９ These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 6: m is 1 or 2, n is 1, X １ is N or CH, X ２ , X ３ and X ４ N is, R １ is hydrogen, unsubstituted C １－６ Alkyl alkyl group, unsubstituted C １－６ Alkoxy group, unsubstituted carbon ３－１０ Cycloalkyl groups, unsubstituted 3- to 12-membered heterocycloalkyl groups, unsubstituted C ６－１２ An aryl group, or one or more unsubstituted R groups １－８ A 5-12 member heteroaryl group substituted by, Each R １－８ Independently, C １－６ It is an alkyl group, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, R ３ This is either not substituted or has one or more R's. ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Each R ３－９ These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group and 5- to 12-membered heteroaryl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. Scheme 7: m is 1 or 2, n is 1, X ２ and X ３ N is, 【Chemistry 39】 teeth, 【Chemistry 40】 And, Each R ２ These are, independently, halogens, unsubstituted or one or more R ２－１ C is replaced by １－６ Alkyl alkyl groups, or one or more unsubstituted R groups ２－２ C is replaced by １－６ It is an alkoxy group, Each R ２－１ and R ２－２ It is, independently, a halogen, R ３ This is either not substituted or has one or more R's. ３－９ A 4- to 12-membered heterocycloalkenyl group substituted by, Each R ３－９ These are independently oxo groups or halogens. In each 4- to 12-membered heterocycloalkenyl group, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently one, two, or three. A compound represented by formula I according to any one of claims 1 to 4, characterized by the above, a pharmaceutically acceptable salt thereof, or an isotope compound thereof.

6. (1) R １ This is either scheme 1 or scheme 2 below, Scheme 1: R １ These are hydrogen, deuterium, cyano group, hydroxyl group, fluorine, methyl group, 【Chemistry 41】 And preferably, R １ is hydrogen, methyl group, 【Chemistry 42】 And, Scheme 2: R １ These are hydrogen, deuterium, cyano group, hydroxyl group, fluorine, methyl group, 【Chemistry 43】 And, Preferably, R １ is hydrogen, methyl group, 【Chemistry 44】 Being (2) R ２ teeth, 【Chemistry 45】 It must be F or Cl, and (3) Caution ３ is a methyl group, 【Chemistry 46】 And preferably, R ３ teeth, 【Chemistry 47】 Or it is a methyl group, for example, 【Chemistry 48】 Being A compound represented by formula I according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, or an isotope compound thereof, characterized in that it satisfies one or more of the following conditions.

7. （１） 【Chemistry 49】 This is either scheme 1 or scheme 2 below, Scheme 1: [Transformation 50] teeth, 【Chemistry 51】 【Chemistry 52】 Preferably, 【Chemistry 53】 teeth, 【Chemistry 54】 Being Scheme 2: 【Transformation 55】 teeth, 【Transformation 56】 【Chemistry 57】 And, Preferably, 【Chemistry 58】 teeth, 【Chemistry 59】 And, more, 【Transformation 60】 teeth, 【Chemistry 61】 And, Most preferably, 【Transformation 62】 teeth, 【Transformation 63】 Being and （２） 【Chemistry 64】 teeth, 【Transformation 65】 Preferably, 【Chemical Formula 66】 teeth, 【Transformation 67】 Being A compound represented by formula I according to claim 6, a pharmaceutically acceptable salt thereof, or an isotope compound thereof, characterized in that it satisfies one or two of the following conditions.

8. The compound represented by the above formula I is 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 A compound represented by formula I according to claim 1, characterized in that it is one of the compounds of the formulas, a pharmaceutically acceptable salt thereof, or an isotope thereof.

9. (1) Substance A is a compound represented by formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt or isotope thereof, (2) Pharmaceutical additives and, A pharmaceutical composition containing the following:

10. The use of a compound represented by formula I according to any one of claims 1 to 8, substance A which is a pharmaceutically acceptable salt or isotope thereof, or the pharmaceutical composition according to claim 9 in the preparation of a polymerase theta inhibitor.

11. Use of substance A, which is a compound represented by formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt or isotope thereof, or the pharmaceutical composition according to claim 9, in the preparation of a drug for treating and / or preventing lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

12. Use of substance A, which is a compound represented by formula I according to any one of claims 1 to 8, a pharmaceutically acceptable salt or isotope thereof, or the pharmaceutical composition according to claim 9, in the preparation of a drug for treating and / or preventing polymerase theta-related disease, which is lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

13. A compound represented by formula II or a salt thereof, 【Chemistry 75】 R ｖ It is a halogen, Preferably, the compound represented by formula II is 【Transformation 76】 That is, A compound or its salt.

14. A method for treating a disease or polymerase theta-related disorder, comprising the step of administering to a subject substance A which is a compound represented by formula I as described in any one of claims 1 to 8, a pharmaceutically acceptable salt or isotope compound thereof, or a pharmaceutical composition as described in claim 9, characterized in that the disease or polymerase theta-related disorder is independently lung cancer, breast cancer, HR-deficient ovarian cancer, gastric cancer, prostate cancer, pancreatic adenocarcinoma, or colon cancer.

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