Biaromatic ring amide compound and application thereof

Abstract

The invention discloses a biaromatic ring amide compound and application thereof. The invention provides a compound as shown in a formula I or pharmaceutically acceptable salt thereof. The small molecule compound provided by the invention has a good inhibition effect on Pol theta enzyme and / or PARP1 enzyme, further has a relatively strong proliferation inhibition effect on DLD1BRCA2- / -cells, has an extremely weak proliferation inhibition effect on DLD1 wild-type cells and shows very good selectivity, and further, the compound provided by the invention can be used for overcoming drug resistance, reducing the dosage and reducing the toxic and side effects, and has a good application prospect. The purposes of expanding indications and improving the treatment effect are achieved. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024100763815 with the filing date of January 18, 2024 and Chinese Patent Application No. 202410641255X with the filing date of May 22, 2024. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

[0002] The present invention relates to a biaryl amide compound and its applications. Background Art

[0003] This patent aims to develop a dual-target small molecule compound inhibitor that simultaneously targets poly ADP-ribose polymerases (PARPs) and DNA polymerase theta (Polθ / POLQ) and inhibits the biological activities of both. Such an inhibitor has suitable efficacy and biological pharmacodynamics for tumor targeted therapy.

[0004] PARPs are a family of multifunctional post-translational modification enzymes, and 17 family members (PARP1, PARP2,... PARP17) have been discovered so far. They are involved in various biological functions, including replication, recombination, chromatin remodeling, DNA damage repair, etc. Tumor cells with homologous recombination deficiency (HRD), especially BRCA1 / 2-deficient tumor cells, have a synthetic lethal effect on PARP inhibitors (PARPi). PARPi, as a targeted anti-tumor drug, has been extensively studied. Currently, more than 6 PARPis have been marketed, such as Olaparib, Rucaparib, Niraparib, Talazoparib, Fluazoparib, and Pamiparib, etc. However, PARPi resistance is very common clinically. More than 40% of BRCA1 / 2-deficient patients do not respond to PARPi or develop drug resistance after treatment. Moreover, all PARPis have hematotoxicity, which affects the treatment duration and dosage. Hematological monitoring is required for patients receiving the drug, and timely treatment should be carried out when side effects occur. Developing a new generation of PARPi, expanding the indication range of PARPi, and reducing side effects have always been the key directions for new drug development.

[0005] PARP1 and PARP2 are the most well-studied members of the PARP family, and all marketed PARPis are PARP1 / 2 inhibitors. PARP1 is activated at DNA damage sites, catalyzes the PARylation (poly ADP-ribosylation) reaction on target proteins, and mediates the recruitment of DNA damage repair proteins. It is a key protein for repairing single strand breaks (SSBs) in the base excision repair pathway, and the repair process is accompanied by the release of PARP1 / 2 from DNA. The deletion of the PARP1 gene has a synthetic lethal effect with BRCA1 and BRCA2-deficient tumor cells. Some studies have reported that PARP2 is a protein essential for the survival of hematopoietic stem / progenitor cells, and PARP2 deficiency will lead to a shortened erythrocyte life cycle, affect the differentiation of erythroid progenitor cells, and ultimately result in hematotoxicity. Known evidence suggests that PARP1 inhibition is the main source of the tumor suppressive activity of PARPis, while PARP2 inhibition may be the source of hematotoxicity. Therefore, this patent designs a selective inhibitor targeting PARP1.

[0006] Since HRD (especially BRCA1 and 2 mutations) is a prerequisite for the anti-tumor activity of PARPis, homologous recombination repair restoration caused by various reasons ultimately leads to drug resistance, including DNA replication fork protection, overactivation of PARylation, reversion mutations, epigenetic changes, and pharmacokinetic changes, etc. Currently, combination therapy is mainly used to overcome PARPi resistance. Among them, the synergistic effect of POLQi and PARPi has been verified in many aspects.

[0007] POLQ is a key protein in the microhomology mediated end-joining (MMEJ) repair pathway and is a unique multifunctional polymerase. Non-homologous end joining (NHEJ), homologous recombination (HR), and MMEJ together constitute the three main mechanisms of DNA damage repair.

[0008] Research findings indicate that the polymerase domain of POLQ is essential for DNA extension at DSB damage repair sites, while the helicase domain and the intermediate domain play crucial roles in the recognition and binding of POLQ to substrates. POLQ can disrupt the interaction between DNA and the damage repair complex (such as competitively binding to single-stranded DNA with RAD51), inhibiting the HR repair pathway. POLQ deficiency forms synthetic lethality with HRD. Recent studies have shown that POLQ is also involved in biological functions such as repairing ssDNA gap filling and DNA replication arrest. The loss of its function will lead to increased replication stress in tumor cells and apoptosis. At present, there are multiple anti-tumor drug studies targeting POLQ in pre-clinical or phase I clinical research, making it a highly promising cancer treatment target.

[0009] Christopher Lord and others found that POLQi (ART558) has a synthetic lethal effect with 53BP1 / Shieldin-deficient BRCA1 mutant cells, suggesting that POLQi and PARP inhibitors have synergistic effects when used in combination, and may overcome PARPi resistance under specific conditions. Simon Boulton and others found that in BRCA1 / 2-deficient cells, POLQ deficiency or inhibition leads to the accumulation of post-replicative ssDNA gaps, and this phenomenon is exacerbated by PARPi. These evidences indicate that POLQ is not only a potential single-agent treatment target, but also has a synergistic effect with PARPi in biological mechanisms, which can reduce the effective dose of PARPi, reduce drug toxicity, and overcome specific PARPi resistance. It is reported that POLQi has a synergistic effect when used in combination with marketed PARPis such as Olaparib and Niraparib in BRCA1 and BRCA2 mutant tumor cell lines and mouse in vivo models.

[0010] In summary, PARP1 and POLQ are not only proven single-agent cancer treatment targets, but also have a synergistic effect in mechanisms. Designing dual-target small molecule inhibitors can help overcome drug resistance, reduce the dosage, reduce side effects, achieve the purpose of expanding the indications and improving the treatment effect compared with single-target inhibitors. Summary of the Invention

[0011] The technical problem to be solved by the present invention is that there are few small molecule inhibitors that can simultaneously target PARP1 and POLQ in the prior art. For this reason, the present invention provides a biaryl amide compound and its application. The small molecule compound provided by the present invention has a good inhibitory effect on Polθ enzyme and / or PARP1 enzyme. Further, it has a strong inhibitory effect on the proliferation of DLD1 BRCA2- / - cells and a very weak inhibitory effect on the proliferation of DLD1 wild-type cells, showing good selectivity. Furthermore, the compound of the present application can overcome drug resistance, reduce the dosage, and reduce the toxic and side effects, so as to achieve the purpose of expanding the indication and improving the treatment effect.

[0012] The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

[0013]

[0014] m is 0, 1, 2, 3 or 4;

[0015] n is 0, 1, 2 or 3;

[0016] X 1 and X 2 are independently N or CH;

[0017] Each R 2 is independently deuterium, halogen, cyano, amino, hydroxyl, -COOR 2-7 、-C(O)R 2-8 、-C(O)N(R 2-9 )2、 -N(R 2-12 )2、unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy, unsubstituted or substituted by one or more R 2-3 substituted C 2-6 alkenyl, unsubstituted or substituted by one or more R 2-4 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 2-5 substituted C 3-10 cycloalkyl, unsubstituted or substituted by one or more R 2-6 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-13 substituted 4- to 12-membered heterocycloalkenyl;

[0018] Each R 2-1 、R 2-2 、R 2-3 、R 2-4, R 2-5 , R 2-6 and R 2-13 are independently deuterium, a hydroxyl group, a cyano group or a halogen;

[0019] Each R 2-7 , R 2-8 , R 2-9 and R 2-12 are independently hydrogen or C 1-6 alkyl;

[0020] Each R 2-10 and R 2-11 are independently a hydroxyl group or C 1-6 alkyl; or two Rs 2-11 together with the P atom to which they are attached form a 5- to 10-membered alkanheterocycle, the heteroatom in the 5- to 10-membered alkanheterocycle being P (phosphorus) and the number of heteroatoms being 1;

[0021] Each R 3 is independently -N(R 3-7 )2, -C(O)N(R 2-9 )2, -O-5- to 12-membered heteroaryl, C 3-1 alkyl which is unsubstituted or substituted by one or more Rs 1-6 , C 3-2 alkenyl which is unsubstituted or substituted by one or more Rs 2-6 , C 3-3 alkynyl which is unsubstituted or substituted by one or more Rs 2-6 , C 3-4 cycloalkyl which is unsubstituted or substituted by one or more Rs 3-6 , 3- to 12-membered heteroalkyl which is unsubstituted or substituted by one or more Rs 3-5 , 4- to 12-membered heteroalkenyl which is unsubstituted or substituted by one or more Rs 3-9 , 5- to 12-membered heteroaryl which is unsubstituted or substituted by one or more Rs 3-6 or C 3-10 aryl which is unsubstituted or substituted by one or more Rs 6-12 ;

[0022] Each R 3-1 , R 3-2 and R 3-3 are independently 3- to 12-membered heteroalkyl which is unsubstituted or substituted by one or more Rs 3-1-1 or 5- to 12-membered heteroaryl which is unsubstituted or substituted by one or more Rs 3-1-2 ;

[0023] Each R 3-4 , R 3-5 and R 3-9Independently an oxo group (=O), halogen, cyano group, hydroxyl group, -N(R 3-5-3 )2, unsubstituted or substituted by one or more R 3-5-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-5-2 substituted C 1-6 alkoxy, unsubstituted or substituted by one or more R 3-5-5 substituted C 3-6 cycloalkyl or unsubstituted or substituted by one or more R 3-5-6 substituted 3- to 12-membered heterocycloalkyl;

[0024] Each R 3-6 and R 3-10 independently is an oxo group, halogen, cyano group, hydroxyl group, -N(R 3-6-3 )2, unsubstituted or substituted by one or more R 3-6-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-5-2 substituted C 1-6 alkoxy, unsubstituted or substituted by one or more R 3-5-5 substituted C 3-6 cycloalkyl, unsubstituted or substituted by one or more R 3-6-2 substituted 3- to 12-membered heterocycloalkyl;

[0025] Each R 3-7 independently is hydrogen, unsubstituted or substituted by one or more R 3-7-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-8-1 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 3-7-2 substituted 5- to 12-membered heteroaryl;

[0026] Each R 3-8 independently is unsubstituted or substituted by one or more R 3-7-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-8-1 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 3-7-2 substituted 5- to 12-membered heteroaryl;

[0027] Each R 3-1-1 and R 3-1-2 independently is a hydroxyl group, cyano group, halogen or C 1-6 alkyl;

[0028] Each R 3-1-3Independently unsubstituted or substituted by one or more R 3-1-3-1 substituted 3- to 12-membered heterocycloalkyl;

[0029] Each R 3-1-3-1 is independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0030] Each R 3-4-1 , R 3-5-3 and R 3-6-3 is independently hydrogen or C 1-6 alkyl;

[0031] Each R 3-5-1 , R 3-5-2 and R 3-7-1 is independently deuterium, hydroxy, cyano or halogen;

[0032] Each R 3-5-4 and R 3-7-3 is independently C 1-6 alkyl or C 3-6 cycloalkyl;

[0033] Each R 3-5-5 , R 3-5-6 and R 3-6-2 is independently hydroxy, cyano, halogen or C 1-6 alkyl;

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

[0035] Each R 3-7-2 and R 3-8-1 is independently hydroxy, cyano, halogen or C 1-6 alkyl;

[0036] Ring A is a 5- to 12-membered heteroaryl ring;

[0037] R 1 is hydrogen, deuterium, cyano, hydroxy, halogen, -NHC(O)R b , -NHS(O)2R c , -S(O)2NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , -C(O)R j , -S(O)2R k , -C(O)N(R m )2, -NH2, -SF5, unsubstituted or substituted by one or more R 1-3Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy, unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-6 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-7 Substituted C 6-12 Aryl is unsubstituted or substituted with one or more R 1-8 substituted 5-12 membered heteroaryl;

[0038] R b , R c , R d , R f , R g , R h , R i , R j , R k and R m are independently unsubstituted or substituted with one or more R 1-9 Substituted C 3-10 Cycloalkyl, unsubstituted or substituted with one or more R 1-10 substituted 3-12 membered heterocycloalkyl, unsubstituted or replaced by one or more R 1-11 Substituted C 6-12 Aryl, unsubstituted or substituted with one or more R 1-12 substituted 5-12 membered heteroaryl or unsubstituted or with one or more R 1 -13 Substituted C 1-6 alkyl;

[0039] Each R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R 1-10 , R 1-11 , R 1-12 and R 1-13 are independently halogen, C 1-6 Alkyl, -S(O)2C 1-6 Alkyl or -P(O)(C 1-6 Alkyl)2;

[0040] Ring E is unsubstituted or substituted with one or more R e-1 The benzene ring is substituted or unsubstituted or replaced by one or more R e-1 Substituted 5-12 membered heteroaromatic ring;

[0041] Ring F is unsubstituted or substituted by one or more R e-2 and is a 4- to 12-membered heteroalkene ring;

[0042] Each R e-1 is independently halogen or an unsubstituted or R-substituted 2-1 C 1-6 alkyl;

[0043] Each R e-2 is independently an oxo group (=O), halogen, or an unsubstituted or R-substituted 2-1 C 1-6 alkyl;

[0044] L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 5 -L 6 -, -L 2 -L 4 -L 5 -L 6 -, -L 1 -L 2 -L 3 -L 5 -L 6 - or -L 2 -L 3 -L 5 -L 6 -; (In each L, L 6 is connected to ring E and the other end of L is connected to ring A)

[0045] Each -L 1 - is independently Each R P1 is independently deuterium, halogen, or C 1-6 alkyl, or two Rs P1 together with the carbon atom to which they are attached form a C 3-10 subcycloalkyl or a 3- to 12-membered heterocycloalkyl; Ring G is independently a 3- to 12-membered alkheterocycle;

[0046] each - L 2 - independently is unsubstituted or substituted by one or more R P2 C - alkylene, unsubstituted or substituted by one or more R 1-14 substituted C - alkylene, unsubstituted or substituted by one or more R P2 substituted C - alkylene, unsubstituted or substituted by one or more R 2-14 substituted C - alkynylene, unsubstituted or substituted by one or more R P2 substituted C - alkynylene, unsubstituted or substituted by one or more R 3-10 substituted C - cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3 - 12 - membered heteroalkylene or unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroaryl; each C 1-14 - alkylene and C 2-14 one or more methylene units in - alkynylene are independently optionally replaced by R P3 each R P3 independently is C 3-10 - cycloalkylene or 3 - 12 - membered heteroalkylene;

[0047] each - L 3 - independently is

[0048] each - L 4 - independently is unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered arylene, unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted C 3-10 - cycloalkylene;

[0049] Ring H is a 5 - 12 - membered heteroaromatic ring, t1 is 0, 1, 2, 3 or 4;

[0050] each - L 5 - independently is unsubstituted or substituted by one or more R P2 substituted 3 - 12 - membered heteroalkylene, unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted 4 - 12 - membered heteroalkenylene; Ring P is independently a 5 - 12 - membered heteroaromatic ring; Ring Q is independently a 3 - 12 - membered alkanheterocyclic ring;

[0051] n1 and n2 are independently 0, 1 or 2;

[0052] each - L 6- Independently unsubstituted or substituted by one or more R P2 alkylene; 1-14

[0053] Each R P2 is independently halogen;

[0054] In each of 3- to 12-membered heterocycloalkyl, 3- to 12-membered alkheterocycle, 4- to 12-membered heterocycloalkenyl, 4- to 12-membered alkenheterocycle, 4- to 12-membered heteroalkenylene, 5- to 12-membered heteroaryl, -O-5- to 12-membered heteroaryl, 5- to 12-membered heteroaromatic ring, 3- to 12-membered heteroalkylene and 5- to 10-membered heteroarylene, the heteroatoms are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

[0055] In the compound of formula I or its pharmaceutically acceptable salt; the definitions of certain groups can be as described below, and the definitions of other groups can be as described in any of the above schemes (hereinafter referred to as "in a certain preferred scheme").

[0056] In a certain preferred scheme, each of the halogens is independently fluorine, chlorine, bromine or iodine.

[0057] In a certain preferred scheme, each of the C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0058] In a certain preferred scheme, each of the C 1-6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0059] In a certain preferred scheme, each of the C 2-6 alkenyl is independently vinyl, propenyl or allyl.

[0060] In a certain preferred scheme, each of the C 2-6 alkynyl is independently ethynyl, propynyl or propargyl.

[0061] In a certain preferred scheme, each of the C 3-10 cycloalkyl and each of the C 3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0062] In a certain preferred scheme, each of the 3- to 12-membered heterocycloalkyl is independently 3- to 9-membered heterocycloalkyl, such as 3- to 6-membered heterocycloalkyl or 5- to 9-membered heterocycloalkyl.

[0063] ​In a preferred embodiment, each of the 3- to 12-membered heterocycloalkyl groups is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2;

[0064] The monocyclic ring can be a 3- to 6-membered monocyclic heterocycloalkyl group or a 5- to 9-membered monocyclic heterocycloalkyl group;

[0065] The fused ring can be a 5- to 9-membered fused heterocycloalkyl group, such as a 3-membered fused 6-membered heterocyclic group.

[0066] In a preferred embodiment, the heteroatoms in each of the 3- to 12-membered heterocycloalkyl groups are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1 or 2.

[0067] In a preferred embodiment, each of the 4- to 12-membered heterocyclic alkenyl groups is independently a 5- to 6-membered heterocyclic alkenyl group.

[0068] In a preferred embodiment, the heteroatom of each of the 4- to 12-membered heterocyclic alkenyl groups is N, and the number of heteroatoms can independently be 1 or 2.

[0069] In a preferred embodiment, the number of double bonds in each of the 4- to 12-membered heterocyclic alkenyl groups is independently 1 or 2, such as 2.

[0070] In a preferred embodiment, each of the 5- to 12-membered heteroaryl groups is independently a monocyclic or fused ring, and the number of rings in the fused ring can be 2.

[0071] In a preferred embodiment, each of the 5- to 12-membered heteroaryl groups is independently a 5- to 6-membered heteroaryl group.

[0072] In a preferred embodiment, the heteroatoms of each of the 5- to 12-membered heteroaryl groups are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1, 2, or 3.

[0073] In a preferred embodiment, each of the C 6-12 aryl groups is independently a phenyl group or a naphthyl group.

[0074] In a preferred embodiment, each of the 5- to 12-membered heteroaromatic rings is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2.

[0075] In a preferred embodiment, each of the 5- to 12-membered heteroaromatic rings is independently a 5- to 10-membered heteroaromatic ring, such as a 5- to 6-membered heteroaromatic ring or an 8- to 10-membered heteroaromatic ring.

[0076] In a preferred embodiment, each of the 3- to 12-membered subheterocycloalkyl groups is independently a monocyclic, bridged ring, spiro ring, or fused ring; the number of rings in the bridged ring, spiro ring, or fused ring can be 2; preferably a monocyclic ring.

[0077] In a preferred embodiment, each of the 3- to 12-membered heteroalkylidenes is independently a 3- to 8-membered heteroalkylidene, such as a 3- to 6-membered heteroalkylidene.

[0078] In a preferred embodiment, the heteroatoms of each of the 3- to 12-membered heteroalkylidenes are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1 or 2.

[0079] In a preferred embodiment, each of the 5- to 10-membered heteroaryls is independently a 5- to 6-membered heteroaryl or an 8- to 10-membered heteroaryl.

[0080] In a preferred embodiment, each of the 5- to 10-membered heteroaryls is independently a monocyclic or fused ring, and the number of rings in the fused ring can be 2.

[0081] In a preferred embodiment, the heteroatom in each of the 5- to 10-membered heteroaryls is N, and the number of heteroatoms can independently be 1, 2, or 3.

[0082] In a preferred embodiment, each of the C 3-10 alkylidenes is independently a C 3-6 alkylidene or a C 5-10 alkylidene.

[0083] In a preferred embodiment, each of the C 3-10 alkylidenes is independently a monocyclic, bridged, spiro, or fused ring; the number of rings in the bridged, spiro, or fused ring can be 2;

[0084] The monocyclic ring can be a C 3-6 monocyclic alkylidene, such as cyclopropylidene, cyclobutylidene, cyclopentylidene, or cyclohexylidene;

[0085] The bridged ring can be a C 5-10 bridged alkylidene, such as a 4-membered bridged 4-membered alkylidene, a 4-membered bridged 5-membered alkylidene, or a 4-membered bridged 6-membered alkylidene;

[0086] The fused ring can be a C 5-10 fused alkylidene, such as a 4-membered fused 5-membered alkylidene, a 4-membered fused 6-membered alkylidene, a 5-membered fused 5-membered alkylidene, a 5-membered fused 6-membered alkylidene, or a 6-membered fused 6-membered alkylidene;

[0087] The spiro ring can be a C 5-10 spiro alkylidene, such as a 4-membered spiro 4-membered alkylidene, a 4-membered spiro 5-membered alkylidene, a 4-membered spiro 6-membered alkylidene, a 5-membered spiro 4-membered alkylidene, a 5-membered spiro 5-membered alkylidene, a 5-membered spiro 6-membered alkylidene, a 6-membered spiro 4-membered alkylidene, or a 6-membered spiro 5-membered alkylidene.

[0088] In a preferred embodiment, each of the 3- to 12-membered alkheterocycles is monocyclic.

[0089] In a preferred embodiment, each of the 3- to 12-membered alkanheterocycles is independently a 3- to 6-membered alkanheterocycle.

[0090] In a preferred embodiment, the heteroatom of each of the 3- to 12-membered alkanheterocycles is N, and the number of heteroatoms can independently be 1 or 2.

[0091] In a preferred embodiment, each of the plurality is independently 2, 3, 4, or 5, such as 2 or 3.

[0092] In a preferred embodiment, R 2 wherein the halogen is independently fluorine, chlorine, bromine, or iodine, such as fluorine or chlorine.

[0093] In a preferred embodiment, R e-1 , R 2-1 , R 3-9 , R 1 , R P1 and R P2 wherein the halogen is independently fluorine, chlorine, bromine, or iodine, such as fluorine.

[0094] In a preferred embodiment, R e-2 wherein each C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0095] In a preferred embodiment, R 2 , R 3 , R 2-9 , R 3-9 , R 3-5 , R 3-6 , R 1 and R P1 wherein each C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl.

[0096] In a preferred embodiment, R 2-11 wherein each C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as ethyl.

[0097] In a preferred embodiment, R 2-11 wherein two R 2-11 together with the P atom to which they are attached form a 5- to 6-membered alkanheterocycle, the heteroatom in the 5- to 6-membered alkanheterocycle is P, and the number of heteroatoms is 1; for example is

[0098] In a certain preferred embodiment, R 2 wherein the one or more R 2-1 substituted C 1-6 alkyl is

[0099] In a certain preferred embodiment, R 1 and R 2 wherein each C 1-6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.

[0100] In a certain preferred embodiment, R 1 wherein each C 3-10 cycloalkyl is independently C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and further such as cyclopropyl.

[0101] In a certain preferred embodiment, R 3 wherein each C 2-6 alkynyl is independently ethynyl, propynyl or propargyl, for example ethynyl.

[0102] In a certain preferred embodiment, R 3 wherein each 3- to 12-membered heterocycloalkyl is independently a 3- to 9-membered heterocycloalkyl, such as a 3- to 6-membered or 5- to 9-membered heterocycloalkyl.

[0103] In a certain preferred embodiment, R 3 wherein each 3- to 12-membered heterocycloalkyl is independently monocyclic or fused-ring; the number of rings in the fused-ring can be 2;

[0104] the monocyclic ring can be a 3- to 6-membered monocyclic heterocycloalkyl or a 5- to 9-membered monocyclic heterocycloalkyl;

[0105] the fused-ring can be a 5- to 9-membered fused-ring heterocycloalkyl, such as a 3-membered fused 6-membered heterocycloalkyl.

[0106] In a certain preferred embodiment, R 3 wherein the heteroatoms in each 3- to 12-membered heterocycloalkyl are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1 or 2.

[0107] In a certain preferred embodiment, R 3 wherein each 3- to 12-membered heterocycloalkyl is a 3- to 9-membered heterocycloalkyl, the heteroatoms of the 3- to 9-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the 3- to 9-membered heterocycloalkyl is monocyclic or fused-ring, and the number of rings in the fused-ring is 2; for example, morpholinyl, piperazinyl or For another example

[0108] In a certain preferred embodiment, R 3 Among them, each of the 4- to 12-membered heteroalkenyl groups is independently a 5- to 6-membered heteroalkenyl group.

[0109] In a certain preferred embodiment, R 3 Among them, the heteroatom of each of the 4- to 12-membered heteroalkenyl groups is N, and the number of heteroatoms can independently be 1 or 2.

[0110] In a certain preferred embodiment, R 3 Among them, the number of double bonds in each of the 4- to 12-membered heteroalkenyl groups is independently 1 or 2, for example, 2.

[0111] In a certain preferred embodiment, R 3 Among them, each of the 4- to 12-membered heteroalkenyl groups is independently a 5- to 6-membered heteroalkenyl group, the heteroatom of the 5- to 6-membered heteroalkenyl group is N, the number of heteroatoms is 1 or 2, and the number of double bonds in the 5- to 6-membered heteroalkenyl group is 1 or 2, for example For another example

[0112] In a certain preferred embodiment, R 3 Among them, each of the 5- to 12-membered heteroaryl groups is independently a monocyclic or fused ring, and the number of rings in the fused ring can be 2.

[0113] In a certain preferred embodiment, R 3 Among them, each of the 5- to 12-membered heteroaryl groups is independently a 5- to 6-membered heteroaryl group.

[0114] In a certain preferred embodiment, R 3 Among them, the heteroatoms of each of the 5- to 12-membered heteroaryl groups are independently selected from one or two of N and O, and the number of heteroatoms can independently be 1, 2, or 3.

[0115] In a certain preferred embodiment, R 3 Among them, each of the 5- to 12-membered heteroaryl groups is independently a 5- to 6-membered monocyclic heteroaryl group, the heteroatoms of the 5- to 6-membered monocyclic heteroaryl group are selected from one or two of N and O, and the number of heteroatoms is 1, 2, or 3; for example For another example

[0116] In a certain preferred embodiment, R 3 Among them, each of the 5- to 12-membered heteroaryl groups is For example

[0117] In a certain preferred embodiment, R 3-3Among them, each of the 3- to 12-membered heterocycloalkyl groups is independently a 3- to 9-membered heterocycloalkyl group, such as a 3- to 6-membered heterocycloalkyl group or a 5- to 9-membered heterocycloalkyl group.

[0118] In a certain preferred embodiment, R 3-3 Among them, each of the 3- to 12-membered heterocycloalkyl groups is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2;

[0119] The monocyclic ring can be a 3- to 6-membered monocyclic heterocycloalkyl group or a 5- to 9-membered monocyclic heterocycloalkyl group;

[0120] The fused ring can be a 5- to 9-membered fused heterocycloalkyl group, such as a 3-membered fused 6-membered heterocyclic group.

[0121] In a certain preferred embodiment, R 3-3 Among them, the heteroatoms in each of the 3- to 12-membered heterocycloalkyl groups are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1 or 2.

[0122] In a certain preferred embodiment, the R 3-3 Among them, each of the 3- to 12-membered heterocycloalkyl groups is independently a 3- to 6-membered monocyclic heterocycloalkyl group, the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl group are selected from one or both of N and O, the number of heteroatoms is 1 or 2, such as oxetanyl, and for another example

[0123] In a certain preferred embodiment, the R 3-3 Among them, the 3- to 12-membered heterocycloalkyl group substituted by one or more R 3-1-1 is

[0124] In a certain preferred embodiment, in ring A, each of the 5- to 12-membered heteroaryl rings is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2.

[0125] In a certain preferred embodiment, in ring A, each of the 5- to 12-membered heteroaryl rings is independently a 5- to 10-membered heteroaryl ring, such as a 5- to 6-membered heteroaryl ring or an 8- to 10-membered heteroaryl ring.

[0126] In a certain preferred embodiment, in ring A, the heteroatoms of each of the 5- to 12-membered heteroaryl rings are selected from one or both of N and S, and the number of heteroatoms is 1, 2, 3, 4, or 5;

[0127] In a certain preferred embodiment, in ring A, the 5- to 12-membered heteroaryl ring is independently a 5- to 10-membered heteroaryl ring; the 5- to 10-membered heteroaryl ring is a monocyclic or fused ring, the number of rings in the fused ring is 2; the heteroatoms in the 5- to 10-membered heteroaryl ring are selected from one or both of N and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; for example

[0128] In a certain preferred embodiment, in ring E, the benzene ring substituted by one or more R e-1 is

[0129] In a certain preferred embodiment, in ring F, each of the 4- to 12-membered heteroalkenyl rings is independently a 5- to 6-membered heteroalkenyl ring.

[0130] In a certain preferred embodiment, in ring F, the heteroatom of each of the 4- to 12-membered heteroalkenyl rings is N, and the number of heteroatoms can be 1 or 2.

[0131] In a certain preferred embodiment, in ring F, the number of double bonds in each of the 4- to 12-membered heteroalkenyl rings is 1 or 2.

[0132] In a certain preferred embodiment, in ring F, each of the 4- to 12-membered heteroalkenyl rings is a 5- to 6-membered heteroalkenyl ring, the heteroatom of the 5- to 6-membered heteroalkenyl ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2. For example

[0133] In a certain preferred embodiment, in ring F, the 4- to 12-membered heteroalkenyl ring substituted by one or more R e-2 is

[0134] In a certain preferred embodiment, in rings E and P, each of the 5- to 12-membered heteroaromatic rings is independently a monocyclic ring.

[0135] In a certain preferred embodiment, in rings E and P, each of the 5- to 12-membered heteroaromatic rings is independently a 5- to 10-membered heteroaromatic ring, such as a 5- to 6-membered heteroaromatic ring.

[0136] In a certain preferred embodiment, in rings E and P, the heteroatom of each of the 5- to 12-membered heteroaromatic rings is N, and the number of heteroatoms can be 1, 2, or 3.

[0137] In a certain preferred embodiment, in rings E and P, the 5- to 12-membered heteroaromatic ring is independently a 5- to 6-membered monocyclic heteroaromatic ring, the heteroatom in the 5- to 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; for example, a pyridine ring.

[0138] In a certain preferred embodiment, in ring Q, each of the 3- to 12-membered heteroalkyl rings is a monocyclic ring.

[0139] In a certain preferred embodiment, in ring Q, each of the 3- to 12-membered heteroalkyl rings is independently a 3- to 6-membered heteroalkyl ring.

[0140] In a certain preferred embodiment, in ring Q, the heteroatom of each of the 3- to 12-membered heteroalkyl rings is N, and the number of heteroatoms can be 1 or 2.

[0141] In a preferred embodiment, in ring Q, the 3- to 12-membered alicyclic heterocycle is a 3- to 6-membered monocyclic alicyclic heterocycle, the heteroatom of the 3- to 6-membered monocyclic alicyclic heterocycle is N, and the number of heteroatoms is 1 or 2. For example, a piperazine ring, and for another example

[0142] In a preferred embodiment, R P1 In, the C 3-10 subcycloalkyl group is independently a C 3-6 monocyclic subcycloalkyl group, such as a subcyclopropyl group, and for another example

[0143] In a preferred embodiment, R P1 In, the 3- to 12-membered hetero-subcycloalkyl group is independently a 3- to 6-membered monocyclic hetero-subcycloalkyl group, the heteroatom of the 3- to 6-membered monocyclic hetero-subcycloalkyl group can be selected from one or two of N and O, and the number of heteroatoms can be 1 or 2. For example, an oxasubcyclobutyl group or an azasubcyclobutyl group, and for another example

[0144] In a preferred embodiment, in ring G, the 3- to 12-membered alicyclic heterocycle is independently a 3- to 6-membered monocyclic alicyclic heterocycle, the heteroatom of the 3- to 6-membered monocyclic alicyclic heterocycle is N, and the number of heteroatoms is 1. For example is

[0145] In a preferred embodiment, L 2 In, each C 1-14 subalkyl group is independently a C 1-8 subalkyl group, and the C 1-8 subalkyl group can be a straight-chain subalkyl group. For example

[0146] In a preferred embodiment, the C P2 subalkyl group substituted by one or more R 1-14 is

[0147] In a preferred embodiment, L 2 In, each C 2-14 subalkynyl group is independently a C 2-6 subalkynyl group, and the C 2-6 subalkynyl group can be a straight-chain subalkynyl group. For example For another example For yet another example

[0148] In a preferred embodiment, L 2 and R P3 In, each C 3-10 subcycloalkyl group is independently a C3-6 Subcycloalkyl or C 5-10 Subcycloalkyl.

[0149] In a preferred embodiment, L 2 and R P3 In, each of the C 3-10 Subcycloalkyl is independently monocyclic, bridged, spiro or fused; the number of rings in the bridged, spiro or fused ring can be 2;

[0150] The monocyclic ring can be C 3-6 Monocyclic subcycloalkyl, such as cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene;

[0151] The bridged ring can be C 5-10 Bridged subcycloalkyl, such as 4-membered bridge 4-membered subcycloalkyl, 4-membered bridge 5-membered subcycloalkyl or 4-membered bridge 6-membered subcycloalkyl;

[0152] The fused ring can be C 5-10 Fused subcycloalkyl, such as 4-membered fused 5-membered subcycloalkyl, 4-membered fused 6-membered subcycloalkyl, 5-membered fused 5-membered subcycloalkyl, 5-membered fused 6-membered subcycloalkyl or 6-membered fused 6-membered subcycloalkyl;

[0153] The spiro ring can be C 5-10 Spiro subcycloalkyl, such as 4-membered spiro 4-membered subcycloalkyl, 4-membered spiro 5-membered subcycloalkyl, 4-membered spiro 6-membered subcycloalkyl, 5-membered spiro 4-membered subcycloalkyl, 5-membered spiro 5-membered subcycloalkyl, 5-membered spiro 6-membered subcycloalkyl, 6-membered spiro 4-membered subcycloalkyl or 6-membered spiro 5-membered subcycloalkyl.

[0154] In a preferred embodiment, L 2 and R P3 In, each of the C 3-10 Subcycloalkyl is independently cyclopropylidene, cyclobutylidene, cyclohexylidene, 5-membered fused 5-membered subcycloalkyl, 4-membered bridge 6-membered subcycloalkyl or 4-membered spiro 4-membered subcycloalkyl, for example

[0155] In a preferred embodiment, L 2 and R P3 In, each of the 3- to 12-membered hetero-subcycloalkyl is independently monocyclic, bridged, spiro or fused; the number of rings in the bridged, spiro or fused ring can be 2, preferably monocyclic.

[0156] In a preferred embodiment, L 2 and R P3 In, each of the 3- to 12-membered hetero-subcycloalkyl is independently 3- to 8-membered hetero-subcycloalkyl, such as 3- to 6-membered hetero-subcycloalkyl.

[0157] In a preferred embodiment, L2 and R P3 Among them, each 3- to 12-membered heteroalkyl group independently selects one or two of N and O as heteroatoms, and the number of heteroatoms can independently be 1 or 2.

[0158] In a certain preferred embodiment, L 2 and R P3 Among them, each 3- to 12-membered heteroalkyl group is independently a 3- to 6-membered monocyclic heteroalkyl group. The heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group independently select one or two of N and O, and the number of heteroatoms is independently 1 or 2. For example, azetidinyl or piperidinyl, and for another example

[0159] In a certain preferred embodiment, L 2 Among them, each 5- to 10-membered heteroaryl group is independently a 5- to 6-membered heteroaryl group or an 8- to 10-membered heteroaryl group.

[0160] In a certain preferred embodiment, L 2 Among them, each 5- to 10-membered heteroaryl group is independently a monocyclic or fused ring, and the number of rings of the fused ring can be 2.

[0161] In a certain preferred embodiment, L 2 Among them, the heteroatoms in each 5- to 10-membered heteroaryl group are N, and the number of heteroatoms can independently be 1, 2, or 3.

[0162] In a certain preferred embodiment, L 2 Among them, each 5- to 10-membered heteroaryl group is independently a 5- to 6-membered monocyclic heteroaryl group. The heteroatoms of the 5- to 6-membered monocyclic heteroaryl group are N, and the number of heteroatoms is independently 1, 2, or 3. For example, imidazolyl or pyrazolyl, and for another example

[0163] In a certain preferred embodiment, L 4 Among them, each 5- to 10-membered arylene group is phenylene or naphthylene, such as phenylene.

[0164] In a certain preferred embodiment, L 4 Among them, each 5- to 10-membered heteroaryl group is independently a 5- to 6-membered heteroaryl group or an 8- to 10-membered heteroaryl group.

[0165] In a certain preferred embodiment, L 4 Among them, each 5- to 10-membered heteroaryl group is independently a monocyclic or fused ring, and the number of rings of the fused ring can be 2.

[0166] In a certain preferred embodiment, L 4Among them, the heteroatoms in each 5- to 10-membered heteroarylene are N, and the number of heteroatoms can independently be 1, 2, or 3.

[0167] In a certain preferred embodiment, L 4 Among them, each 5- to 10-membered heteroarylene is independently a 5- to 6-membered monocyclic heteroarylene, the heteroatoms of the 5- to 6-membered monocyclic heteroarylene are N, and the number of heteroatoms can independently be 1, 2, or 3. For example, pyridinylene, and for another example For another example

[0168] In a certain preferred embodiment, L 4 Among them, the 5- to 10-membered heteroarylene substituted by one or more R P2 is

[0169] In a certain preferred embodiment, L 4 Among them, the 5- to 10-membered arylene substituted by one or more R P2 is

[0170] In a certain preferred embodiment, L 4 Among them, each C 3-10 subcycloalkyl is independently a C 3-6 subcycloalkyl, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or bicyclo[1.1.1]pentylene, and for another example bicyclo[1.1.1]pentylene, and for another example

[0171] In a certain preferred embodiment, in ring H, the 5- to 10-membered heteroaryl ring is a 5- to 6-membered heteroaryl ring, the heteroatoms in the 5- to 6-membered heteroaryl ring are selected from N, and the number of heteroatoms is 1, 2, or 3. For example, a pyridine ring.

[0172] In a certain preferred embodiment, L 5 Among them, each 3- to 12-membered heterocycloalkyl is independently a monocyclic, bridged, spiro or fused ring; the number of rings in the bridged, spiro or fused ring can be 2, and preferably it is a monocyclic ring.

[0173] In a certain preferred embodiment, L 5 Among them, each 3- to 12-membered heterocycloalkyl is independently a 3- to 8-membered heterocycloalkyl, such as a 3- to 6-membered heterocycloalkyl.

[0174] In a certain preferred embodiment, L 5 Among them, the heteroatoms of each 3- to 12-membered heterocycloalkyl are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1 or 2.

[0175] In a certain preferred embodiment, L5 Among them, each 3- to 12-membered heteroalicyclic group is independently a 3- to 6-membered monocyclic heteroalicyclic group. The heteroatoms of the 3- to 6-membered monocyclic heteroalicyclic group are independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2. For example, piperazinyl, and for another example

[0176] In a certain preferred embodiment, L 5 Among them, each 5- to 10-membered heteroaryl group is independently a 5- to 6-membered heteroaryl group or an 8- to 10-membered heteroaryl group.

[0177] In a certain preferred embodiment, L 5 Among them, each 5- to 10-membered heteroaryl group is independently monocyclic or fused-ring, and the number of rings of the fused-ring can be 2.

[0178] In a certain preferred embodiment, L 5 Among them, the heteroatoms in each 5- to 10-membered heteroaryl group are N, and the number of heteroatoms can be independently 1, 2, or 3.

[0179] In a certain preferred embodiment, L 5 Among them, each 5- to 10-membered heteroaryl group is independently monocyclic or fused-ring, the number of rings of the fused-ring is 2, the heteroatoms in each 5- to 10-membered heteroaryl group are N, and the number of heteroatoms can be independently 1, 2, or 3. For example, pyridinyl For another example

[0180] In a certain preferred embodiment, L 5 Among them, each 4- to 12-membered heteroallenyl group is independently a 5- to 6-membered heteroallenyl group. The heteroatom of the 5- to 6-membered heteroallenyl group can be N, the number of heteroatoms can be 1 or 2, and the number of double bonds of the 5- to 6-membered heteroallenyl group can be 1 or 2. For example For another example

[0181] In a certain preferred embodiment, L 6 Among them, each C 1-14 alkylene group is independently a C 1-8 alkylene group, and the C 1-8 alkylene group can be a straight-chain alkylene group. For example For another example

[0182] In a certain preferred embodiment, X 1 is N.

[0183] In a certain preferred embodiment, X 2 is N.

[0184] In a preferred embodiment, m is 1, 2, 3 or 4, such as 2 or 3.

[0185] In a preferred embodiment, n is 1, 2 or 3; such as 1.

[0186] In a preferred embodiment, each R 2 is independently deuterium, a halogen, an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl or an unsubstituted or one or more R 2-2 substituted C 1-6 alkoxy; preferably, each R 2 is independently deuterium, an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl or an unsubstituted or one or more R 2-2 substituted C 1-6 alkoxy.

[0187] In a preferred embodiment, each R 2-1 and R 2-2 are independently a halogen.

[0188] In a preferred embodiment, each R 3 is independently -C(O)N(R 2-9 )2, an unsubstituted or one or more R 3-1 substituted C 1-6 alkyl, an unsubstituted or one or more R 3-3 substituted C 2-6 alkynyl, an unsubstituted or one or more R 3-5 substituted 3-12 membered heterocycloalkyl, an unsubstituted or one or more R 3-9 substituted 4-12 membered heterocycloalkenyl or an unsubstituted or one or more R 3-6 substituted 5-12 membered heteroaryl;

[0189] preferably, each R 3 is independently -C(O)N(R 2-9 )2, an unsubstituted or one or more R 3-1 substituted C 1-6 alkyl, an unsubstituted or one or more R 3-3 substituted C 2-6 alkynyl, an unsubstituted or one or more R 3-5 substituted 3-9 membered heterocycloalkyl, an unsubstituted or one or more R 3-9 substituted 5-6 membered heterocycloalkenyl or an unsubstituted or one or more R 3-6Substituted 5- or 6-membered monocyclic heteroaryl; the heteroatoms of the 3- to 9-membered heterocycloalkyl are selected from one or both of N and O, the number of heteroatoms is 1 or 2, the 3- to 9-membered heterocycloalkyl is monocyclic or fused-ring, and the number of rings in the fused-ring is 2; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2; the heteroatoms of the 5- or 6-membered monocyclic heteroaryl are selected from one or both of N and O, and the number of heteroatoms is 1, 2, or 3;

[0190] More preferably, each R 3 is independently unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl, the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2;

[0191] Most preferably, each R 3 is independently unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2.

[0192] In a preferred embodiment, each R 2-9 is independently hydrogen or C 1-6 alkyl.

[0193] In a preferred embodiment, each R 3-1 and R 3-3 are independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 12-membered heterocycloalkyl; preferably, each R 3-1 and R 3-3 are independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 6-membered monocyclic heterocycloalkyl, the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.

[0194] In a preferred embodiment, each R 3-1-1 is hydroxy.

[0195] In a preferred embodiment, each R 3-5 is independently oxo (=O), halogen, or unsubstituted or substituted by one or more R 3-5-1 substituted C 1-6 alkyl; preferably, each R 3-9 is independently oxo (=O), halogen, or C1-6 alkyl; more preferably, each R 3-5 is independently an oxo group or C 1-6 alkyl.

[0196] In a certain preferred embodiment, each R 3-5-1 is independently deuterium or a halogen.

[0197] In a certain preferred embodiment, each R 3-9 is independently an oxo group (=O), a halogen, or an unsubstituted or one or more R 3-5-1 substituted C 1-6 alkyl; preferably, each R 3-9 is independently an oxo group (=O), a halogen, or C 1-6 alkyl; more preferably, each R 3-9 is independently an oxo group (=O) or a halogen.

[0198] In a certain preferred embodiment, each R 3-6 is independently an unsubstituted or one or more R 3-6-1 substituted C 1-6 alkyl; preferably, each R 3-6 is independently an unsubstituted C 1-6 alkyl.

[0199] In a certain preferred embodiment, each R 3-6-1 is independently a halogen.

[0200] In a certain preferred embodiment, ring A is a 5- to 10-membered heteroaryl ring, the 5- to 10-membered heteroaryl ring is a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaryl ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4, or 5.

[0201] In a certain preferred embodiment, R 1 is hydrogen, deuterium, cyano, halogen, -NH2, -SF5, an unsubstituted or one or more R 1-3 substituted C 1-6 alkyl, an unsubstituted or one or more R 1-4 substituted C 1-6 alkoxy, or an unsubstituted or one or more R 1-5 substituted C 3-10 cycloalkyl, preferably, the C 3-10 cycloalkyl is C 3-6 cycloalkyl; more preferably, R 1 is hydrogen, deuterium, or halogen, and most preferably, R 1 is hydrogen or deuterium.

[0202] In a certain preferred embodiment, each R 1-3 , R1-4 and R 1-5 is independently a halogen or a C 1-6 alkyl group.

[0203] In a certain preferred embodiment, each R 2-11 is independently a C 1-6 alkyl group; or two Rs 2-11 together with the P atom to which they are attached form a 5- to 10-membered alkanheterocyclic ring, the heteroatom in the 5- to 10-membered alkanheterocyclic ring is P, and the number of heteroatoms is 1; preferably, the 5- to 10-membered alkanheterocyclic ring is a 5- to 6-membered alkanheterocyclic ring.

[0204] In a certain preferred embodiment, ring E is independently an unsubstituted or one or more R e-1 substituted benzene ring or an unsubstituted or one or more R e-1 substituted 5- to 6-membered monocyclic heteroaromatic ring, the heteroatom in the 5- to 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; preferably, ring E is independently an unsubstituted 5- to 6-membered monocyclic heteroaromatic ring.

[0205] In a certain preferred embodiment, each R e-1 is independently a halogen or a C 1-6 alkyl group.

[0206] In a certain preferred embodiment, ring F is independently a 4- to 12-membered alkenheterocyclic ring substituted by one or more R e-2 groups; preferably, the 4- to 12-membered alkenheterocyclic ring is a 5- to 6-membered alkenheterocyclic ring, the heteroatom in the 5- to 6-membered alkenheterocyclic ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2.

[0207] In a certain preferred embodiment, each R e-2 is independently an oxo group or an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl group; preferably, each R e-2 is independently an oxo group or an unsubstituted C 1-6 alkyl group.

[0208] In a certain preferred embodiment, L is selected from any of the following options:

[0209] Option 1: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L4 -L 5 -L 6 -、-L 4 -L 5 -L 6 -、-L 5 -L 6 -、-L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -;

[0210] Solution 2: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L 6 -、-L 5 -L 6 -、-L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -;

[0211] Solution 3: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 3 -L 4 -L 5 -L 6- or -L 4 -L 5 -L 6 -;

[0212] Option 4: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L 6 -、-L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -;

[0213] Option 5: -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 -;

[0214] Option 6: -L 5 -L 6 -。

[0215] In a preferred embodiment, L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L6 - or -L 2 -L 4 -L 5 -L 6 -.

[0216] In a preferred embodiment, L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 -,-L 2 -L 4 -L 5 -L 6 - or -L 5 -L 6 -.

[0217] In a preferred embodiment, ring A is a single ring and L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -.

[0218] In a preferred embodiment, ring A is a fused ring and L is -L 5 -L 6 -.

[0219] In a preferred embodiment, each -L 1 - is independently each R P1 is independently deuterium, a halogen, or C 1-6 alkyl, or two RsP1 together with the carbon atom to which it is attached to form a C 3-6 monocyclic cycloalkylene or 3- to 6-membered monocyclic heteroalkylene; the heteroatom of the 3- to 6-membered monocyclic heteroalkylene is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; ring G is independently a 3- to 6-membered monocyclic heterocycloalkane, the heteroatom of the 3- to 6-membered monocyclic heterocycloalkane is N, and the number of heteroatoms is 1; preferably, each -L 1 - is independently More preferably, it is

[0220] In a certain preferred embodiment, each -L 2 - is independently unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 substituted C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3- to 6-membered monocyclic heteroalkylene or unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl; the heteroatom of the 3- to 6-membered monocyclic heteroalkylene is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; each C 1-8 alkylene and C 2-6 alkynylene, one or more methylene units of which are optionally replaced by R P3 substitute, each R P3 is independently C 3-10 cycloalkylene or 3- to 6-membered monocyclic heteroalkylene;

[0221] Preferably, each -L 2 - is unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 substituted C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3- to 6-membered monocyclic heteroalkylene, unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl or wherein, Z 1Independently a single bond or O, Z 2 Independently a single bond, O, C 3-10 Subcycloalkyl or 3- to 6-membered monocyclic heteroalkyl (Z 1 and Z 2 are not simultaneously a single bond); m1 is independently 0, 1 or 2; m2 is independently 0, 1 or 2; m3 is independently 0, 1 or 2; (m1, m2 and m3 are not simultaneously 0), the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3;

[0222] More preferably, each -L 2 - is independently an unsubstituted or one or more R P2 substituted C 1-8 alkylene, unsubstituted or one or more R P2 substituted C 3-10 subcycloalkyl, unsubstituted or one or more R P2 substituted 3- to 6-membered monocyclic heteroalkyl or unsubstituted or one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl, the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3;

[0223] Most preferably, each -L 2 - is independently an unsubstituted or one or more R P2 substituted C 1-8 alkylene, unsubstituted or one or more R P2 substituted 3- to 6-membered monocyclic heteroalkyl or unsubstituted or one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl; the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3;

[0224] Even more preferably, each -L 2 - is independently an unsubstituted C 1-8 alkylene or unsubstituted or one or more R P2 substituted 3- to 6-membered monocyclic heteroalkyl; the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2.

[0225] In a certain preferred embodiment, each -L 2 - is independently an unsubstituted or one or more RP2 Substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 Substituted C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 Substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 Substituted 3- to 6-membered monocyclic heteroalkylene, unsubstituted or substituted by one or more R P2 Substituted 5- to 6-membered heteroaryl or wherein, Z 1 independently is O, Z 2 independently is a single bond or O; m1 independently is 0, 1 or 2; m2 independently is 0, 1 or 2; m3 independently is 0, 1 or 2; Z 1 and Z 2 are not simultaneously a single bond, m1, m2 and m3 are not simultaneously 0, the heteroatoms of the 3- to 6-membered monocyclic heteroalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5- to 6-membered heteroaryl are N, and the number of heteroatoms is 1, 2 or 3.

[0226] In a preferred embodiment, each -L 3 - independently is

[0227] In a preferred embodiment, each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene, unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl or unsubstituted or substituted by one or more R P2 substituted C 3-10 cycloalkylene; the heteroatoms of the 5- to 6-membered monocyclic heteroaryl are N, and the number of heteroatoms is 1, 2 or 3; ring H is a 5- to 6-membered heteroaromatic ring, the heteroatoms in the 5- to 6-membered heteroaromatic ring are selected from N, and the number of heteroatoms is 1, 2 or 3, and t1 is 0, 1, 2, 3 or 4;

[0228] Preferably, each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl, the heteroatoms of the 5- to 6-membered monocyclic heteroaryl are N, and the number of heteroatoms is 1, 2 or 3; more preferably, it is an unsubstituted 5- to 6-membered monocyclic heteroaryl.

[0229] In a preferred embodiment, each of the -L 4 - independently is unsubstituted or substituted by one or more R P2A substituted phenylene group or an unsubstituted or one or more R-substituted P2 5- or 6-membered heteroarylene group, the heteroatoms of which are N and the number of heteroatoms is 1, 2 or 3; preferably, each -L 4 - independently is an unsubstituted or one or more R-substituted P2 phenylene group or an unsubstituted 5- or 6-membered heteroarylene group.

[0230] In a preferred embodiment, each -L 5 - independently is an unsubstituted or one or more R-substituted P2 3- to 6-membered monocyclic heteroalkyl group, an unsubstituted or one or more R-substituted P2 5- to 10-membered heteroarylene group or an unsubstituted or one or more R-substituted P2 5- to 6-membered heteroalkenyl group; each of the 5- to 10-membered heteroarylene groups is monocyclic or fused-ring, the number of fused rings is 2, the heteroatoms of each 5- to 10-membered heteroarylene group are N and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 6-membered heteroalkenyl group are N and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl group is 1 or 2; ring P is independently a 5- or 6-membered monocyclic heteroaromatic ring, the heteroatoms in the 5- or 6-membered monocyclic heteroaromatic ring are N and the number of heteroatoms is 1 or 2; ring Q is independently a 3- to 6-membered monocyclic heteroalkane, the heteroatoms of the 3- to 6-membered monocyclic heteroalkane are N and the number of heteroatoms is 1 or 2;

[0231] Preferably, each -L 5 - independently is an unsubstituted 3- to 6-membered monocyclic heteroalkyl group, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.

[0232] In a preferred embodiment, each -L 5 - independently is an unsubstituted 3- to 6-membered monocyclic heteroalkyl group or an unsubstituted 5- to 6-membered heteroalkenyl group, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5- to 6-membered heteroalkenyl group are N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl group is 1 or 2; preferably, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group are N and the number of heteroatoms is 1 or 2.

[0233] In a preferred embodiment, each -L 6 - independently is an unsubstituted or one or more R-substituted P2 C 1-8 alkylene group, preferably, an unsubstituted C 1-8 alkylene group.

[0234] In a preferred embodiment, each R P2 is independently a halogen.

[0235] In a preferred embodiment, n1 and n2 are independently 0, 1 or 2.

[0236] In a preferred embodiment, the compound represented by Formula I is not any of the following compounds:

[0237]

[0238] In a preferred embodiment, each -L 1 - is independently Preferably, it is a single bond, where the 1-position is connected to Ring A and the 2-position is connected to L 2 connected; more preferably, it is where the 1-position is connected to Ring A and the 2-position is connected to L 2 connected; most preferably, it is where the 1-position is connected to Ring A and the 2-position is connected to L 2 connected.

[0239] In a preferred embodiment, each -L 2 - is independently

[0240] Preferably, each -L 2 - is independently where the 1-position is connected to L 1 connected and the 2-position is connected to L 3 connected;

[0241] More preferably, it is where the 1-position is connected to L 1 connected and the 2-position is connected to L 3 connected;

[0242] More preferably, each -L 2 - is independently where the 1-position is connected to L 1 connected and the 2-position is connected to L 3 connected;

[0243] Most preferably, each -L 2 - is independently where the 1-position is connected to L 1 connected and the 2-position is connected to L3 Connection

[0244] In a preferred embodiment, each -L 2 - independently is Preferably, it is where the 1-position is connected to L 1 connected, and the 2-position is connected to L 3 connected; more preferably, it is where the 1-position is connected to L 1 connected, and the 2-position is connected to L 3 connected; more preferably, it is where the 1-position is connected to L 1 connected, and the 2-position is connected to L 3 connected.

[0245] In a preferred embodiment, each -L 3 - independently is Preferably, it is where the 1-position is connected to L 2 connected, and the 2-position is connected to L 4 connected; more preferably, it is where the 1-position is connected to L 2 connected, and the 2-position is connected to L 4 connected.

[0246] In a preferred embodiment, each -L 4 - independently is

[0247] Preferably, each -L 4 - independently is where the 1-position is connected to L 3 connected, and the 2-position is connected to L 5 connected;

[0248] More preferably, each -L 4 - independently is selected from Option A or Option B:

[0249] Option A: Each -L 4 - independently is where the 1-position is connected to L 3 connected, and the 2-position is connected to L 5 connected;

[0250] Option B: Each -L 4 - independently is where the 1-position is connected to L3 Connected, the 2-position is connected to L 5 Connection.

[0251] In a preferred embodiment, each -L 4 - is independently Preferably, it is Wherein the 1-position is connected to L 3 Connected, the 2-position is connected to L 5 Connected; more preferably, it is Wherein the 1-position is connected to L 3 Connected, the 2-position is connected to L 5 Connected; most preferably, it is Wherein the 1-position is connected to L 3 Connected, the 2-position is connected to L 5 Connected.

[0252] In a preferred embodiment, each -L 5 - is independently Preferably, it is Wherein the 1-position is connected to L 4 Connected, the 2-position is connected to L 6 Connected; more preferably, it is Wherein the 1-position is connected to L 4 Connected, the 2-position is connected to L 6 Connected.

[0253] In a preferred embodiment, each -L 5 - is independently Preferably, it is Wherein the 1-position is connected to L 4 Connected, the 2-position is connected to L 6 Connected; more preferably, it is Wherein the 1-position is connected to L 4 Connected, the 2-position is connected to L 6 Connected.

[0254] In a preferred embodiment, each -L 6 - is

[0255] In a preferred embodiment, L is

[0256]

[0257] Wherein the 1-position is connected to ring A, and the 2-position is connected to ring E;

[0258] Preferably, it is wherein the 1-position is connected to ring A, and the 2-position is connected to ring E;

[0259] More preferably, it is selected from Scheme 1 or Scheme 2,

[0260] Scheme 1: L is wherein the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E;

[0261] Scheme 2:

[0262]

[0263] In a certain preferred embodiment, L is

[0264]

[0265] wherein the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; preferably, it is wherein the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; more preferably, it is selected from Scheme 1 or Scheme 2, Scheme 1: is wherein the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; Scheme 2:

[0266] In a certain preferred embodiment, ring A is Preferably, ring A is More preferably, it is

[0267] In a certain preferred embodiment, ring A is

[0268] In a certain preferred embodiment, it is

[0269] Preferably, it is Among them, the 1-position is connected to NH, and the 2-position is connected to L;

[0270] More preferably, is Among them, the 1-position is connected to NH, and the 2-position is connected to L;

[0271] Most preferably, is Among them, the 1-position is connected to NH, and the 2-position is connected to L.

[0272] In a certain preferred embodiment, is Among them, the 1-position is connected to NH, and the 2-position is connected to L;

[0273] Preferably, is Among them, the 1-position is connected to NH, and the 2-position is connected to L.

[0274] In a certain preferred embodiment, R 1 is hydrogen, fluorine, methyl, methoxy, cyano, amino, -SF5, cyclopropyl, More preferably, R 1 is hydrogen.

[0275] In a certain preferred embodiment, is

[0276] Among them, the 1-position is connected to NH, and the 2-position is connected to L; more preferably, it is Among them, the 1-position is connected to NH, and the 2-position is connected to L, most preferably, it is Among them, the 1-position is connected to NH, and the 2-position is connected to L.

[0277] In a certain preferred embodiment, each R 2 is independently Cl or F; more preferably, it is

[0278] In a certain preferred embodiment, is For example For another example

[0279] In a certain preferred embodiment, each R 3 is independently methyl,

[0280] In a certain preferred embodiment, each R3 independently is methyl, such as methyl or for another example

[0281] In a certain preferred embodiment, is

[0282] In a certain preferred embodiment, in, is Preferably, is More preferably, it is

[0283] In a certain preferred embodiment, in the compound of formula I or a pharmaceutically acceptable salt thereof, the compound of formula I is the compound of formula I-1,

[0284]

[0285] In a certain preferred embodiment,

[0286] m is 1, 2, 3 or 4;

[0287] n is 1, 2 or 3;

[0288] X 1 and X 2 are independently N;

[0289] Each R 2 is independently deuterium, halogen, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy;

[0290] Each R 2-1 and R 2-2 are independently halogen;

[0291] Each R 3 is independently -C(O)N(R 2-9 )2, unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-3 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 3-5 substituted 3-9 membered heterocycloalkyl, unsubstituted or substituted by one or more R 3-9A substituted 5- or 6-membered heteroalkenyl, or an unsubstituted or one or more R- 3-6 substituted 5- or 6-membered monocyclic heteroaryl; the heteroatoms of the 3- to 9-membered heteroalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds in the 5- or 6-membered heteroalkenyl is 1 or 2; the heteroatoms of the 5- or 6-membered monocyclic heteroaryl are selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3;

[0292] Each R 2-9 is independently hydrogen or C 1-6 alkyl;

[0293] Each R 3-1 and R 3-3 are independently an unsubstituted or one or more R- 3-1-1 substituted 3- to 6-membered monocyclic heteroalkyl, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2;

[0294] Each R 3-1-1 is a hydroxyl group;

[0295] Each R 3-5 is independently an oxo group (=O), a halogen, or an unsubstituted or one or more R- 3-5-1 substituted C 1-6 alkyl;

[0296] Each R 3-5-1 is independently deuterium or a halogen;

[0297] Each R 3-9 is independently an oxo group (=O), a halogen, or an unsubstituted or one or more R- 3-5-1 substituted C 1-6 alkyl;

[0298] Each R 3-6 is independently an unsubstituted or one or more R- 3-6-1 substituted C 1-6 alkyl;

[0299] Each R 3-6-1 is independently a halogen;

[0300] Ring A is a 5- to 10-membered heteroaryl ring, the 5- to 10-membered heteroaryl ring is a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaryl ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0301] R 1 is hydrogen, deuterium, cyano, halogen, -NH2, -SF5, unsubstituted or substituted by one or more R 1-3 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 1-4 substituted C 1-6 alkoxy or unsubstituted or substituted by one or more R 1-5 substituted C 3-6 cycloalkyl;

[0302] Each R 1-3 , R 1-4 and R 1-5 independently is halogen or C 1-6 alkyl;

[0303] Each R 2-11 independently is C 1-6 alkyl; or two R 2-11 together with the P atom to which they are attached form a 5- or 6-membered alkanheterocycle, the heteroatom in the 5- or 6-membered alkanheterocycle is P, and the number of heteroatoms is 1;

[0304] Each ring E independently is an unsubstituted or R-substituted benzene ring or an unsubstituted or R-substituted 5- or 6-membered monocyclic heteroaromatic ring, the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; e-1 substituted by one or more R e-1 substituted 5- or 6-membered monocyclic heteroaromatic ring, the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2;

[0305] Each R e-1 independently is halogen or C 1-6 alkyl;

[0306] Each ring F independently is a 5- or 6-membered alkenheterocycle substituted by one or more R e-2 substituted 5- or 6-membered alkenheterocycle, the heteroatom in the 5- or 6-membered alkenheterocycle is N, and the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2;

[0307] Each R e-2 independently is an oxo group or an unsubstituted or R-substituted C 2-1 alkyl; 1-6 alkyl;

[0308] L independently is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L5 -L 6 -,-L 4 -L 5 -L 6 -,-L 5 -L 6 -,-L 2 -L 4 -L 5 -L 6 -,-L 1 -L 2 -L 3 -L 5 -L 6 -or -L 2 -L 3 -L 5 -L 6 -;(In each L, L 6 is connected to ring E, and the other end of L is connected to ring A);

[0309] Each -L 1 -is independently Each R P1 is independently deuterium, a halogen, or C 1-6 alkyl, or two Rs P1 together with the carbon atom to which they are attached form C 3-6 monocyclic subcycloalkyl or 3- to 6-membered monocyclic subheterocycloalkyl, the heteroatoms of the 3- to 6-membered monocyclic subheterocycloalkyl being selected from one or two of N and O, and the number of heteroatoms being 1 or 2; ring G is independently a 3- to 6-membered monocyclic alkheterocycle, the heteroatom of the 3- to 6-membered monocyclic alkheterocycle being N, and the number of heteroatoms being 1;

[0310] Each -L 2 -is independently unsubstituted or substituted by one or more Rs P2 substituted C 1-8 alkylene, unsubstituted or substituted by one or more Rs P2 substituted C 2-6 alkynylene, unsubstituted or substituted by one or more Rs P2 substituted C 3-10 subcycloalkyl, unsubstituted or substituted by one or more Rs P2 substituted 3- to 6-membered monocyclic subheterocycloalkyl or unsubstituted or substituted by one or more Rs P2 substituted 5- to 6-membered monocyclic subheteroaryl; the heteroatoms of the 3- to 6-membered monocyclic subheterocycloalkyl being selected from one or two of N and O, and the number of heteroatoms being 1 or 2; the heteroatoms of the 5- to 6-membered monocyclic subheteroaryl being N, and the number of heteroatoms being 1, 2, or 3; each C 1-8 alkylene and C 2-6One or more methylene units in the alkynylene group are optionally replaced by R P3 where each R P3 is independently C 3-10 subcycloalkyl or 3- to 6-membered monocyclic heterocycloalkyl;

[0311] each -L 3 - is independently

[0312] each -L 4 - is independently unsubstituted or substituted by one or more R P2 substituted phenylene, unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl or unsubstituted or substituted by one or more R P2 substituted C 3-10 subcycloalkyl; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2, or 3; ring H is a 5- to 6-membered heteroaromatic ring, ring H is a 5- to 6-membered heteroaromatic ring, the heteroatoms in the 5- to 6-membered heteroaromatic ring are selected from N, and the number of heteroatoms is 1, 2, or 3, and t1 is 0, 1, 2, 3, or 4;

[0313] each -L 5 - is independently unsubstituted or substituted by one or more R P2 substituted 3- to 6-membered monocyclic heterocycloalkyl, unsubstituted or substituted by one or more R P2 substituted 5- to 10-membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered heteroalkenyl; each of the 5- to 10-membered heteroaryls is monocyclic or fused-ring, the number of fused rings is 2, the heteroatoms of each of the 5- to 10-membered heteroaryls are N, and the number of heteroatoms is 1, 2, or 3; the heteroatoms of the 5- to 6-membered heteroalkenyl are N, and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl is 1 or 2; ring P is independently a 5- to 6-membered monocyclic heteroaromatic ring, the heteroatoms in the 5- to 6-membered monocyclic heteroaromatic ring are N, and the number of heteroatoms is 1 or 2; ring Q is independently a 3- to 6-membered monocyclic alkanheterocyclic ring, the heteroatoms of the 3- to 6-membered monocyclic alkanheterocyclic ring are N, and the number of heteroatoms is 1 or 2;

[0314] n1 and n2 are independently 0, 1, or 2;

[0315] each -L 6 - is independently unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene;

[0316] each R P2is independently a halogen.

[0317] In a preferred embodiment,

[0318] m is 1, 2, 3 or 4;

[0319] n is 1;

[0320] X 1 and X 2 are independently N;

[0321] Each R 2 is independently deuterium, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy;

[0322] Each R 2-1 and R 2-2 are independently a halogen;

[0323] R 3 is unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2;

[0324] Each R 3-1 is independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 6-membered monocyclic heteroalkyl, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2;

[0325] Each R 3-1-1 is a hydroxyl group;

[0326] Each R 3-9 is independently an oxo group (=O), a halogen or unsubstituted or substituted by one or more R 3-5-1 substituted C 1-6 alkyl;

[0327] Each R 3-5-1 is independently deuterium or a halogen;

[0328] Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is monocyclic or fused, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0329] R1 is hydrogen, deuterium or a halogen;

[0330] Each ring E is independently an unsubstituted or one or more R- e-1 substituted benzene ring or an unsubstituted or one or more R- e-1 substituted 5- or 6-membered heteroaromatic ring, the heteroatom in the 5- or 6-membered heteroaromatic ring being N and the number of heteroatoms being 1 or 2;

[0331] Each R e-1 is independently a halogen or C 1-6 alkyl;

[0332] Each ring F is independently a 5- or 6-membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom in the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2;

[0333] Each R e-2 is independently an oxo group or an unsubstituted or one or more R- 2-1 substituted C 1-6 alkyl;

[0334] L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 5 -L 6 -, -L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; (in each L, L 6 is connected to ring E and the other end of L is connected to ring A);

[0335] Each -L 1 - is independently

[0336] Each - L 2 - independently is unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 substituted C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heterocycloalkylene, unsubstituted or substituted by one or more R P2 substituted 5 - 6 - membered heteroarylene or wherein, Z 1 independently is O, Z 2 independently is a single bond or O; m1 independently is 0, 1 or 2; m2 independently is 0, 1 or 2; m3 independently is 0, 1 or 2; the heteroatoms of the 3 - 6 - membered monocyclic heterocycloalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5 - 6 - membered heteroarylene are N, and the number of heteroatoms is 1, 2 or 3;

[0337] Each - L 3 - independently is

[0338] Each - L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene or unsubstituted or substituted by one or more R P2 substituted 5 - 6 - membered heteroarylene; the heteroatoms of the 5 - 6 - membered heteroarylene are N, and the number of heteroatoms is 1, 2 or 3;

[0339] Each - L 5 - independently is unsubstituted 3 - 6 - membered monocyclic heterocycloalkylene or unsubstituted 5 - 6 - membered heteroallenyl, the heteroatoms of the 3 - 6 - membered monocyclic heterocycloalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5 - 6 - membered heteroallenyl are N, and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5 - 6 - membered heteroallenyl is 1 or 2;

[0340] Each - L 6 - independently is unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene;

[0341] Each R P2 independently is halogen.

[0342] In a certain preferred embodiment,

[0343] m is 1, 2, 3 or 4;

[0344] n is 1;

[0345] X 1 and X 2 are independently N;

[0346] Each R 2 is independently deuterium, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy;

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

[0348] Each R 3 is independently unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- to 6-membered heteroalkenyl; the heteroatom of the 5- to 6-membered heteroalkenyl is N, and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl is 1 or 2;

[0349] Each R 3-1 is independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 6-membered monocyclic heteroalkyl, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2;

[0350] Each R 3-1-1 is hydroxy;

[0351] Each R 3-9 is independently oxo (=O), halogen or unsubstituted or substituted by one or more R 3-5-1 substituted C 1-6 alkyl;

[0352] Each R 3-5-1 is independently deuterium or halogen;

[0353] Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is monocyclic or fused, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5;

[0354] R 1 is hydrogen, deuterium or halogen;

[0355] Each ring E is independently unsubstituted or substituted by one or more Re-1 A substituted benzene ring, or an unsubstituted benzene ring or a benzene ring substituted with one or more Rs e-1 A substituted 5- or 6-membered monocyclic heteroaromatic ring, wherein the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2;

[0356] Each R e-1 independently is a halogen or a C 1-6 alkyl;

[0357] Each ring F independently is a 5- or 6-membered enheterocyclic ring substituted with one or more Rs e-2 wherein the heteroatom in the 5- or 6-membered enheterocyclic ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2;

[0358] Each R e-2 independently is an oxo group or an unsubstituted or R-substituted C 2-1 alkyl; 1-6 1

[0359] L independently is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 5 -L 6 -, -L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; (in each L, L is connected to ring E, and the other end of L is connected to ring A); 6 1

[0360] Each -L 1 - independently is

[0361] Each -L 2 - independently is an unsubstituted or R-substituted P2Substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 Substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3- to 6-membered monocyclic heteroalkylene or unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl; the heteroatoms of the 3- to 6-membered monocyclic heteroalkylene are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5- to 6-membered monocyclic heteroaryl are N, and the number of heteroatoms is 1, 2 or 3;

[0362] each -L 3 - independently is

[0363] each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl; the heteroatoms of the 5- to 6-membered monocyclic heteroaryl are N, and the number of heteroatoms is 1, 2 or 3;

[0364] each -L 5 - independently is a 3- to 6-membered monocyclic heteroalkylene, the heteroatoms of the 3- to 6-membered monocyclic heteroalkylene are selected from one or both of N and O, and the number of heteroatoms is 1 or 2;

[0365] each -L 6 - independently is unsubstituted or substituted by one or more R P2 Substituted C 1-8 alkylene;

[0366] each R P2 independently is halogen.

[0367] In a certain preferred embodiment,

[0368] is

[0369] m is 1, 2, 3 or 4;

[0370] X 1 and X 2 independently are N;

[0371] each R 2 independently is deuterium, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy;

[0372] each R2-1 and R 2-2 are each independently halogen;

[0373] R 3 is each independently unsubstituted C 1-6 alkyl or an unsubstituted or one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2;

[0374] Each R 3-9 is independently an oxo group (=O) or halogen;

[0375] Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, or 3;

[0376] R 1 is hydrogen or deuterium;

[0377] Each ring E is independently an unsubstituted 5- or 6-membered monocyclic heteroaromatic ring, and the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2;

[0378] Each ring F is independently a 5- or 6-membered alkenyl hetero ring substituted with one or more R e-2 ; the heteroatom of the 5- or 6-membered alkenyl hetero ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2;

[0379] Each R e-2 is independently an oxo group or unsubstituted C 1-6 alkyl;

[0380] L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 -; (in each L, L 6 is connected to ring E, and the other end of L is connected to ring A);

[0381] each - L 1 - independently is

[0382] each - L 2 - independently is unsubstituted C 1-8 alkylene or unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heteroalkyl; the heteroatoms of the 3 - 6 - membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2;

[0383] each - L 3 - independently is

[0384] each - L 4 - independently is unsubstituted 5 - 6 - membered monocyclic heteroaryl; the heteroatom of the 5 - 6 - membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3;

[0385] each - L 5 - independently is substituted 3 - 6 - membered monocyclic heteroalkyl, the heteroatoms of the 3 - 6 - membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2;

[0386] each - L 6 - independently is unsubstituted C 1-8 alkylene;

[0387] each R P2 independently is halogen.

[0388] In a certain preferred embodiment,

[0389] m is 1, 2, 3 or 4;

[0390] n is 1;

[0391] X 1 and X 2 independently is N;

[0392] each R 2 independently is deuterium, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy;

[0393] each R 2-1 and R 2-2 independently is halogen;

[0394] each R 3 independently is unsubstituted or substituted by one or more R3-9 Substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, and the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2;

[0395] Each R 3-9 Independently is an oxo group (=O) or a halogen;

[0396] Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring is a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4, or 5;

[0397] R 1 Is hydrogen, deuterium, or a halogen;

[0398] Each ring E is independently an unsubstituted or one or more R- e-1 Substituted benzene ring or an unsubstituted or one or more R- e-1 Substituted 5- or 6-membered monocyclic heteroaromatic ring, the heteroatom of the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2;

[0399] Each R e-1 Independently is a halogen or C 1-6 Alkyl;

[0400] Each ring F is independently a 5- or 6-membered heteroalkene ring substituted with one or more R e-2 The heteroatom of the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2;

[0401] Each R e-2 Independently is an oxo group or an unsubstituted or one or more R- 2-1 Substituted C 1-6 Alkyl;

[0402] L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 5 -L 6 - or -L 2 -L 4 -L5 -L 6 -; (in each L, L 6 is connected to ring E, and the other end of L is connected to ring A);

[0403] each -L 1 - is independently

[0404] each -L 2 - is independently unsubstituted or substituted by one or more R P2 -substituted C 1-8 -alkylene, unsubstituted or substituted by one or more R P2 -substituted 3- to 6-membered monocyclic heteroalkyl or unsubstituted or substituted by one or more R P2 -substituted 5- to 6-membered monocyclic heteroaryl; the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2, or 3;

[0405] each -L 3 - is independently

[0406] each -L 4 - is independently unsubstituted or substituted by one or more R P2 -substituted 5- to 6-membered monocyclic heteroaryl; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2, or 3;

[0407] each -L 5 - is independently a 3- to 6-membered monocyclic heteroalkyl, and the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2;

[0408] each -L 6 - is independently unsubstituted or substituted by one or more R P2 -substituted C 1-8 -alkylene;

[0409] each R P2 is independently a halogen;

[0410] and ring A and L satisfy the following situation (1) or situation (2)

[0411] Situation (1): Ring A is monocyclic, and L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -;

[0412] Case (2): Ring A is a fused ring and L is -L 5 -L 6 -.

[0413] In a preferred embodiment, the compound represented by formula I is any one of the following compounds:

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] The present invention provides a pharmaceutical composition comprising:

[0426] (1) a compound represented by formula I as described in any one of the present invention or a pharmaceutically acceptable salt thereof, and

[0427] (2) a pharmaceutical excipient.

[0428] The present invention provides the use of a substance A in the preparation of a Polθ enzyme and / or PARP1 enzyme inhibitor, wherein the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0429] The present invention provides the use of a substance A in the preparation of a medicament for treating and / or preventing diseases related to Polθ enzyme and / or PARP1 enzyme, wherein the diseases related to Polθ enzyme and / or PARP1 enzyme may be breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, and the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0430] The present invention provides the use of a substance A in the preparation of a medicament for treating and / or preventing breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, and the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0431] The present invention provides a substance A for use as a treatment, and the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0432] The present invention provides a substance A for treating and / or preventing breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, and the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0433] The present invention provides a method for treating and / or preventing breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, which comprises the following step: administering (a therapeutically effective amount of) a substance A to a subject, and the substance A is a compound represented by formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition.

[0434] Detailed description: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0435] Those skilled in the art can understand that, according to the convention used in the art, the used in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0436] In this article, a single dash "-" can be added in front of the substituents used, indicating that the named substituent is connected to the parent part through a single bond.

[0437] When any variable (such as R 2-1 ) appears more than once in the composition or structure of the compound, its definition in each case is independent. Therefore, for example, if a group is substituted by 0-2 R 2-1 , then the group may optionally be substituted by at most two R 2-1 , and R 2-1 in each caseThere are independent options. In addition, combinations of substituents and / or their variants are only permitted if such combinations result in stable compounds.

[0438] When one of the variables is selected from a single bond, it means that the two groups it connects are directly linked. For example, when L represents a single bond in A-L-Z, it indicates that the structure is actually A-Z.

[0439] The term "plurality" means 2, 3, 4, or 5, preferably 2 or 3.

[0440] In the claims of this application, "one or more of the following conditions are met", the "more" means 2, 3, 4, or more, and the maximum value of the "more" is the maximum numerical value of the conditions recited in each claim. For example, if a claim recites 8 conditions, "one or more of the following conditions are met" in this claim means any integer from 1 to 8, such as 1, 2, 3, 4, 5, 6, 7, or 8.

[0441] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patients" are preferably mammals, more preferably humans.

[0442] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base.

[0443] When the listed linking groups do not specify their linking directions, their linking directions are the same as the reading order from left to right. For example, the linking group L in 1 -L 2 -L 3 -L 4 -L 5 -L 6 - is -L at this time, 1 -L 2 -L 3 -L 4 -L 5 -L 6 - connects ring A and ring E in the same direction as the reading order from left to right to form Specifically in a certain embodiment, for example, when L is it means that the methylene at the 1-position is connected to ring A and the methylene at the 2-position is connected to ring E.

[0444] When the number of a linking group is 0, such as when m1 is 0 in it means is a single bond,

[0445] "Halogen" means fluorine, chlorine, bromine or iodine.

[0446] "Oxo" means =O, where an oxygen atom replaces two hydrogens on the same carbon atom, i.e., a carbonyl group replaces a methylene group.

[0447] "Alkyl" (e.g., C 1-14 alkyl, C 1-8 alkyl, C 1-6 alkyl) means a straight-chain or branched-chain alkyl group having the specified number of carbon atoms. For example, C1-C 14 alkyl means an alkyl group containing 1-14 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and similar alkyl groups, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0448] "Alkoxy" means the group -O-R X , where R X is an alkyl group as defined above, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0449] "Alkenyl" means a straight-chain or branched-chain monovalent alkenyl group having at least two carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, and the one or more carbon-carbon double bonds can be internal or terminal. "C 2-6 alkenyl" means a straight-chain or branched-chain alkenyl group containing 2-6 carbon atoms. Examples of alkenes include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2-propenyl, hexenyl, etc., preferably vinyl, propenyl or allyl.

[0450] "Alkynyl" means a straight-chain or branched-chain monovalent alkynyl group having at least two carbon atoms, containing one or more carbon-carbon triple bonds and no carbon-carbon double bonds, and the one or more carbon-carbon triple bonds can be internal or terminal. "C 2-6 alkynyl" means a straight-chain or branched-chain alkynyl group containing 2-6 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C 2-4 alkynyl", more preferably ethynyl, propynyl or propargyl.

[0451] Unless otherwise specified, the number of atoms in a ring is usually defined as the ring member count. For example, a "3-10 membered ring" means a "ring" composed of 3-10 atoms arranged in a ring.

[0452] "Cycloalkyl" means a saturated monocyclic or polycyclic hydrocarbon group; "C 3-10"Cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms, and said C3-C 10 The cycloalkyl group includes C3-C6, C5-C 10 , C3-C8, etc. "Cycloalkyl" can be a monocyclic cycloalkyl group or a polycyclic cycloalkyl group, and the polycyclic cycloalkyl group includes spiro, fused, and bridged cycloalkyl groups.

[0453] Non-limiting examples of the monocyclic cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and preferably cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0454] "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between monocyclic rings. For example, C 5-10 Spirocycloalkyl groups, such as 4-spiro-4-membered cycloalkyl, 4-spiro-5-membered cycloalkyl, 4-spiro-6-membered cycloalkyl, 5-spiro-4-membered cycloalkyl, 5-spiro-5-membered cycloalkyl, 5-spiro-6-membered cycloalkyl, 6-spiro-4-membered cycloalkyl, or 6-spiro-5-membered cycloalkyl. Non-limiting examples of the spirocycloalkyl group include spiro[3.3]heptyl, etc.

[0455] "Fused cycloalkyl" refers to a completely carbonaceous polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. Preferred is a bicyclic fused cycloalkyl group, such as 4-fused-4-membered cycloalkyl, 4-fused-5-membered cycloalkyl, 4-fused-6-membered cycloalkyl, 5-fused-5-membered cycloalkyl, 5-fused-6-membered cycloalkyl, or 6-fused-6-membered cycloalkyl. Non-limiting examples of the fused cycloalkyl group include bicyclo[3.3.0]octyl.

[0456] "Bridged cycloalkyl" refers to a completely carbonaceous polycyclic group in which any two rings share two non-directly connected carbon atoms. Preferred is a bicyclic bridged cycloalkyl group, such as 4-bridged-4-membered cycloalkyl, 3-bridged-5-membered cycloalkyl, 4-bridged-5-membered cycloalkyl, or 4-bridged-6-membered cycloalkyl. Non-limiting examples of the bridged cycloalkyl group include bicyclo[1.1.1]pentyl, bicyclo[3.1.1]heptyl.

[0457] "Heterocycloalkyl" refers to a saturated monocyclic or polycyclic cycloalkyl group having a specified number of ring atoms (e.g., 3-12 membered, 4-12 membered, 3-10 membered, 5-6 membered, 3-8 membered, 3-6 membered, 3-9 membered, 4-6 membered, 5-6 membered, and 5-9 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (e.g., one or more of N, O, S, and P, preferably one or more of N, O, and S). "Heterocycloalkyl" can be a monocyclic heterocycloalkyl group or a polycyclic heterocycloalkyl group, and the polycyclic heterocycloalkyl group includes spiro, fused, and bridged cycloalkyl groups; preferably a monocyclic heterocycloalkyl group.

[0458] The monocyclic heterocycloalkyl is preferably a 3- to 8-membered monocyclic heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O or S; non-limiting examples of the monocyclic heterocycloalkyl include azetidinyl, oxetanyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), etc.

[0459] "Heterospirocycloalkyl" refers to a polycyclic group in which a single carbon atom (referred to as a spiro atom) is shared between monocycles.

[0460] "Heterofused cycloalkyl" refers to a fully carbon polycyclic group in which each ring in the group shares an adjacent pair of carbon atoms with other rings in the system.

[0461] "Heterobicycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms.

[0462] "Alkyl heterocycle" refers to a saturated monocyclic or polycyclic ring system having a specified number of ring atoms (e.g., 3-12 membered, 4-12 membered, 3-10 membered, 5-6 membered, 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered and 5-9 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified heteroatom type (e.g., one or more of N, O, S and P, preferably one or more of N, O and S), and is preferably monocyclic. In certain embodiments of the present invention, the alkyl heterocycle is

[0463] "Heterocyclic alkenyl" refers to a cyclic unsaturated monovalent group having a specified number of ring atoms (e.g., 4-12 membered, 5-6 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), and containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, and is preferably monocyclic. Heterocyclic alkenyls include, but are not limited to, etc.

[0464] "Alkenyl heterocycle" refers to a cyclic ring system having a specified number of ring atoms (e.g., 4-12 membered, 5-6 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom type (one or more of N, O and S), and containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, and is preferably monocyclic. Monocyclic alkenyl heterocyclic groups include, but are not limited to,

[0465] The term "aryl" refers to a cyclic group consisting only of carbon atoms having a specified number of carbon atoms (e.g., C 6-10 ), which is monocyclic or polycyclic, and each ring has aromaticity (complies with Hückel's rule). Aryls include, but are not limited to, phenyl, naphthyl, etc.

[0466] "Heteroaryl" refers to a heteroaromatic system having a specified number of ring atoms (e.g., 5-12 membered, 5-10 membered, 5-6 membered), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatoms (one or more of N, O, and S). "Heteroaryl" is monocyclic or fused-ring, and a fused-ring refers to a carbocyclic polycyclic group in which each ring in the group shares an adjacent pair of carbon atoms with other rings in the system. When it is a fused-ring, at least one ring is aromatic, and the number of rings in the fused-ring can be 2. In certain embodiments of the present invention, "heteroaryl" can be pyridyl, imidazolyl or pyrazolyl, etc.

[0467] "Heteroaromatic ring" refers to a heteroaromatic cyclic system having a specified number of ring atoms (e.g., 5-12 membered, 5-10 membered, 5-6 membered, 8-10 membered), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatoms (one or more of N, O, and S). It is monocyclic or fused-ring, and a fused-ring refers to a carbocyclic polycyclic group in which each ring in the group shares an adjacent pair of carbon atoms with other rings in the system. When it is a fused-ring, at least one ring is aromatic, and the number of rings in the fused-ring can be 2. In certain embodiments of the present invention, "heteroaromatic ring" is a pyridine ring,

[0468] "Subunit" refers to a divalent group. For example, alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, heteroalkylene refers to a divalent heteroalkyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl groups are as defined above.

[0469] "Optionally" means that the subsequently described event or circumstance may, but need not, occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally alkyl-substituted heteroalkyl group" means that the alkyl group may, but need not, be present, and this description includes the cases where the heteroalkyl group is substituted by an alkyl group and the cases where the heteroalkyl group is not substituted by an alkyl group.

[0470] The term "pharmaceutical excipient" refers to excipients and additives used in the production of drugs and the formulation of prescriptions, and is all substances contained in a pharmaceutical preparation except for the active ingredient.

[0471] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thus exert its biological activity.

[0472] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0473] The term "treatment" means administering the compounds or formulations described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0474] (i) inhibiting the disease or disease state, i.e., curbing its development;

[0475] (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to subside.

[0476] The term "therapeutically effective amount" means the amount of the compound of the present application that (i) treats a specific disease, condition or disorder, (ii) alleviates, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0477] The term "patient" refers to any animal that is about to receive or has received administration of the compound or composition according to an embodiment of the present invention, preferably a mammal, and most preferably a human. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.

[0478] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0479] The reagents and raw materials used in the present invention are all commercially available.

[0480] The positive and progressive effects of the present invention are as follows: The small molecule compound provided by the present invention has good inhibitory effects on Polθ enzyme and PARP1 enzyme. Further, it has a strong inhibitory effect on the proliferation of DLD1 BRCA2- / - cells, and has a very weak inhibitory effect on the proliferation of DLD1 wild-type cells, showing good selectivity. Furthermore, the compound of the present application can overcome drug resistance, reduce the dosage, reduce the toxic and side effects, and achieve the purpose of expanding the indications and improving the therapeutic effect. Detailed Embodiments

[0481] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples described herein. The experimental methods without specific conditions noted in the following examples are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0482] All compounds of the present invention can be synthesized by those skilled in the art of organic chemistry through different methods. The general synthetic schemes for preparing the compounds of the present invention are described below. These schemes are general and do not mean to limit the possible 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. In addition, the various steps in the synthesis can be carried out in an alternative order to obtain the desired one or more compounds. The preparation and example sections described below give examples of preparing the compounds of the present invention by the methods described in the general schemes. The preparation of compounds with chiral centers in the examples can be carried out by techniques mastered by those skilled in the art. For example, chiral compounds can be prepared by chiral resolution of racemic products through HPLC; alternatively, the example compounds can be prepared by known methods to obtain chiral compounds.

[0483] The chemical reactions and synthetic techniques described herein are carried out in the reagents and corresponding solvents described in the text, and the corresponding reaction yields are also affected by the reagents and solvents used. In addition, it should be understood that in the synthetic methods described below, all mentioned reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experiment duration, and reaction feeding order, should be regarded as the standard operating conditions for the reaction, which should be easily recognizable by those skilled in the art. At the same time, it can also be understood by those skilled in the art of organic synthesis. The functional groups present on each part of the molecule must be compatible with the reagents used and the reaction itself. For the limitation that some of the functional groups present on each part of the molecule are not compatible with the reaction conditions, alternative methods must be used, which will be obvious to those skilled in the art. For the need to judge and adjust the order of synthetic steps, or select a specific synthetic process scheme to obtain the compounds required by the present invention, it is obvious. This can be understood and easily recognized by those skilled in the art of organic synthesis. It should also be recognized that another major consideration in designing any synthetic route in this field is the reasonable selection of protecting groups to tolerate the reactive functional groups present in the compounds described in the present invention. Specifically, reference can be made to the works of authoritative figures in the chemical field such as Greene et al. (Protective Groups in Organic Synthesis, Third Edition, Wiley and Sons (1999)).

[0484] Examples

[0485] The preparation of the compounds and the intermediates used in the preparation of the compounds can be prepared using the procedures shown in the following examples and related procedures. The methods and conditions used in these examples and the actual compounds prepared in these examples are not meant to be limiting, but rather to illustrate how to prepare the relevant compounds. The starting materials and reagents used in these examples, when not prepared by the procedures described herein, are generally commercially available, or reported in the relevant chemical literature, or can be prepared by using the procedures described in the chemical literature.

[0486] In the examples given herein, the term "drying and concentration" generally refers to adding anhydrous sodium sulfate or magnesium sulfate to dry the solution in an organic solvent, then filtering and removing the solvent from the filtrate (usually carried out under reduced pressure and at a temperature suitable for the stability of the compound being prepared). Column chromatography is usually carried out using conventional column chromatography or flash column chromatography for column separation and purification, or using a pre-packed silica gel column on a medium-pressure chromatograph (Biotage Isola One), and eluting with the specified solvent or solvent mixture. In some cases, a 20 cm x 20 cm x 0.5 mm or 20 cm x 20 cm x 1 mm silica gel plate in a suitable solvent system is used to rapidly purify the final product by preparative thin-layer chromatography. Preparative high-performance liquid chromatography (HPLC) is carried out using a reverse-phase column (Waters Sunfire C18, Waters Xbridge C18 or similar reverse-phase columns) sized to fit the amount of compound being separated, usually eluting with a gradient of the concentration of methanol or acetonitrile added to the aqueous phase, and the eluent containing 0.05% or 0.1% formic acid, trifluoroacetic acid or 10 mM ammonium acetate, with the elution rate matching the size of the reverse-phase column used and the resolution of the compound being prepared.

[0487] List of Abbreviations

[0488]

[0489]

[0490] Intermediate 1: 2''-Difluoromethyl-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid

[0491]

[0492] Step 1: Benzyl 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylate

[0493] Under nitrogen protection at room temperature, to a mixed solution of 6-chloro-4-iodonicotinic acid benzyl ester (5.0 g, 13.40 mmol) in 1,4-dioxane (50 mL) and water (10 mL) were successively added 2-difluoromethyl-5-methoxy-4-boronate pyridine (4.58 g, 16.08 mmol), potassium phosphate (8.53 g, 40.21 mmol) and (1,1'-bis(di-tert-butylphosphino)ferrocene)palladium(II) dichloride (865 mg, 0.294 mmol). The reaction mixture was stirred at 90 °C for 1.5 hours under nitrogen protection. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 30% ethyl acetate) to obtain the target compound (white solid, 3.06 g, yield 56.5%). LC / MS (ESI) m / z: 405.1 [M+H] + .

[0494] Step 2: Benzyl 2''-difluoromethyl-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylate

[0495] Under nitrogen protection at room temperature, 6-chloro-2'-difluoromethyl-5'-methoxy-4,4'-bipyridine-3-carboxylic acid benzyl ester (3.0 g, 7.42 mmol), 3-fluoropyridin-2(1H)-one (1.26 g, 11.15 mmol), copper(I) 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 with nitrogen three times and stirred at 100 °C for 1 hour under nitrogen protection. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 30% - 70% ethyl acetate) to obtain the target compound (white solid, 1.41 g, yield 39.5%). LC / MS (ESI) m / z: 482.2 [M+H] + .

[0496] Step 3: 2''-Difluoromethyl-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid

[0497] Under nitrogen protection at room temperature, 10% palladium on carbon (300 mg) was added to a solution of benzyl 2''-difluoromethyl-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylate (1.4 g, 2.91 mmol) in methanol (14 mL). The mixture was purged with nitrogen three times and stirred at room temperature for 3 hours under a hydrogen atmosphere at 1 atm. After the reaction was complete, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (brown solid, 1.01 g, yield 88.7%). LC / MS (ESI) m / z: 392.1 [M+H] + .

[0498] Intermediate 2: 4-(1-((3-Ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid Step 1: Ethyl 2-(4-bromo-2-nitrobenzyl)butyrate

[0499]

[0500] Step 2: 7-Bromo-3-ethylquinolin-2(1H)-one

[0501] Under nitrogen protection, a suspension of 60% sodium hydride (20.9 g, 0.52 mmol) in anhydrous tetrahydrofuran (1 L) was cooled to 0 °C, and ethyl 2-(diethoxyphosphoryl)butyrate (132 g, 0.52 mol) was added to the suspension in portions. After addition, the mixture was stirred for 0.5 hour. The reaction system was cooled to -78 °C, and 4-bromo-2-nitrobenzaldehyde (50 g, 0.22 mol) was added, and the mixture was stirred for 2 hours. After the reaction was complete, saturated ammonium chloride aqueous solution was added, stirred for 3 minutes, and extracted with ethyl acetate. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 20% ethyl acetate) to obtain the target compound (colorless oil, 29 g, yield 40%). LC / MS (ESI) m / z: 328 [M+H] + .

[0502] Step 3: 3-Ethyl-7-(hydroxymethyl)quinolin-2(1H)-one

[0503] Under nitrogen protection, iron powder (36 g, 642 mmol) was added to a solution of ethyl 2-(4-bromo-2-nitrobenzylidene)butyrate (26 g, 79 mmol) in glacial acetic acid (700 mL). The reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane and methanol, filtered to remove the solid, and concentrated again under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 10% methanol) to obtain the target compound (white solid, 2.5 g, yield 12%). LC / MS (ESI) m / z: 252 [M+H] + .

[0504] Step 4: 7-(Chloromethyl)-3-ethylquinolin-2(1H)-one

[0505] Under nitrogen protection, (tributylstannyl)methanol (3.8 mg, 11.8 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (800 mg, 0.99 mmol) were added to 1,4-dioxane (50 mL) of 7-bromo-3-ethylquinolin-2(1H)-one (2.5 g, 9.9 mmol). After displacing nitrogen three times, the reaction solution was stirred at 80 °C for 16 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 15% methanol) to obtain the target compound (white solid, 700 mg, yield 39%). LC / MS (ESI) m / z: 204 [M+H] + .

[0506] Step 5: tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0507] Under nitrogen protection, 3-ethyl-7-(hydroxymethyl)quinolin-2(1H)-one (1 g, 4.5 mmol) and a catalytic amount of N,N-dimethylformamide (18 mg, 0.25 mmol) were dissolved in dichloromethane (20 mL). At 0 °C, thionyl chloride (1.76 g, 14.7 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (white solid, 900 mg, yield 83%). LC / MS (ESI) m / z: 222 [M+H] + .

[0508] Step 6: Methyl 4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate hydrochloride

[0509] Under nitrogen protection, methyl 4-bromobenzoate (1 g, 4.67 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.16 g, 7.01 mmol) and potassium carbonate (1.93 g, 14.01 mmol) were dissolved in 1,4-dioxane (25 mL), and then 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (34 mg, 0.047 mmol) was added. The reaction mixture was stirred at 100 °C overnight under nitrogen protection. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 70% ethyl acetate) to obtain the target compound (yellow solid, 1.4 g, yield 94.6%). LC / MS (ESI) m / z: 318 [M+H] + .

[0510] Step 7: Methyl 4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-

[0511] tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 4.41 mmol) and methanol (10 mL) were added to a reaction flask, and 4N hydrochloric acid dioxane (10 mL) solution was added to the mixture. The reaction mixture gradually became clear, and it was stirred at room temperature for 1 hour, during which a solid precipitated. The reaction mixture was concentrated under reduced pressure, and then triturated with ethyl acetate to obtain the target compound (1.1 g, yellow solid, yield 91%). LC / MS (ESI) m / z: 218 [M+H] + .

[0512] 4-yl)benzoate Step 8: 4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-

[0513] At room temperature, methyl 4-(1,2,3,6-tetrahydropyridin-4-yl)benzoate hydrochloride (140 mg, 0.55 mmol), 7-(chloromethyl)-3-ethylquinolin-2(1H)-one (122 mg, 0.55 mmol), sodium iodide (9 mg, 0.055 mmol) and N,N-diisopropylethylamine (355 mg, 2.75 mmol) were dissolved in acetonitrile (4 mL). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane and water were added to the mixture, and it was separated into layers. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ether to obtain the target compound (200 mg, yellow solid, yield 90.4%). LC / MS (ESI) m / z: 403 [M+H] + .

[0514] 4-yl)benzoic acid 4-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzoic acid

[0515] At room temperature, methyl 4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoate (200 mg, 0.50 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, and an aqueous solution (3 mL) of lithium hydroxide hydrate (104 mg, 2.5 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH was adjusted to ~3 with 1 N hydrochloric acid. An oily substance precipitated out, was dissolved in a small amount of acetonitrile, and freeze-dried. The freeze-dried solid was dissolved in methanol, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was further slurried with acetonitrile to obtain the target compound (180 mg, yellow solid, yield 93%). LC / MS (ESI) m / z: 389 [M+H] + .

[0516] Intermediate 3: Step 1: Methyl 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzoate Step 2: 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzoic acid

[0517]

[0518] Example 1: 2''-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) methyl)piperazin-1-yl)picolylamino)-1,3,4-thiadiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,

[0519] At room temperature, methyl 4-(piperazin-1-yl)benzoate (120 mg, 0.54 mmol), 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (121 mg, 0.54 mmol), sodium iodide (8 mg, 0.054 mmol), and N,N-diisopropylethylamine (348 mg, 2.7 mmol) were dissolved in acetonitrile (4 mL). The reaction solution was stirred at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane and water were added to the mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was slurried with ether to obtain the target compound (140 mg, yellow solid, yield 63.3%). LC / MS (ESI) m / z: 407 [M+H] + .

[0520] 2':4',4''-terpyridine]-5'-carboxamide Step 1: 7-(Chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0521] At room temperature, methyl 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzoate (140 mg, 0.34 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, and an aqueous solution (3 mL) of lithium hydroxide hydrate (72 mg, 1.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH was adjusted to ~3 with 1 N hydrochloric acid. An oily substance precipitated out, was dissolved in a small amount of acetonitrile, and freeze-dried. The freeze-dried solid was dissolved in methanol, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was further slurried with acetonitrile to obtain the target compound (120 mg, yellow solid, yield 89%). LC / MS (ESI) m / z: 393 [M+H] + .

[0522] Step 2: N-(5-Amino-1,3,4-thiadiazol-2-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo 2H-[1,2':4',4''-bipyridine]-5'-carboxamide Step 3: tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0523]

[0524] Step 4: Methyl 5-(piperazin-1-yl)picolinate hydrochloride

[0525] Under an ice bath, 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (200 mg, 0.98 mmol) and N,N-dimethylformamide (0.01 mL, 0.098 mmol) were dissolved in anhydrous dichloromethane (6 mL), and then thionyl chloride (0.42 mL, 5.88 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled, and saturated aqueous sodium bicarbonate was slowly added to adjust the pH to ~7. The mixture was separated into layers, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified under reduced pressure to obtain the target compound (yellow solid, 210 mg, yield 96.3%). LC / MS (ESI) m / z: 223.2 [M+H] + .

[0526] Step 5: Methyl 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate Step 6: 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinic acid

[0527] At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (200 mg, 0.51 mmol), 2,5-diamino-1,3,4-thiadiazole (59.4 mg, 0.51 mmol) and N,N-diisopropylethylamine (198 mg, 1.533 mmol) were dissolved in N,N-dimethylformamide (10 mL). 1H-Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (399 mg, 0.77 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and 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: 2 - 7% methanol) to obtain the target compound (yellow solid, 160 mg, yield 64%). LC / MS (ESI) m / z: 490.2 [M+H] + .

[0528] Step 7: 2''-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)-1,3,4-thiadiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0529] Under nitrogen protection, methyl 5-bromopyridine-2-carboxylate (950 mg, 4.40 mmol), tert-butyl piperazine-1-carboxylate (819 mg, 4.40 mmol) and cesium carbonate (4.3 g, 13.2 mmol) were dissolved in toluene (25 mL), and then 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (205 mg, 0.44 mmol) and tris(dibenzylideneacetone)dipalladium (121 mg, 0.13 mmol) were added. The reaction solution was stirred at 100 °C overnight under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 70% ethyl acetate) to obtain the target compound (yellow solid, 420 mg, yield 29.7%). LC / MS (ESI) m / z: 322.3 [M+H] + .

[0530] ​

[0531] tert-Butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (420 mg, 1.31 mmol) and methanol (3 mL) were added to a reaction flask, 4N hydrochloric acid dioxane (3 mL) solution was added to the mixture, the reaction solution gradually became clear, and it was stirred at room temperature for 1 hour, and a solid precipitated. The reaction solution was concentrated under reduced pressure, and the residue was triturated with ethyl acetate to obtain the target compound (330 mg, yellow solid, yield 98%). LC / MS (ESI) m / z: 222.3 [M+H]+ .

[0532] ​ ​

[0533] At room temperature, methyl 5-(piperazin-1-yl)picolinate hydrochloride (162 mg, 0.63 mmol), 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (140 mg, 0.63 mmol), sodium iodide (9.42 mg, 0.063 mmol) and N,N-diisopropylethylamine (406 mg, 3.14 mmol) were dissolved in acetonitrile (20 mL), and the reaction solution was stirred at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane and water were added to the mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with ether to give the target compound (230 mg, yellow solid, yield 89.8%). LC / MS (ESI) m / z: 408.4 [M+H] + .

[0534] ​ ​

[0535] At room temperature, methyl 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (220 mg, 0.54 mmol) and tetrahydrofuran (4 mL) were added to a reaction flask, and an aqueous solution (4 mL) of lithium hydroxide hydrate (113 mg, 2.7 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH value was adjusted to 3 with 1N hydrochloric acid. An oil separated out, which was dissolved in a small amount of acetonitrile and freeze-dried. The freeze-dried solid was dissolved in methanol, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was further triturated with acetonitrile to give the target compound (140 mg, yellow solid, yield 72.5%). LC / MS (ESI) m / z: 394.0 [M+H] + .

[0536] ​ (piperazin-1-yl)pyridinecarboxamido)-1,3,4-thiadiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2': 4',4”-terpyridine]-5'-carboxamide

[0537] At room temperature, N-(5-amino-1,3,4-thiadiazol-2-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamide (30 mg, 0.061 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (24.1 mg, 0.061 mmol), and N-methylimidazole (30.2 mg, 0.37 mmol) were dissolved in acetonitrile (1 mL) and N,N-dimethylformamide (1 mL). After stirring at 70 °C for 5 minutes, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (34.4 mg, 0.12 mmol) in acetonitrile (1 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and saturated brine, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the target compound (2 mg, white solid, yield 3.8%). 1 H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 12.17 (s, 1H), 11.94 (s, 1H), 9.01 (s, 1H), 8.53 - 8.51 (m, 2H), 8.48 - 8.46 (m, 1H), 8.07 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.75 (m, 2H), 7.60 - 7.51 (m, 2H), 7.16 - 6.85 (m, 1H), 6.45 - 6.40 (m, 1H), 3.72 (s, 3H), 3.55 (s, 2H), 3.48 - 3.44 (m, 4H), 3.24 - 3.09 (m, 4H), 2.60 - 2.55 (m, 2H), 1.23 - 1.17 (m, 3H). LC / MS (ESI) (m / z): 865 [M + H] + .

[0538] Example 2: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- (yl)methyl)piperazin-1-yl)pyridinecarboxamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H- [1,2':4',4”-terpyridine]-5'-carboxamide

[0539]

[0540] Step 1: Benzyl (5-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyr idine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)carbamate

[0541] At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (86 mg, 0.22 mmol), benzyl (5-amino-1,2,4-thiadiazol-3-yl)carbamate (50 mg, 0.200 mmol) and 1-methylimidazole (66 mg, 0.80 mmol) were dissolved in acetonitrile (2 mL). After stirring at 70 °C for one minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (84 mg, 0.30 mmol) in acetonitrile (0.5 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 2 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with water and saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 80 mg, yield 64%). LC / MS (ESI) m / z: 624.2 [M+H] + .

[0542] Step 2: N-(3-Amino-1,2,4-thiadiazol-5-yl)-2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-ox o-2H-[1,2':4',4”-bipyridine]-5'-carboxamide

[0543] Benzyl (5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)carbamate (80 mg, 0.13 mmol) and trifluoroacetic acid (3 mL) were added to a reaction flask, and the reaction mixture was stirred at 80 °C for two hours. The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 50 mg, yield 79.6%). LC / MS (ESI) m / z: 490.2 [M+H] + .

[0544] Step 3: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- (yl)methyl)piperazin-1-yl)pyridinecarboxamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H- [1,2':4',4”-terpyridine]-5'-carboxamide

[0545] At room temperature, N-(3-amino-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (20 mg, 0.041 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (16 mg, 0.041 mmol) and N-methylimidazole (20 mg, 0.25 mmol) were dissolved in acetonitrile (2 mL) and N,N-dimethylformamide (0.5 mL). After stirring at 70 °C for one minute, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (23 mg, 0.082 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 2 hours. After filtration of the mixture, it was purified by preparative HPLC to obtain the target compound (0.92 mg, white solid, yield 2.6%). 1 H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.46 - 10.20 (m, 1H), 9.12 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 7.97 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.58 - 7.51 (m, 1H), 7.48 (d, J = 9.3 Hz, 1H), 7.34 - 7.29 (m, 1H), 7.09 - 6.79 (m, 1H), 6.45 - 6.37 (m, 1H), 3.68 (s, 3H), 3.67 (s, 2H), 3.47 (s, 4H), 3.31 - 3.29 (m, 4H), 2.58 - 2.57 (m, 2H), 1.21 - 1.16 (m, 3H). LC / MS (ESI) (m / z): 865 [M + H] + .

[0546] Example 3: 2”-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl) methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyr idine]-5'-carboxamide

[0547]

[0548] Step 1: tert-Butyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1-carboxylate

[0549] At room temperature, to a solution of 7-(chloromethyl)-3-ethyl-1,2-dihydropyrido[3,2-b]pyridin-2-one (140 mg, 0.629 mmol) and 2-methylpropan-2-yl piperazine-1-carboxylate (117.1 mg, 0.629 mmol) in acetonitrile (3 mL) were successively added DIEA (406.3 mg, 3.15 mmol) and potassium iodide (20.9 mg, 0.126 mmol). The mixture was stirred at 80 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, ethyl acetate and water were added to the reaction solution, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 5 - 20% ethyl acetate) to obtain the target compound (white solid, 190 mg, yield 81.1%). LC / MS (ESI) m / z: 373.3 [M+H] + .

[0550] Step 2: 3-Ethyl-7-(piperazin-1-ylmethyl)-1,5-naphthyridin-2(1H)-one

[0551] Under an ice bath, trifluoroacetic acid (TFA, 0.2 mL, 2.55 mmol) was added to a solution of tert-butyl 4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazine-1-carboxylate (190 mg, 0.51 mmol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure to obtain the target compound (light yellow oil, 130 mg, yield: 93.6%). LC / MS (ESI) m / z: 273.1 [M+H] + .

[0552] Step 3: 7-((4-(5-Amino-1,3,4-thiadiazol-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naph thyridin-2(1H)-one

[0553] At room temperature, 3-ethyl-7-(piperazin-1-ylmethyl)-1,2-dihydropyrido[3,2-b]pyridin-2-one (130 mg, 0.48 mmol) was dissolved in DMF (4 mL), and then 5-bromo-1,3,4-thiadiazol-2-amine (85.9 mg, 0.48 mmol) and potassium carbonate (197.9 mg, 1.43 mmol) were added. The reaction solution was stirred at 80 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with acetonitrile, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 80 mg, yield 45.1%). LC / MS (ESI) m / z: 372.1 [M+H] + .

[0554] Step 4: 2”-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)meth yl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyr idine]-5'-carboxamide

[0555] At room temperature, 7-((4-(5-amino-1,3,4-thiadiazol-2-yl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (70 mg, 0.19 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (73.7 mg, 0.18 mmol) and N-methylimidazole (77.4 mg, 0.942 mmol) were dissolved in acetonitrile (2 mL). After stirring at 70 °C for 5 minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (79.3 mg, 0.28 mmol) was added, and then the reaction mixture was stirred at 70 °C for an additional 2 hours. Ethyl acetate and water were added to the reaction mixture, and the layers were separated. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (eluent: acetonitrile / 0.1% aqueous formic acid, gradient: 25% - 90%) to obtain the target compound (white solid, 6.7 mg, yield 4.77%). 1 H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 11.86 (s, 1H), 8.96 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.85 (d, J = 7.1 Hz, 1H), 7.73 (d, J = 17.4 Hz, 2H), 7.62 (s, 1H), 7.59 - 7.54 (m, 1H), 6.99 (t, J = 55.1 Hz, 1H), 6.45 - 6.39 (m, 1H), 3.74 (s, 3H), 3.65 (s, 2H), 3.42 (s, 4H), 2.59 - 2.52 (m, 4H), 2.51 (s, 2H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 745 [M+H] + .

[0556] Example 4: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- (yl)methyl)piperazin-1-yl)pyridinecarboxamidopropionamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2- Oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0557]

[0558] Step 1: Ethyl 3-(5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) pyridinecarboxamido)propionate

[0559] At room temperature, 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolonic acid (60 mg, 0.15 mmol), 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg, 0.23 mmol), and N,N-diisopropylethylamine (98.55 mg, 0.76 mmol) were dissolved in N,N-dimethylformamide (6 mL). Ethyl beta-alaninate hydrochloride (49 mg, 0.31 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 48 mg, yield 63.9%). LC / MS (ESI) m / z: 493.5 [M+H] + .

[0560] Step 2: 3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) pyridinecarboxamido)propanoic acid

[0561] At room temperature, ethyl 3-(5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide)propionate (48 mg, 0.097 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask. Subsequently, an aqueous solution (1 mL) of lithium hydroxide hydrate (20 mg, 0.49 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH was adjusted to ~3 with 1 N hydrochloric acid. A white solid precipitated out, was filtered, and the solid was dried under reduced pressure to obtain the target compound (32 mg, white solid, yield 71%). LC / MS (ESI) m / z: 465.5 [M+H] + .

[0562] Step 3: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridinecarboxamido)propanamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2- oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0563] At room temperature, N-(3-amino-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (20 mg, 0.041 mmol), 3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamidopropanoic acid (19 mg, 0.041 mmol), and N-methylimidazole (20 mg, 0.25 mmol) were dissolved in acetonitrile (2 mL) and N,N-dimethylformamide (0.5 mL). After stirring at 70 °C for one minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (17 mg, 0.061 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 70 °C for 3 hours. After filtration, the mixture was purified by preparative HPLC to obtain the target compound (10 mg, white solid, yield 26%). 1 H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 11.87 (s, 1H), 10.98 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.47 (t, J = 6.0 Hz, 1H), 8.42 (s, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.86 (t, J = 7.3 Hz, 2H), 7.77 (s, 2H), 7.64 (s, 1H), 7.61 - 7.54 (m, 1H), 7.41 (d, J = 6.6 Hz, 1H), 7.01 (t, J = 55.0 Hz, 1H), 6.47 - 6.39 (m, 1H), 3.68 (s, 3H), 3.56 (d, J = 6.6 Hz, 2H), 3.37 (s, 4H), 3.33 - 3.25 (m, 4H), 2.74 (s, 2H), 2.60 - 2.52 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 936 [M+H] + .

[0564] Example 5: 2''-(Difluoromethyl)-N-(3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0565]

[0566] Step 1: Benzyl 4-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate

[0567] A mixture of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (150 mg, 0.538 mmol) and benzyl piperazine-1-carboxylate (592 mg, 2.69 mmol) was melted and stirred at 120 °C for 3 h. After completion of the reaction, it was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50 - 70% ethyl acetate) to obtain the target compound (colorless oil, 130 mg, yield 57.5%). LC / MS (ESI) (m / z): 420 [M+H] + .

[0568] Step 2: Benzyl 4-(5-amino-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate hydrochloride

[0569] At room temperature, 1,4-dioxane hydrochloride (5 mL) was added to a reaction flask containing benzyl 4-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (130 mg, 0.310 mmol). The reaction solution was stirred at room temperature for 16 h. After completion of the reaction, it was concentrated under reduced pressure to obtain the target compound (colorless solid, 90 mg, yield 86.5%). LC / MS (ESI) (m / z): 320 [M+H] + .

[0570] Step 3: Benzyl 4-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate

[0571] At room temperature, N-methylimidazole (115 mg, 1.40 mmol) was added to a solution of 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (90 mg, 0.23 mmol) and benzyl 4-(5-amino-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate hydrochloride (90 mg, 0.28 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 70 °C for 30 minutes. Then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (162 mg, 0.58 mmol) was added to the reaction mixture. After the reaction was complete, water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5 - 15% methanol) to obtain the target compound (white solid, 40 mg, yield 25.2%). LC / MS (ESI) (m / z): 693 [M+H] + .

[0572] Step 4: 2''-(Difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(3-(piperazin-1-yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4''-terpyridine]-5'-carboxamide trifluoroacetate

[0573] At room temperature, trifluoroacetic acid (1 mL) was added to a reaction flask containing benzyl 4-(5-(2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2'-:4'-,4'-terpyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)piperazine-1-carboxylate (40 mg, 0.058 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain the target compound (white solid, 25 mg, yield 78.1%). LC / MS (ESI) (m / z): 559 [M+H] + .

[0574] Step 5: 2''-(Difluoromethyl)-N-(3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0575] At room temperature, N,N-diisopropylethylamine (17 mg, 0.135 mmol) and sodium iodide (13.5 mg, 0.09 mmol) were added to a solution of 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(3-(piperazin-1-yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4''-bipyridine]-5'-carboxamide trifluoroacetate (25 mg, 0.045 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (10 mg, 0.045 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, H2O solution with 10 - 50% acetonitrile and 0.1% FA) to give the target compound (white solid, 3 mg, yield 9.1%). 1 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 11.85 (s, 1H), 9.02 (s, 1H), 8.52 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.07 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.75 (d, J = 7.0 Hz, 2H), 7.63 (s, 1H), 7.59 - 7.51 (m, 1H), 7.00 (t, J = 55.1 Hz, 1H), 6.46 - 6.38 (m, 1H), 3.70 (s, 3H), 3.64 (s, 2H), 3.61 - 3.50 (m, 4H), 3.40 - 3.35 (m, 2H), 3.32 - 3.23 (m, 2H), 2.59 - 2.53 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 745 [M + H] + .

[0576] Example 6: 2”-(Difluoromethyl)-N-(3-(3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)-3-oxopropyl)amino)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo- 2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0577]

[0578] Step 1: Ethyl 3-((benzyloxy)carbonyl)amino)propionate

[0579] At room temperature, benzyl chloroformate (3.49 g, 20.49 mmol) was slowly added to a solution of ethyl 3-aminopropionate (2 g, 17.08 mmol) and triethylamine (2.33 g, 18.03 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 5 - 20% ethyl acetate) to obtain the target compound (pale yellow solid, 2.9 g, yield 67.6%). LC / MS (ESI) m / z: 252 [M+H] + .

[0580] Step 2: 3-((Benzyloxy)carbonyl)amino)propanoic acid

[0581] At room temperature, a solution of lithium hydroxide hydrate (1.45 g, 34.6 mmol) in water (1 mL) was added to a mixed solution of ethyl 3-((benzyloxy)carbonyl)amino)propionate (2.9 g, 11.54 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred at room temperature for half an hour. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH value was adjusted to ~4 with 1N hydrochloric acid, and a solid precipitated. The solid was filtered, washed twice with water, added with a small amount of acetonitrile and water, and freeze-dried to obtain the target compound (white solid, 1.6 g, yield 62.1%). LC / MS (ESI) m / z: 224 [M+H] + .

[0582] Step 3: tert-Butyl 4-(3-((benzyloxy)carbonyl)amino)propanoyl)piperazine-1-carboxylate

[0583] At room temperature, tert-butyl piperazine-1-carboxylate (0.89 g, 4.779 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.04 g, 5.38 mmol) and N,N-diisopropylethylamine (1.39 g, 10.75 mmol) were added to a solution of 3-((benzyloxy)carbonyl)amino)propanoic acid (0.8 g, 3.58 mmol) in N,N-dimethylformamide (8 mL). The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 50% ethyl acetate) to obtain the target compound (white solid, 1.3 g, yield 92.9%). LC / MS (ESI) m / z: 392 [M+H] + .

[0584] Step 4: Benzyl (3-oxo-3-(piperazin-1-yl)propyl)carbamate

[0585] 4-(3-((Benzyloxy)carbonyl)amino)propanoyl)piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 3.321 mmol) was dissolved in 4N hydrochloric acid / dioxane (10 mL) solution, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound (0.9 g, white solid, yield 93.0%). LC / MS (ESI) m / z: 292 [M+H] + .

[0586] Step 5: Benzyl (3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-oxopropyl)carbamate

[0587] To a solution of benzyl (3-oxo-3-(piperazin-1-yl)propyl)carbamate (43.2 mg, 0.15 mmol) in acetonitrile (3 mL) was added 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (30 mg, 0.14 mmol), sodium iodide (2 mg, 0.013 mmol), and N,N-diisopropylethylamine (104.5 mg, 0.8 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered to remove salts, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 50% ethyl acetate) to obtain the target compound (40 mg, white solid, yield 62%). LC / MS (ESI) m / z: 478 [M+H] + .

[0588] Step 6: 7-((4-(3-aminopropanoyl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0589] Benzyl (3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-oxopropyl)carbamate (120 mg, 0.251 mmol) was dissolved in trifluoroacetic acid (1 mL), and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound (77.5 mg, white solid, yield 90%). LC / MS (ESI) m / z: 344 [M+H] + .

[0590] Step 7: 2''-(Difluoromethyl)-N-(3-(3-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-oxopropyl)amino)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0591] Dissolve N-(3-bromo-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamide (64 mg, 0.11 mmol) in 1,4-dioxane (2 mL). Subsequently, add 7-((4-(3-aminopropionyl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (40 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.33 mmol). Stir the reaction mixture at 110 °C for 16 h. Dilute the reaction mixture with water, extract with ethyl acetate, combine the organic phases, wash with saturated brine, and concentrate under reduced pressure. The residue is separated by preparative HPLC (C18, H2O solution with 10 - 50% acetonitrile and 0.1% FA) to obtain the target compound (1.01 mg, yellow solid, yield 0.13%). 1 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 7.90 (s, 1H), 7.88 (d, J = 6.8 Hz, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 6.98 (t, J = 55.3 Hz, 1H), 6.40 (d, J = 4.6 Hz, 1H), 3.68 (s, 3H), 3.04 - 3.00 (m, 4H), 2.95 (s, 2H), 2.75 - 2.71 (m, 2H), 2.69 - 2.65 (m, 2H), 2.37 - 2.35 (m, 2H), 2.34 - 2.31 (m, 4H), 1.17 (t, J = 7.5 Hz, 3H). LC / MS (ESI) (m / z): 816 [M + H] + .

[0592] Example 7: 2”-(Difluoromethyl)-N-(3-(2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridinecarboxamido)acetamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2- oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0593]

[0594] Step 1: tert-Butyl (2-((5-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyr idine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)amino)-2-oxoethyl)carbamate

[0595] At room temperature, N-(3-amino-1,2,4-thiadiazol-5-yl)-2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxamide (16 mg, 0.033 mmol), N-tert-butoxycarbonylglycine (8.6 mg, 0.049 mmol) and N,N-diisopropylethylamine (21 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL). Subsequently, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.049 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and water, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 20 mg, yield 94.6%). LC / MS (ESI) m / z: 647.5 [M+H] + .

[0596] Step 2: N-(3-(2-Aminoacetamido)-1,2,4-thiadiazol-5-yl)-2”-(difluoromethyl)-3-fluoro-5”-meth oxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxamide hydrochloride

[0597] At room temperature, (2-((5-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)amino)-2-oxoethyl) carbamic acid tert-butyl ester (20 mg, 0.031 mmol) and methanol (1 mL) were added to a reaction flask, and 4N hydrochloric acid dioxane (3 mL) solution was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and triturated with ethyl acetate to obtain the target compound (13 mg, light yellow solid, yield 72%). LC / MS (ESI) m / z: 547.3 [M+H] + .

[0598] Step 3: 2”-(Difluoromethyl)-N-(3-(2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridinecarboxamido)acetamido)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2- oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0599] At room temperature, N-(3-(2-aminoacetamido)-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamide hydrochloride (13 mg, 0.022 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (13 mg, 0.033 mmol) and N,N-diisopropylethylamine (14 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (2 mL), then HATU (13 mg, 0.033 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to obtain the target compound (8 mg, white solid, yield 39%).

[0600] 1 H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 11.85 (s, 1H), 11.07 (s, 1H), 9.06 (s, 1H), 8.64 (t, J = 5.8 Hz, 1H), 8.51 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.08 (s, 1H), 7.89 - 7.83 (m, 2H), 7.77 - 7.75 (m, 2H), 7.63 (s, 1H), 7.61 - 7.54 (m, 1H), 7.42 (dd, J = 8.9, 2.7 Hz, 1H), 7.01 (t, J = 55.1 Hz, 1H), 6.45 - 6.40 (m, 1H), 4.24 (s, 2H), 3.69 (s, 3H), 3.66 (s, 2H), 3.39 - 3.35 (m, 4H), 2.61 - 2.53 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 922 [M + H] + .

[0601] Example 8: 2”-(Difluoromethyl)-N-(3-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridinecarboxamido)piperidin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy- 2-Oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0602]

[0603] Step 1: tert-Butyl ((3-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate

[0604] A mixture of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.72 mmol) and benzyl piperidin-4-ylcarbamate (842 mg, 3.6 mmol) was melted and stirred at 120 °C for 2 h. After the reaction was complete, it was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40 - 70% ethyl acetate) to give the target compound (colorless oil, 170 mg, yield 54.6%). LC / MS (ESI) (m / z): 434 [M+H] + .

[0605] Step 2: Benzyl (1-(5-amino-1,2,4-thiadiazol-3-yl)piperidin-4-yl)carbamate hydrochloride

[0606] At room temperature, 1,4-dioxane hydrochloride (5 mL) was added to a reaction flask containing tert-butyl (3-(4-((benzyloxy)carbonyl)amino)piperidin-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (150 mg, 0.35 mmol). The reaction solution was stirred at room temperature for 16 h. After the reaction was complete, it was concentrated under reduced pressure to give the target compound (colorless solid, 70 mg, yield 55%). LC / MS (ESI) (m / z): 334 [M+H] + .

[0607] Step 3: Benzyl (1-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)piperidin-4-yl)carbamate

[0608] At room temperature, N-methylimidazole (62 mg, 0.76 mmol) was added to a solution of 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (74 mg, 0.19 mmol) and benzyl (1-(5-amino-1,2,4-thiadiazol-3-yl)piperidin-4-yl)carbamate hydrochloride (70 mg, 0.19 mmol) in acetonitrile (3 mL). The reaction mixture was stirred at 70 °C for 30 minutes. Then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (106 mg, 0.38 mmol) was added to the reaction mixture. After the reaction was complete, water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol, gradient: 5 - 15% methanol) to obtain the target compound (white solid, 90 mg, yield 67%). LC / MS (ESI) (m / z): 707 [M+H] + .

[0609] Step 4: N-(3-(4-Aminopiperidin-1-yl)-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0610] At room temperature, trifluoroacetic acid (2 mL) was added to a reaction flask containing benzyl (1-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)piperidin-4-yl)carbamate (90 mg, 0.13 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the target compound (white solid, 60 mg, yield 83%). LC / MS (ESI) (m / z): 573 [M+H] + .

[0611] Step 5: 2''-(Difluoromethyl)-N-(3-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamido)piperidin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0612] At room temperature, N-(3-(4-aminopiperidin-1-yl)-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (30 mg, 0.052 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (30.6 mg, 0.078 mmol) and N,N-diisopropylethylamine (20 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (2 mL), then HATU (39.5 mg, 0.1 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (C18, H2O solution with 10 - 50% acetonitrile and 0.1% TFA) to obtain the target compound (6.7 mg, white solid, yield 9.3%). 1 H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 11.91 (s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.29 (s, 2H), 8.09 (s, 1H), 7.87 (d, J = 6.3 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.60 - 7.55 (m, 1H), 7.44 (s, 1H), 7.02 (t, J = 55.1 Hz, 1H), 6.48 - 6.39 (m, 1H), 4.26 (d, J = 12.7 Hz, 2H), 4.09 - 3.89 (m, 2H), 3.73 - 3.70 (m, 3H), 3.55 - 3.46 (m, 4H), 3.13 - 3.03 (m, 3H), 2.93 (s, 1H), 2.62 - 2.54 (m, 4H), 1.88 - 1.80 (m, 2H), 1.71 - 1.60 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 948 [M + H] + .

[0613] Example 9: 2''-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5'-methoxy-2-oxo-2H-[1, 2':4',4''-terpyridine]-5'-carboxamide

[0614]

[0615] Step 1: Benzyl 4-(pyridin-3-yl)piperazine-1-carboxylate

[0616] Under nitrogen protection at room temperature, 3-iodopyridine (1.0 g, 4.9 mmol) was dissolved in anhydrous toluene (20 mL) solution, and then benzyl 1-piperazine carbonate (1.4 g, 6.4 mmol), cesium carbonate (4.8 g, 14.7 mmol), palladium(II) acetate (111 mg, 0.49 mmol) and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (305 mg, 0.49 mmol) were added to the reaction solution. The reaction solution was stirred at 100 °C for 16 hours under nitrogen protection. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 30 - 50% petroleum ether) to obtain the target compound (white solid, 1.0 g, yield 69.0%). LC / MS (ESI) m / z: 298.1 [M+H] + .

[0617] Step 2: Benzyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate

[0618] At room temperature, benzyl 4-(pyridin-3-yl)piperazine-1-carboxylate (1.0 g, 3.4 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and then N-bromosuccinimide (730 mg, 4.1 mmol) was added portionwise to the reaction solution. The reaction solution was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 30 - 50% petroleum ether) to obtain the target compound (white solid, 0.9 g, yield 70.9%). LC / MS (ESI) m / z: 376.1 [M+H] + .

[0619] Step 3: Benzyl 4-(6-(trimethylstannyl)pyridin-3-yl)piperazine-1-carboxylate

[0620] Under nitrogen protection, benzyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate (0.9 g, 2.4 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and then hexamethylditin (629 mg, 1.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (277 mg, 0.49 mmol) were added to the reaction solution. The reaction solution was stirred at 100 °C for 2 hours under nitrogen protection until the reaction was complete, and the reaction solution was directly used for the next step. LC / MS (ESI) m / z: 462.1 [M+H] + .

[0621] Step 4: Benzyl 4-(6-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1- carboxylate

[0622] Under nitrogen protection, tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (670 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (277 mg, 0.49 mmol) were added to the reaction solution of the previous step. The reaction solution was stirred at 100 °C for 2 hours under nitrogen protection. The mixture was diluted with ethyl acetate, washed successively with saturated potassium fluoride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 40 - 50% petroleum ether) to obtain the target compound (yellow solid, 230 mg, two-step yield 19.3%). LC / MS (ESI) m / z: 497.2 [M+H] + .

[0623] Step 5: Benzyl 4-(6-(5-amino-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate

[0624] Under an ice-water bath, benzyl 4-(6-(5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate (230 mg, 0.464 mmol) was dissolved in anhydrous dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was slowly added dropwise under the ice-water bath. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, then diluted with water, adjusted to pH ~ 8 with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (yellow solid, 120 mg, yield 65.6%). LC / MS (ESI) m / z: 397.2 [M+H] + .

[0625] Step 6: Benzyl 4-(6-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-ter pyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate

[0626] Under nitrogen protection at room temperature, benzyl 4-(6-(5-amino-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate (50 mg, 0.13 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5-carboxylic acid (49 mg, 0.13 mmol) and N-methylimidazole (41 mg, 0.51 mmol) were dissolved in anhydrous acetonitrile (2 mL). After stirring at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (71 mg, 0.25 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 12% methanol) to obtain the target compound (yellow solid, 36 mg, yield 37.5%). LC / MS (ESI) m / z: 770.2 [M+H] + .

[0627] Step 7: 2''-(Difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(3-(5-(piperazin-1-yl)pyridin-2- yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0628] At room temperature, benzyl 4-(6-(5-(2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5-carboxamido)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)piperazine-1-carboxylate (36 mg, 0.047 mmol) was dissolved in trifluoroacetic acid (1 mL). The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid to obtain the target compound (yellow solid, 23 mg, yield 77.2%). LC / MS (ESI) m / z: 636.2 [M+H] + .

[0629] Step 8: 2''-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1, 2':4',4''-terpyridine]-5'-carboxamide

[0630] At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(3-(5-(piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (23 mg, 0.036 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (10 mg, 0.047 mmol) were dissolved in anhydrous acetonitrile (2 mL), and then sodium iodide (0.6 mg, 0.004 mmol) and N,N-diisopropylethylamine (14 mg, 0.11 mmol) were added to the reaction solution. The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was filtered, and the filtrate was separated by preparative HPLC (C18, an aqueous solution containing 0.1% TFA with 10 - 50% acetonitrile) to obtain the target compound (white solid, 2 mg, yield 6.9%). 1 H NMR (400 MHz, DMSO-d6) δ 13.96 (s, 1H), 12.20 (s, 1H), 10.14 (s, 1H), 9.08 (s, 1H), 8.58 - 8.45 (m, 3H), 8.12 (s, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.82 (s, 1H), 7.78 (s, 2H), 7.61 - 7.50 (m, 2H), 7.02 (t, J = 55.1 Hz, 1H), 6.48 - 6.39 (m, 1H), 4.63 - 4.41 (m, 2H), 4.19 - 4.01 (m, 2H), 3.74 - 3.67 (m, 2H), 3.68 (s, 3H), 3.30 - 3.25 (m, 2H), 2.61 - 2.53 (m, 4H), 1.22 - 1.17 (m, 3H). LC / MS (ESI) (m / z): 822 [M + H] + .

[0631] Example 10: 2''-(Difluoromethyl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpy ridine]-5'-carboxamide

[0632]

[0633] Step 1: Benzyl 4-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)piperazine-1-carboxylate

[0634] Under nitrogen protection at room temperature, tert-butyl (6-bromobenzo[d]thiazol-2-yl)carbamate (350 mg, 1.1 mmol) and benzyl piperazine-1-carboxylate (468 mg, 2.1 mmol) were dissolved in 2-methyltetrahydrofuran (20 mL). Subsequently, (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (89 mg, 0.11 mmol) and lithium bis(trimethylsilyl)amide (5.3 mL, 5.3 mmol, 1 M in THF) were added. The reaction mixture was stirred at 85 °C for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated brine, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 40 - 50% ethyl acetate) to obtain the target compound (pale yellow solid, 130 mg, yield 26.1%). LC / MS (ESI) m / z: 469.2 [M+H] + .

[0635] Step 2: Benzyl 4-(2-aminobenzo[d]thiazol-6-yl)piperazine-1-carboxylate

[0636] Under an ice-water bath, benzyl 4-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-6-yl)piperazine-1-carboxylate (130 mg, 0.28 mmol) was dissolved in dichloromethane (2.5 mL). Subsequently, trifluoroacetic acid (0.7 mL) was added. After the addition was complete, the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was adjusted to neutral with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed successively with water and saturated brine, and then concentrated under reduced pressure. The residue was purified by trituration with acetonitrile to obtain the target compound (orange solid, 100 mg, yield 97.8%). LC / MS (ESI) m / z: 369.2 [M+H] + .

[0637] Step 3: Benzyl 4-(2-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyrid ine]-5'-carboxamido)benzo[d]thiazol-6-yl)piperazine-1-carboxylate

[0638] At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (62 mg, 0.17 mmol), benzyl 4-(2-aminobenzothiazol-6-yl)piperazine-1-carboxylate (62 mg, 0.17 mmol) and N-methylimidazole (55 mg, 0.67 mmol) were dissolved in acetonitrile (5 mL). After the reaction mixture was stirred at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (93 mg, 0.33 mmol) was added to the reaction mixture. The reaction mixture became substantially clear, and then the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 80 - 100% ethyl acetate) to obtain the target compound (yellow solid, 90 mg, yield 73.1%). LC / MS (ESI) m / z: 742.3 [M+H] + .

[0639] Step 4: 2''-(Difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(6-(piperazin-1-yl)benzo[d]thia -2-yl)-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0640] At room temperature, benzyl 4-(2-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamido)benzothiazol-6-yl)piperazine-1-carboxylate (90 mg, 0.12 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to neutral with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (yellow solid, 63 mg, yield 85.5%). LC / MS (ESI) m / z: 608.3 [M+H] + .

[0641] Step 5: 2”-(Difluoromethyl)-N-(6-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)meth yl)piperazin-1-yl)benzo[d]thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]- 5'-carboxamide

[0642] At room temperature, 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (9 mg, 0.04 mmol), sodium iodide (1 mg, 0.007 mmol) and N,N-diisopropylethylamine (22 mg, 0.17 mmol) were added to a solution of 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(6-(piperazin-1-yl)benzo[d]thiazol-2-yl)-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (20 mg, 0.033 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filtrate was separated by preparative HPLC (C18, 30 - 65% acetonitrile in an aqueous solution containing 0.1% FA) to obtain the target compound (yellow solid, 8.44 mg, yield 32.3%). 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 12.21 (s, 1H), 9.01 (s, 1H), 8.56 (s, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 7.88 - 7.84 (m, 1H), 7.82 (s, 1H), 7.81 - 7.78 (m, 1H), 7.76 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.60 - 7.56 (m, 2H), 7.24 - 7.19 (m, 1H), 7.01 (t, J = 55.1 Hz, 1H), 6.47 - 6.40 (m, 1H), 4.56 (s, 2H), 3.95 - 3.78 (m, 2H), 3.70 (s, 3H), 3.34 - 3.23 (m, 4H), 3.06 - 2.95 (m, 2H), 2.61 - 2.55 (m, 2H), 1.22 - 1.18 (m, 3H). LC / MS (ESI) (m / z): 794 [M + H] + . Example 11: 2”-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro- 1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzo[d]thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1, 2':4',4”-terpyridine]-5'-carboxamide

[0643]

[0644] Step 1: tert-Butyl (5-bromobenzo[d]thiazol-2-yl)carbamate

[0645] At room temperature, 5-bromobenzo[d]thiazol-2-amine (500 mg, 2.2 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and then di-tert-butyl dicarbonate (528 mg, 2.4 mmol) and 4-dimethylaminopyridine (27 mg, 0.22 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 40 - 60% petroleum ether) to obtain the target compound (white solid, 560 mg, yield 77.9%). LC / MS (ESI) m / z: 329.0 [M+H] + .

[0646] Step 2: Benzyl 4-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-5-yl)piperazine-1-carboxylate

[0647] Under nitrogen protection, tert-butyl (5-bromobenzo[d]thiazol-2-yl)carbamate (400 mg, 1.2 mmol) was dissolved in anhydrous 2-methyltetrahydrofuran (5 mL), and then benzyl 1-piperazine carbonate (396 mg, 1.8 mmol), lithium bis(trimethylsilyl)amide (1.2 mL, 2.4 mmol, 2.0 M), and palladium(II) 2-(dicyclohexylphosphino)-2',6'-diisopropoxy-1,1'-biphenyl-2-yl)-2-amino-1,1'-biphenyl-2-yl) (100 mg, 0.12 mmol) were added to the reaction solution. The reaction solution was stirred at 85 °C for 16 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 50 - 80% petroleum ether) to obtain the target compound (yellow solid, 160 mg, yield 28.4%). LC / MS (ESI) m / z: 469.2 [M+H] + .

[0648] Step 3: Benzyl 4-(2-aminobenzo[d]thiazol-5-yl)piperazine-1-carboxylate

[0649] At room temperature, dissolve benzyl 4-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-5-yl)piperazine-1-carboxylate (160 mg, 0.34 mmol) in anhydrous dichloromethane (2 mL), and then slowly add trifluoroacetic acid (0.5 mL) dropwise under an ice-water bath. The reaction solution is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure to remove trifluoroacetic acid, then diluted with water, and the pH is adjusted to ~8 with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the target compound (yellow solid, 90 mg, yield 71.4%). LC / MS (ESI) m / z: 369.2 [M+H] + .

[0650] Step 4: Benzyl 4-(2-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyr idine]-5'-carboxamido)benzo[d]thiazol-5-yl)piperazine-1-carboxylate

[0651] Under nitrogen protection, dissolve benzyl 4-(2-aminobenzo[d]thiazol-5-yl)piperazine-1-carboxylate (50 mg, 0.136 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (53 mg, 0.136 mmol) and N-methylimidazole (47 mg, 0.544 mmol) in anhydrous acetonitrile (2 mL). After stirring at 70 °C for five minutes, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (76 mg, 0.27 mmol) to the reaction solution, and then the reaction solution is stirred at 70 °C for 1 hour. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 12% methanol) to obtain the target compound (yellow solid, 53 mg, yield 52.5%). LC / MS (ESI) m / z: 742.2 [M+H] + .

[0652] Step 5: 2”-(Difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-N-(5-(piperazin-1-yl)benzo[d]thia zol-2-yl)-2H-[1,2':4',4”-bipyridine]-5'-carboxamide

[0653] At room temperature, dissolve benzyl 4-(2-(2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamido)benzo[d]thiazol-5-yl)piperazine-1-carboxylate (53 mg, 0.072 mmol) in trifluoroacetic acid (1 mL). The reaction solution is stirred at 80 °C for 1 hour under nitrogen protection. The reaction solution is concentrated under reduced pressure to remove trifluoroacetic acid to obtain the target compound (yellow solid, 38 mg, yield 88.4%). LC / MS (ESI) m / z: 608.2 [M+H] + .

[0654] Step 6: 2”-(Difluoromethyl)-N-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzo[d]thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]- 5'-carboxamide

[0655] At room temperature, 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(5-(piperazin-1-yl)benzo[d]thiazol-2-yl)-2H-[1,2':4',4''-bipyridine]-5'-carboxamide (38 mg, 0.063 mmol) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (17 mg, 0.076 mmol) were dissolved in anhydrous acetonitrile (2 mL), and then sodium iodide (0.9 mg, 0.006 mmol) and N,N-diisopropylethylamine (24 mg, 0.19 mmol) were added to the reaction solution. The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was filtered, and the filtrate was separated by preparative HPLC (C18, an aqueous solution containing 0.1% FA with 10 - 50% acetonitrile) to obtain the target compound (white solid, 10 mg, yield 20.0%). 1 H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 12.21 (s, 1H), 10.10 (s, 1H), 9.02 (s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 7.5 Hz, 2H), 7.77 (s, 1H), 7.62 - 7.54 (m, 1H), 7.34 (s, 1H), 7.16 - 7.11 (m, 1H), 6.95 (d, J = 55.0 Hz, 1H), 6.50 - 6.38 (m, 1H), 4.57 (s, 2H), 3.98 - 3.86 (m, 2H), 3.74 - 3.68 (m, 2H), 3.70 (s, 3H), 3.35 - 3.23 (m, 2H), 3.17 - 2.95 (m, 2H), 2.63 - 2.56 (m, 2H), 1.24 - 1.16 (m, 3H). LC / MS (ESI) (m / z): 794 [M + H] + .

[0656] Example 12: 2”-(Difluoromethyl)-3-fluoro-N-(3-(6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4- dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarboxamido)propanamido-1,2,4-thiadiazol-5-yl)-5”-meth oxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0657]

[0658] Step 1: 7-(Bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one

[0659] Under an ice-water bath, 8-fluoro-7-(hydroxymethyl)-3-methylquinoxalin-2(1H)-one (100 mg, 0.48 mmol) and triphenylphosphine (302 mg, 1.15 mmol) were dissolved in anhydrous dichloromethane (5 mL). Subsequently, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (407 mg, 1.25 mmol) in dichloromethane (5 mL) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was separated into layers. The aqueous phase was extracted with dichloromethane twice, and the organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound (yellow solid, 440 mg of crude product). LC / MS (ESI) m / z: 271.1 [M+H] + .

[0660] Step 2: tert-Butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0661] Under nitrogen protection, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (116 mg, 0.14 mmol) was added to a mixture of methyl 5-bromo-6-fluoropicolinate (500 mg, 2.14 mmol), tert-butyl piperazine-1-carboxylate (597 mg, 3.21 mmol), and cesium carbonate (1.74 g, 5.34 mmol) in 1,4-dioxane (10 mL). The reaction solution was stirred at 80 °C overnight under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 25% ethyl acetate) to obtain the target compound (yellow solid, 220 mg, yield 33.1%). LC / MS (ESI) m / z: 340.2 [M+H] + .

[0662] Step 3: 5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid

[0663] At room temperature, tert-butyl 4-(2-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (240 mg, 0.71 mmol) and methanol (2 mL) were added to a reaction flask, and an aqueous solution (0.7 mL) of lithium hydroxide hydrate (33 mg, 0.78 mmol) was added. The reaction mixture was stirred at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was extracted twice with dichloromethane. The aqueous phase was cooled to 0 °C, and the pH was adjusted to ~2 with 1 N hydrochloric acid. An oil separated out, and dichloromethane was added for extraction. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (yellow solid, 220 mg, yield 95.6%). LC / MS (ESI) m / z: 326.4 [M+H] + .

[0664] Step 4: tert-Butyl 4-(6-((3-ethoxy-3-oxopropyl)carbamoyl)-2-fluoropyridin-3-yl)piperazine-1-carbox ylate

[0665] At room temperature, 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinic acid (220 mg, 0.68 mmol), ethyl β-alaninate hydrochloride (114 mg, 0.74 mmol), and N,N-diisopropylethylamine (437 mg, 3.38 mmol) were dissolved in N,N-dimethylformamide (6 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (386 mg, 1.01 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and 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: 2 - 7% methanol) to obtain the target compound (yellow solid, 200 mg, yield 69.7%). LC / MS (ESI) m / z: 425.5 [M+H] + .

[0666] Step 5: 3-(5-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-fluoropyridinecarboxamido)propanoic acid

[0667] At room temperature, tert-butyl 4-(6-((3-ethoxy-3-oxopropyl)carbamoyl)-2-fluoropyridin-3-yl)piperazine-1-carboxylate (200 mg, 0.47 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, and an aqueous solution (1 mL) of lithium hydroxide hydrate (40 mg, 0.94 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the aqueous phase was washed twice with ethyl acetate. The aqueous phase was cooled to 0 °C, the pH was adjusted to ~3 with 1 N hydrochloric acid, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound, which was triturated with ether and filtered to obtain the target compound (white solid, 100 mg, yield 53.5%). LC / MS (ESI) m / z: 397.4 [M+H] + .

[0668] Step 6: 4-(6-((3-(((5-((tert-Butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl yl)carbamoyl)-2-fluoropyridin-3-yl)

[0669] tert-Butyl piperazine-1-carboxylate

[0670] At room temperature, 3-(5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-fluoropicolinamido)propanoic acid (100 mg, 0.25 mmol), tert-butyl (3-amino-1,2,4-thiadiazol-5-yl)carbamate (55 mg, 0.25 mmol), and N-methylimidazole (124 mg, 1.51 mmol) were dissolved in acetonitrile (5 mL). After stirring at 70 °C for 1 minute, an acetonitrile (1 mL) solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (106 mg, 0.38 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was filtered, the filter cake was washed with acetonitrile, and dried under reduced pressure to obtain the target compound (100 mg, white solid, yield 66.7%). LC / MS (ESI) m / z: 595.6 [M+H] + .

[0671] Step 7: N-(3-((5-Amino-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl)-6-fluoro-5-(piperazin- 1-yl)pyridinecarboxamide hydrochloride

[0672] At room temperature, tert-butyl 4-(6-((3-(((5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl)carbamoyl)-2-fluoropyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.17 mmol) and methanol (1 mL) were added to a reaction flask. To the mixture was added a 4N hydrochloric acid dioxane (3 mL) solution, and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was filtered, and the filter cake was rinsed with ethyl acetate and dried under reduced pressure to obtain the target compound (50 mg, white solid, yield 69%). LC / MS (ESI) m / z: 395.3 [M+H] + .

[0673] Step 8: N-(3-((5-Amino-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl)-6-fluoro-5-(4- ((5-Fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarboxamide

[0674] At room temperature, N-(3-((5-amino-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl)-6-fluoro-5-(piperazin-1-yl)picolinamide hydrochloride (50 mg, 0.12 mmol), 7-(bromomethyl)-8-fluoro-3-methylquinoxalin-2(1H)-one (20%, 157 mg, 0.12 mmol), sodium iodide (17 mg, 0.12 mmol) and N,N-diisopropylethylamine (90 mg, 0.70 mmol) were dissolved in acetonitrile (10 mL). The reaction solution was stirred at 70 °C for 2 hours. The reaction solution was filtered, and the filter cake was rinsed with acetonitrile and dried under reduced pressure to obtain a crude product, which was then slurried with water, filtered, and dried under reduced pressure to obtain the target compound (22 mg, yellow solid, yield 32.4%). LC / MS (ESI) m / z: 585.4 [M+H] + .

[0675] Step 9: 2”-(Difluoromethyl)-3-fluoro-N-(3-(6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-di hydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridinecarboxamido)propanamido-1,2,4-thiadiazol-5-yl)-5”-methoxy yl-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0676] At room temperature, N-(3-((5-amino-1,2,4-thiadiazol-3-yl)amino)-3-oxopropyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)picolinamide (22 mg, 0.038 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (24 mg, 0.061 mmol) and N-methylimidazole (19 mg, 0.23 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (0.5 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (16 mg, 0.056 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, aqueous solution containing 0.1% FA with 30 - 100% methanol) to obtain the target compound (2.2 mg, white solid, yield 6.1%). 1 H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 12.68 (s, 1H), 10.99 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.48 - 8.45 (m, 1H), 8.11 (s, 1H), 7.88 - 7.85 (m, 2H), 7.77 (s, 1H), 7.70 - 7.64 (m, 2H), 7.60 - 7.56 (m, 1H), 7.43 - 7.42 (m, 1H), 7.01 (t, J = 55 Hz, 1H), 6.45 - 6.42 (m, 1H), 4.50 (s, 2H), 3.68 (s, 3H), 3.58 - 3.48 (m, 6H), 2.75 - 2.72 (m, 2H), 2.48 - 2.44 (m, 4H), 1.24 (s, 3H). LC / MS (ESI) (m / z): 958 [M + H] + .

[0677] Example 13: 2'-(Difluoromethyl)-N-(6-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)benzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0678]

[0679] Step 1: Benzyl 4-(2-(2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide yl)benzo[d]thiazol-6-yl)piperazine-1-carboxylate

[0680] At room temperature, 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40 mg, 0.14 mmol), benzyl 4-(2-aminobenzothiazol-6-yl)piperazine-1-carboxylate (50 mg, 0.14 mmol) and N-methylimidazole (45 mg, 0.55 mmol) were dissolved in acetonitrile (5 mL). After stirring at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (76 mg, 0.27 mmol) was added to the reaction solution. The reaction solution became almost clear, and then the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and 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: 80 - 100% ethyl acetate) to obtain the target compound (yellow solid, 60 mg, yield 68.5%). LC / MS (ESI) m / z: 645.3 [M+H] + .

[0681] Step 2: 2'-(Difluoromethyl)-5'-methoxy-6-methyl-N-(6-(piperazin-1-yl)benzo[d]thiazol-2- yl)-[4,4'-bipyridine]-3-carboxamide

[0682] At room temperature, benzyl 4-(2-(2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)benzothiazol-6-yl)piperazine-1-carboxylate (60 mg, 0.093 mmol) was dissolved in trifluoroacetic acid (5 mL). The reaction solution was stirred at 80 °C for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to make it neutral, and then the reaction solution was diluted with dichloromethane, washed successively with water and saturated brine, and concentrated under reduced pressure to obtain the target compound (pale yellow solid, 40 mg, yield 84.2%). LC / MS (ESI) m / z: 511.3 [M+H] + .

[0683] Step 3: 2'-(Difluoromethyl)-N-(6-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)meth yl)piperazin-1-yl)benzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0684] At room temperature, to a solution of 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(6-(piperazin-1-yl)benzo[d]thiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.078 mmol) in acetonitrile (3 mL) was added 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (18 mg, 0.081 mmol), sodium iodide (2 mg, 0.013 mmol) and N,N-diisopropylethylamine (41 mg, 0.32 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered, and the filter cake was dissolved in dimethyl sulfoxide and separated by preparative HPLC (C18, 50 - 90% methanol containing 0.1% aqueous FA solution) to obtain the target compound (yellow solid, 25.45 mg, yield 46.6%). 1 1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 12.21 (s, 1H), 8.84 (s, 1H), 8.57 (d, J = 1.6 Hz, 1H), 8.46 (s, 1H), 7.82 (s, 1H), 7.81 - 7.78 (m, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 7.24 - 7.18 (m, 1H), 7.00 (t, J = 55.1 Hz, 1H), 4.57 (s, 2H), 3.93 - 3.80 (m, 2H), 3.67 (s, 3H), 3.57 - 3.41 (m, 2H), 3.36 - 3.23 (m, 2H), 3.11 - 2.92 (m, 2H), 2.62 (s, 3H), 2.60 - 2.55 (m, 2H), 1.23 - 1.18 (m, 3H). LC / MS (ESI) (m / z): 697 [M + H] + . Example 14: 2”-(Difluoromethyl)-N-(5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyrid ine-3-yl)methyl)piperazin-1-yl)pyridinecarboxamidyl)benzo[d]thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo- 2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0685]

[0686] Step 1: tert-Butyl (5-nitrobenzo[d]thiazol-2-yl)carbamate

[0687] At room temperature, 5-nitrobenzo[d]thiazol-2-amine (200 mg, 1.03 mmol) was dissolved in tetrahydrofuran (5 mL). Then, di-tert-butyl dicarbonate (337 mg, 1.55 mmol) and 4-dimethylaminopyridine (13 mg, 0.103 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate and washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether, gradient: 40 - 60% petroleum ether) to obtain the target compound (white solid, 240 mg, yield 79.7%). LC / MS (ESI) m / z: 296.1 [M+H] + .

[0688] Step 2: tert-Butyl (5-aminobenzo[d]thiazol-2-yl)carbamate

[0689] Under nitrogen protection, tert-butyl (5-nitrobenzo[d]thiazol-2-yl)carbamate (240 mg, 0.814 mmol) was dissolved in methanol (5 mL), and then 10% palladium hydroxide (24 mg) was added under nitrogen protection. The reaction solution was purged with nitrogen three times and then stirred at room temperature for 1 hour under a hydrogen atmosphere of 1 atm. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the target compound (brown oil, 180 mg, yield 83.7%). LC / MS (ESI) m / z: 266.1 [M+H] + .

[0690] Step 3: tert-Butyl (5-(5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) pyridinecarboxamidyl)benzo[d]thiazol-2-yl)carbamate

[0691] Under nitrogen protection, tert-butyl (5-aminobenzo[d]thiazol-2-yl)carbamate (50 mg, 0.19 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (74 mg, 0.19 mmol), and N-methylimidazole (62 mg, 0.76 mmol) were dissolved in anhydrous acetonitrile (2 mL). After stirring at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (106 mg, 0.38 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 12% methanol) to obtain the target compound (yellow solid, 63 mg, yield 52.5%). LC / MS (ESI) m / z: 641.3 [M+H] + .

[0692] Step 4: N-(2-Aminobenzo[d]thiazol-5-yl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0693] At room temperature, (tert-butyl (5-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)benzo[d]thiazol-2-yl)carbamate (63 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was slowly added dropwise under an ice-water bath. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, the pH was adjusted to ~8 with saturated aqueous sodium bicarbonate, and 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 target compound (yellow solid, 40 mg, yield 75.5%). LC / MS (ESI) m / z: 541.3 [M+H] + . Step 5: 2''-(Difluoromethyl)-N-(5-(4- ((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)benzo[d] thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0694] Under nitrogen protection, N-(2-aminobenzo[d]thiazol-5-yl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide (50 mg, 0.074 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarboxylic acid (30 mg, 0.074 mmol) and N-methylimidazole (24 mg, 0.296 mmol) were dissolved in anhydrous acetonitrile (2 mL). After stirring at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (41 mg, 0.148 mmol) was added to the reaction solution, and the reaction solution was stirred at 70 °C for 1 hour. The reaction solution was filtered, and the filtrate was separated by preparative HPLC (C18, aqueous solution containing 0.1% FA with 10 - 50% acetonitrile) to obtain the target compound (white solid, 8 mg, yield 11.9%). 11H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 12.21 (s, 1H), 10.53 (s, 1H), 9.05 (s, 1H), 8.59 - 8.43 (m, 4H), 8.12 - 8.04 (m, 2H), 7.96 - 7.86 (m, 2H), 7.84 - 7.76 (m, 4H), 7.61 - 7.55 (m, 2H), 7.02 (t, J = 55.1 Hz, 1H), 6.49 - 6.40 (m, 1H), 4.67 - 4.41 (m, 2H), 4.30 - 3.99 (m, 2H), 3.73 (s, 3H), 3.40 - 3.13 (m, 6H), 2.62 - 2.55 (m, 2H), 1.23 - 1.17 (m, 3H). LC / MS (ESI) (m / z): 914 [M + H] + .

[0695] The compounds in Example in Table 1 were synthesized with reference to the synthesis steps of Example 14 using commercially available raw materials.

[0696] Table 1:

[0697]

[0698] Example 16: 2'-(Difluoromethyl)-N-(6-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)benzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bi pyridine]-3-carboxamide

[0699]

[0700] Step 1: tert-Butyl (6-nitrobenzo[D]thiazol-2-yl)carbamate

[0701] Under an ice - water bath, 2 - amino - 6 - nitrobenzothiazole (1 g, 5.13 mmol) and 4 - dimethylaminopyridine (62.6 mg, 0.51 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), and then di - tert - butyl dicarbonate (1.68 g, 7.70 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at 50 °C for 1 hour. The reaction solution was concentrated under reduced pressure. Dichloromethane and water were added to the mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with petroleum ether / ethyl acetate (20 / 1) to obtain the target compound (1.1 g, yellow solid, yield 72.7%). LC / MS (ESI) m / z: 296.1 [M + H] + .

[0702] Step 2: tert-Butyl (6-aminobenzo[D]thiazol-2-yl)carbamate

[0703] Under nitrogen protection, dissolve tert-butyl (6-nitrobenzo[d]thiazol-2-yl)carbamate (300 mg, 1.02 mmol) in methanol (10 mL), and then add 10% palladium on carbon hydroxide (30 mg). The reaction solution is stirred at room temperature overnight under a hydrogen atmosphere at one atmosphere. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure to obtain the target compound (yellow solid, 200 mg, yield 74.2%). LC / MS (ESI) m / z: 266.2 [M+H] + .

[0704] Step 3: tert-Butyl (6-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1- yl)picolylcarbamoyl)benzo[d]thiazol-2-yl)carbamate

[0705] Under nitrogen protection, dissolve tert-butyl (6-aminobenzo[d]thiazol-2-yl)carbamate (34 mg, 0.13 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (50 mg, 0.13 mmol) and N-methylimidazole (63 mg, 0.78 mmol) in acetonitrile (2 mL), and stir the mixture at 70 °C for 10 minutes. Then add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (54 mg, 0.20 mmol). The reaction solution is stirred at 70 °C for 1 hour under nitrogen protection. The reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50 - 70% ethyl acetate) to obtain the target compound (yellow solid, 50 mg, yield 61.0%). LC / MS (ESI) m / z: 641.3 [M+H] + .

[0706] Step 4: N-(2-Aminobenzo[d]thiazol-6-yl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl

[0707] Under an ice-water bath, add trifluoroacetic acid (1 mL) dropwise to a solution of tert-butyl (6-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)benzo[d]thiazol-2-yl)carbamate (50 mg, 0.08 mmol) in dichloromethane (3 mL). After the addition is complete, the reaction solution is stirred at room temperature for 1 hour. The reaction solution is concentrated under reduced pressure to remove trifluoroacetic acid, the pH is adjusted to ~8 with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the target compound (30 mg, yellow oil, yield 71.4%). LC / MS (ESI) m / z: 541.3 [M+H] + .

[0708] Step 5: 2'-(Difluoromethyl)-N-(6-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)picolylcarbamoyl)benzo[d]thiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyr idine]-3-carboxamide

[0709] At room temperature, N-(2-aminobenzothiazol-6-yl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (30 mg, 0.06 mmol), 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (16 mg, 0.06 mmol) and N-methylimidazole (27 mg, 0.36 mmol) were dissolved in acetonitrile (1 mL). After stirring at 70 °C for 5 minutes, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (23 mg, 0.09 mmol) in acetonitrile (1 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and saturated brine, concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, aqueous solution containing 0.1% TFA with 10 - 50% acetonitrile) to obtain the target compound (2 mg, white solid, yield 3.8%). 1 H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H), 8.46 - 8.37 (m, 3H), 8.11 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 18.4 Hz, 3H), 7.63 (s, 1H), 7.57 - 7.54 (m, 1H), 6.77 (t, J = 55.4 Hz, 1H), 4.60 (s, 2H), 3.96 - 3.67 (m, 4H), 3.78 (s, 3H), 3.54 (s, 4H), 2.76 - 2.66 (m, 2H), 2.72 (s, 3H), 1.29 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 817 [M + H] + .

[0710] Example 17: 2''-(Difluoromethyl)-N-(3-((5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyrid in-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)methyl-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2- oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0711]

[0712] Step 1: 3-(Chloromethyl)-1,2,4-thiadiazol-5-amine

[0713] Under an ice-water bath, triethylamine (5.39 mL, 38.77 mmol) and bromine (2.23 g, 14.00 mmol) were slowly added dropwise to a methanol (30 mL) solution of chloroacetamide hydrochloride (2 g, 15.51 mmol). After the addition was complete, a methanol (16 mL) solution of potassium thiocyanate (1.66 g, 17.06 mmol) was added dropwise. The mixture was stirred at 0 °C for 2 h. The reaction solution was concentrated to dryness under reduced pressure. An aqueous sodium bicarbonate solution and ethyl acetate were added to the mixture, and the mixture was separated into layers. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 5% methanol) to obtain the target compound (yellow solid, 580 mg, yield 25%). LC / MS (ESI) m / z: 150.2 [M+H] + .

[0714] Step 2: tert-Butyl (3-(chloromethyl)-1,2,4-thiadiazol-5-yl)carbamate

[0715] At room temperature, 3-(chloromethyl)-1,2,4-thiadiazol-5-amine (260 mg, 1.74 mmol), di-tert-butyl dicarbonate (455 mg, 2.09 mmol), and 4-dimethylaminopyridine (10.62 mg, 0.087 mmol) were dissolved in tetrahydrofuran (12 mL), and then the reaction solution was stirred at 50 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 50% ethyl acetate) to obtain the target compound (yellow solid, 370 mg, yield 85.3%). LC / MS (ESI) m / z: 250.0 [M+H] + .

[0716] Step 3: tert-Butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,4-thiadiazol-5-yl)carbamate butyl

[0717] At room temperature, tert-butyl (3-(chloromethyl)-1,2,4-thiadiazol-5-yl)carbamate (120 mg, 0.48 mmol), potassium phthalimide (107 mg, 0.58 mmol), and N,N-dimethylformamide (5 mL) were added to a reaction flask, and then the reaction solution was stirred at 90 °C for 3 h. Ethyl acetate and water were added to the mixture, and the mixture was separated into layers. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 30% ethyl acetate) to obtain the target compound (yellow solid, 105 mg, yield 60.6%). LC / MS (ESI) m / z: 361.1 [M+H] + .

[0718] Step 4: tert-Butyl (3-(aminomethyl)-1,2,4-thiadiazol-5-yl)carbamate

[0719] At room temperature, tert-butyl (3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,4-thiadiazol-5-yl)carbamate (105 mg, 0.29 mmol) was dissolved in ethanol (6 mL). Hydrazine hydrate (146 mg, 2.33 mmol) was added to the reaction solution, and then the reaction solution was stirred at 80 °C for 18 hours. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was triturated with ethanol and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (yellow solid, 60 mg, yield 89.4%). LC / MS (ESI) m / z: 231.1 [M+H] + .

[0720] Step 5: (3-((5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1- tert-Butyl ((5-amino-1,2,4-thiadiazol-3-yl)methyl)-1,2,4-thiadiazol-5-yl)carbamate

[0721] At room temperature, tert-butyl (3-(aminomethyl)-1,2,4-thiadiazol-5-yl)carbamate (60 mg, 0.22 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (87 mg, 0.22 mmol), and N,N-diisopropylethylamine (143 mg, 1.11 mmol) were dissolved in N,N-dimethylformamide (6 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain an oil, and then triturated with ethyl acetate to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 10% methanol) to obtain the target compound (yellow solid, 60 mg, yield 44.7%). LC / MS (ESI) m / z: 606.3 [M+H] + .

[0722] Step 6: N-((5-Amino-1,2,4-thiadiazol-3-yl)methyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methoxy)piperazin-1-yl)picolinamide hydrochloride Step 7: 2”-(Difluoromethyl)-N-(3-((5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamido)methyl-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0723] At room temperature, tert-butyl (3-((5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)methyl)-1,2,4-thiadiazol-5-yl)carbamate (60 mg, 0.10 mmol) and methanol (1 mL) were added to a reaction flask. 4N hydrochloric acid dioxane (1 mL) solution was added to the mixture. The reaction solution was stirred at room temperature for 18 hours, and a solid precipitated. The reaction solution was filtered, and the solid was rinsed with ethyl acetate and dried to obtain the target compound (40 mg, white solid, yield 74.5%). LC / MS (ESI) m / z: 506.3 [M+H] + .

[0724] Example 18: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide Step 1: 5-Bromopyridine-2-carboximidamide Step 2: tert-Butyl ((3-(2-(5-bromopyridin-2-yl)-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)amino)carbamate

[0725] At room temperature, N-((5-amino-1,2,4-thiadiazol-3-yl)methyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide hydrochloride (40 mg, 0.074 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (29 mg, 0.074 mmol) and N-methylimidazole (36 mg, 0.44 mmol) were dissolved in acetonitrile (5 mL) and N,N-dimethylformamide (1 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (31 mg, 0.11 mmol) in acetonitrile (0.5 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 19 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 20-95% acetonitrile in aqueous solution containing 0.1% TFA) to obtain the target compound (15 mg, white solid, yield 23.1%). 11H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 12.20 (s, 1H), 9.03 (s, 1H), 8.98 (t, J = 6.1 Hz, 1H), 8.56 - 8.55 (m, 1H), 8.51 (s, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.10 (s, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 7.60 - 7.48 (m, 2H), 7.01 (t, J = 55.1 Hz, 1H), 6.45 - 6.40 (m, 1H), 4.68 (d, J = 5.9 Hz, 2H), 4.54 (s, 2H), 4.13 - 4.11 (m, 2H), 3.67 (s, 3H), 3.38 - 3.15 (m, 6H), 2.61 - 2.58 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 879 [M+H] + .

[0726] Step 3: Benzyl 4-(6-(5-(((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate Step 4: Benzyl 4-(6-(5-(5-amino-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate Step 5: Benzyl 4-(6-(5-(5-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate

[0727]

[0728] Step 6: 2”-(Difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-N-(3-(2-(5-(piperazin-1-yl)pyridin-2-yl)-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0729] Under an ice-water bath, 5-bromopyridinecarbonitrile (200 mg, 1.10 mmol) was dissolved in anhydrous methanol (5 mL), and then sodium methoxide in methanol (60 mg, 1.10 mmol, 30% wt) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight. Ammonium chloride (65 mg, 1.21 mmol) was added to the above-mentioned reaction solution, and after addition, the mixture was stirred at 80 °C for 4 hours. The reaction solution was concentrated to remove methanol, diluted with water, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (yellow solid, 160 mg, yield 87.9%). LC / MS (ESI) m / z: 200 [M+H] + .

[0730] Step 7: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide ​

[0731] At room temperature, to a solution of 5-bromopyridine-2-carboximidamide (160 mg, 0.80 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added tert-butyl (3-(2-bromoacetyl)-1,2,4-thiadiazol-5-yl)carbamate (258 mg, 0.80 mmol) and potassium carbonate (444 mg, 3.22 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with water and 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: 50 - 55% ethyl acetate) to obtain the target compound (yellow solid, 60 mg, yield 16.9%). LC / MS (ESI) m / z: 423 [M+H] + .

[0732] ​ ​

[0733] Under nitrogen protection, tert-butyl ((3-(2-(5-bromopyridin-2-yl))-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (60 mg, 0.14 mmol), benzyl piperazine-1-carboxylate (46.9 mg, 0.21 mmol) and cesium carbonate (139 mg, 0.427 mmol) were dissolved in anhydrous 1,4-dioxane (2.5 mL), and then (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (12 mg, 0.014 mmol) was added. The reaction mixture was stirred at 100 °C overnight under nitrogen protection. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60 - 70% ethyl acetate) to obtain the target compound (yellow solid, 60 mg, yield 75.1%). LC / MS (ESI) m / z: 563.3 [M+H] + .

[0734] ​ ​

[0735] Under an ice-water bath, trifluoroacetic acid (1 mL) was added to a solution of benzyl 4-(6-(5-(((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate (60 mg, 0.12 mmol) in dichloromethane (3 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH ~ 8 with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (40 mg, yellow oil, yield 81.1%). LC / MS (ESI) m / z: 463.3 [M+H] + .

[0736] ​ ​

[0737] At room temperature, benzyl 4-(6-(5-(5-amino-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate (40 mg, 0.09 mmol), 2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxylic acid (34 mg, 0.09 mmol), and N-methylimidazole (43 mg, 0.52) were dissolved in acetonitrile (2 mL). After the reaction solution was stirred at 70 °C for 10 minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (36 mg, 0.13 mmol) was added. The reaction solution was continuously stirred at 70 °C for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane and water were added to the mixture, and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 60 - 70% ethyl acetate) to obtain the target compound (yellow solid, 30 mg, yield 41.5%). LC / MS (ESI) m / z: 836.3 [M+H] + .

[0738] ​ ​

[0739] At room temperature, benzyl 4-(6-(5-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)-1H-imidazol-2-yl)pyridin-3-yl)piperazine-1-carboxylate (30 mg, 0.04 mmol) and trifluoroacetic acid (2 mL) were added to a reaction flask, and the reaction mixture was stirred at 80 °C for 1 h. The reaction solution was concentrated under reduced pressure to obtain the target compound (25 mg, yellow solid, yield 99.2%). LC / MS (ESI) m / z: 702.0 [M+H] + .

[0740] ​ ​ ​

[0741] At room temperature, 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (30 mg, 0.14 mmol), sodium iodide (2 mg, 0.013 mmol), and N,N-diisopropylethylamine (104.5 mg, 0.8 mmol) were successively added to a solution of 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-N-(3-(2-(5-(piperazin-1-yl)pyridin-2-yl)-1H-imidazol-5-yl)-1,2,4-thiadiazol-5-yl)-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (25 mg, 0.04 mmol) in acetonitrile (3 mL). The reaction solution was stirred at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 10 - 50% acetonitrile in an aqueous solution containing 0.1% FA) to obtain the target compound (2 mg, white solid, yield 3.8%). 1 H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.18 - 8.13 (m, 2H), 8.04 (s, 1H), 7.94 - 7.88 (m, 3H), 7.84 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.50 - 7.45 (m, 1H), 6.77 (t, J = 55.3 Hz, 1H), 6.53 - 6.46 (m, 1H), 4.50 (s, 2H), 3.77 (s, 3H), 3.76 - 3.64 (m, 4H), 3.47 - 3.39 (m, 4H), 2.72 - 2.66 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H). LC / MS (ESI) (m / z): 888 [M+H]+ .

[0742] Example 19: 2'-(Difluoromethyl)-N-(6-(2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)pyridinecarboxamido)ethyl)benzo[d]thiazol-2-yl)-5-methoxy-6-methyl-[4, 4'-bipyridine]-3-carboxamide

[0743]

[0744] Step 1: Benzyl (4-aminophenethyl)carbamate

[0745] At room temperature, benzyl chloroformate (1.13 g, 6.608 mmol) was slowly added dropwise to a solution of 4-(2-aminoethyl)aniline (1 g, 7.342 mmol) and triethylamine (1.49 g, 14.68 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (pale yellow solid, 500 mg, yield 25.2%). LC / MS (ESI) m / z: 271 [M+H] + .

[0746] Step 2: Benzyl (2-(2-aminobenzo[d]thiazol-6-yl)ethyl)carbamate

[0747] Under nitrogen protection, potassium thiocyanate (539.4 mg, 5.55 mmol) was added to a solution of benzyl (4-aminophenethyl)carbamate (500 mg, 1.85 mmol) in glacial acetic acid (5 mL), and then bromine (296 mg, 1.85 mmol) was slowly added dropwise under an ice-water bath. After the addition was complete, the reaction solution was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was directly evaporated to dryness, and a small amount of ammonia water was added dropwise for quenching. The suspension was filtered, and the filter cake was dissolved in glacial acetic acid and filtered again. The filtrates from the two times were combined and concentrated under reduced pressure to obtain the target compound (brown solid, 270 mg, yield 44.5%), and this product was directly used in the next reaction without purification. LC / MS (ESI) m / z: 328 [M+H] + .

[0748] Step 3: Benzyl (2-(2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido yl)benzo[d]thiazol-6-yl)ethyl)carbamate

[0749] Under nitrogen protection, N-methylimidazole (100.3 mg, 1.22 mmol), 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (179.8 mg, 0.61 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (257.1 mg, 0.92 mmol) were added to a solution of benzyl (2-(2-aminobenzothiazol-6-yl)ethyl)carbamate (200 mg, 0.61 mmol) in acetonitrile (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 80% ethyl acetate) to obtain the target compound (yellow solid, 200 mg, yield 54.2%). LC / MS (ESI) m / z: 604 [M+H] + .

[0750] Step 4: N-(6-(2-aminoethyl)benzo[d]thiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl -[4,4'-bipyridine]-3-carboxamide

[0751] A solution of benzyl (2-(2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)benzothiazol-6-yl)ethyl)carbamate (70 mg, 0.12 mmol) in trifluoroacetic acid (4 mL) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid, and the residue was diluted with dichloromethane, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 40% ethyl acetate) to obtain the target compound (yellow solid, 15 mg, yield 27.5%). LC / MS (ESI) m / z: 470 [M+H] + .

[0752] Step 5: 2'-(Difluoromethyl)-N-(6-(2-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)pyridinecarboxamido)ethyl)benzo[d]thiazol-2-yl)-5-methoxy-6-methyl-[4,4'- bipyridine]-3-carboxamide

[0753] Under nitrogen protection, 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (25.1 mg, 0.064 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (36.4 mg, 0.096 mmol) and N,N-diisopropylethylamine (8.26 mg, 0.064 mmol) were successively added to a solution of N-(6-(2-aminoethyl)benzothiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.064 mmol) in N,N-dimethylformamide (1 mL). After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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 separated by preparative HPLC (C18, 10 - 50% acetonitrile in aqueous solution containing 0.1% FA) to obtain the target compound (white solid, 10.22 mg, yield 18.9%). 1 H NMR (400 MHz, DMSO-d6) 12.90 (s, 1H), 11.85 (s, 1H), 8.83 (s, 1H), 8.52 - 8.46 (m, 1H), 8.44 (s, 1H), 8.42 - 8.38 (m, 1H), 8.28 - 8.23 (m, 1H), 7.84 - 7.80 (m, 2H), 7.75 (s, 1H), 7.72 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.46 (s, 1H), 7.43 - 7.35 (m, 1H), 7.34 - 7.31 (m, 1H), 6.99 (t, J = 55.2 Hz, 1H), 3.68 - 3.64 (m, 5H), 3.59 - 3.53 (m, 2H), 3.30 - 3.27 (m, 2H), 2.95 (t, J = 7.4 Hz, 2H), 2.61 (s, 3H), 2.59 - 2.52 (m, 8H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 845 [M + H] + .

[0754] Example 20: 2”-(Difluoromethyl)-N-(3-((2-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naph thyridin-3-yl)methyl)piperazin-1-yl)pyridinecarboxamido)ethoxy)methyl-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-meth oxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0755]

[0756] Step 1: tert-Butyl (3-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-1,2,4-thiadiazol-5-yl)carbamate Step 2: 3-(2-Aminoethoxy)methyl)-1,2,4-thiadiazol-5-amine hydrochloride

[0757] Under nitrogen protection at 0 °C, N-(tert-butoxycarbonyl)ethanolamine (258 mg, 1.60 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a reaction flask, and sodium hydride (128 mg, 3.20 mmol) with a mass fraction of 60% was added in batches. The reaction mixture was stirred at room temperature for 15 minutes, then tert-butyl (3-(chloromethyl)-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.80 mmol) was added, and the reaction solution was further reacted at room temperature for 2 hours. The reaction mixture was added to a saturated ammonium chloride aqueous solution, and extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / ethyl acetate, gradient: 0 - 30% ethyl acetate) to obtain the target compound (yellow oil, 190 mg, yield 63.4%). LC / MS (ESI) m / z: 375.4 [M+H] + .

[0758] Step 3: N-(2-((5-Amino-1,2,4-thiadiazol-3-yl)methoxy)ethyl)-5-(4-((7-ethyl-6-oxo

[0759] At room temperature, tert-butyl (3-((2-((tert-butoxycarbonyl)amino)ethoxy)methyl)-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.17 mmol) and methanol (3 mL) were added to a reaction flask, 4N hydrochloric acid dioxane (6 mL) solution was added to the mixture, and the reaction solution was stirred at room temperature for 48 hours. A solid precipitated out. The reaction solution was filtered, and the filter cake was washed with ethyl acetate and dried under reduced pressure to obtain the target compound (65 mg, white solid, yield 69%). LC / MS (ESI) m / z: 175.0 [M+H] + .

[0760] 5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)pyridinecarboxamide Step 4: 2”-(Difluoromethyl)-N-(3-((2-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-

[0761] At room temperature, 3-(2-aminoethoxy)methyl)-1,2,4-thiadiazol-5-amine hydrochloride (65 mg, 0.31 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (121 mg, 0.31 mmol) and N,N-diisopropylethylamine (199 mg, 1.54 mmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(7-Azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was triturated with ethyl acetate to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2-10% methanol) to obtain the target compound (yellow solid, 120 mg, yield 70.8%). LC / MS (ESI) m / z: 550.2 [M+H] + .

[0762] 3-yl)methyl)piperazin-1-yl)pyridinecarboxamido)ethoxy)methyl-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy -2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide Example 21: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-

[0763] At room temperature, N-(2-((5-amino-1,2,4-thiadiazol-3-yl)methoxy)ethyl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide (50 mg, 0.091 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (36 mg, 0.091 mmol) and N-methylimidazole (45 mg, 0.55 mmol) were dissolved in acetonitrile (2 mL) and N,N-dimethylformamide (5 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (38 mg, 0.14 mmol) in acetonitrile (1 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 18 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, 20-95% acetonitrile in an aqueous solution containing 0.1% FA) to obtain the target compound (18 mg, white solid, yield 21.4%). 11H NMR (400 MHz, DMSO-d6) δ 13.83 (s, 1H), 11.86 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.46 - 8.35 (m, 2H), 8.28 (d, J = 2.5 Hz, 1H), 8.11 (s, 1H), 7.85 (t, J = 8.0 Hz, 2H), 7.76 - 7.75 (m, 2H), 7.63 (s, 1H), 7.59 - 7.53 (m, 1H), 7.40 (dd, J = 8.9, 2.5 Hz, 1H), 7.01 (t, J = 55.1 Hz, 1H), 6.45 - 6.40 (m, 1H), 4.67 (s, 2H), 3.70 - 3.63 (m, 4H), 3.68 (s, 3H), 3.50 - 3.46 (m, 2H), 3.35 - 3.30 (m, 6H), 2.61 - 2.53 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 923 [M + H] + .

[0764] 3-yl)methyl)piperazin-1-yl)pyridinecarboxamido)azetidin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”- ​ Methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0765]

[0766] Step 1: tert-Butyl (1-(5-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4', 4”-terpyridine]-5'-carboxamide)-1,2,4-thiadiazol-3-yl)azetidin-3-yl)carbamate

[0767] Under nitrogen protection, cesium carbonate (85 mg, 0.27 mmol) and t-BuBrettPhos Pd G3 (10 mg, 0.01 mmol) were added to a solution of N-(3-bromo-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2'':4',4''-bipyridine]-5'-carboxamide (50 mg, 0.09 mmol) and 3-N-Boc-aminocyclobutanamine (20 mg, 0.11 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 120 °C for 16 h under nitrogen protection. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 50 - 100% ethyl acetate) to obtain the target compound (white solid, 10 mg, yield 16%). LC / MS (ESI) (m / z): 645 [M + H] + .

[0768] Step 2: N-(3-(3-Aminoazetidin-1-yl)-1,2,4-thiadiazol-5-yl)-2”-(difluoromethyl)- 3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0769] At 0 °C, trifluoroacetic acid (0.5 mL) was added to a solution of tert-butyl (1-(5-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamido)-1,2,4-thiadiazol-3-yl)azetidin-3-yl)carbamate (10 mg, 0.015 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid, diluted with dichloromethane, and adjusted to pH 8-9 with saturated aqueous sodium bicarbonate. The dichloromethane layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 7 mg). LC / MS (ESI) (m / z): 545 [M+H] + .

[0770] Step 3: 2”-(Difluoromethyl)-N-(3-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)picolinamido)azetidin-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”- methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0771] At room temperature, HATU (7 mg, 0.018 mmol) and N,N-diisopropylethylamine (5 mg, 0.036 mmol) were added to a solution of N-(3-(3-aminoazetidin-1-yl)-1,2,4-thiadiazol-5-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxamide (7 mg, 0.012 mmol) and 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (6 mg, 0.015 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered and separated by preparative HPLC (C18, aqueous solution containing 0.1% FA with 10-50% acetonitrile) to obtain the target compound (white solid, 0.5 mg, yield 4.5%). 11H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 12.19 (s, 1H), 9.15 (d, J = 7.5 Hz, 1H), 9.01 (s, 1H), 8.53 (s, 2H), 8.35 (s, 1H), 7.92 - 7.85 (m, 2H), 7.81 (s, 1H), 7.76 (s, 2H), 7.61 - 7.55 (m, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.22 - 6.86 (m, 2H), 6.47 - 6.40 (m, 1H), 4.93 - 4.85 (m, 1H), 4.56 (s, 2H), 4.35 - 4.27 (m, 2H), 4.19 - 4.14 (m, 2H), 3.71 (s, 3H), 3.22 - 3.09 (m, 4H), 2.60 - 2.56 (m, 2H), 2.56 - 2.52 (m, 4H), 1.22 - 1.17 (m, 3H). LC / MS (ESI) (m / z): 920 [M+H] + .

[0772] Example 22: 2”-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)picolinamidomethyl)thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1, 2':4',4”-bipyridine]-5'-carboxamide

[0773]

[0774] Step 1: tert-Butyl (4-(chloromethyl)thiazol-2-yl)carbamate

[0775] At room temperature, 4-(chloromethyl)thiazol-2-amine (300 mg, 2.02 mmol) and 4-dimethylaminopyridine (12 mg, 0.10 mmol) were dissolved in tetrahydrofuran (5 mL), and then di-tert-butyl dicarbonate (661 mg, 3.03 mmol) was added under an ice bath. 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: 10 - 20% ethyl acetate) to obtain the target compound (yellow solid, 180 mg, yield 35.9%). LC / MS (ESI) m / z: 248.7 [M+H] + .

[0776] Step 2: tert-Butyl (4-((1,3-dioxoisoindolin-2-yl)methyl)thiazol-2-yl)carbamate

[0777] At room temperature, tert-butyl (4-(chloromethyl)thiazol-2-yl)carbamate (180 mg, 0.72 mmol), potassium phthalimide (161 mg, 0.87 mmol) and N,N-dimethylformamide (5 mL) were added to a reaction flask, and then the reaction solution was stirred at 90 °C for 1 hour. Ethyl acetate and water were added to the mixture, and the mixture was separated into layers. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 10 - 30% ethyl acetate) to obtain the target compound (yellow solid, 105 mg, yield 40.4%). LC / MS (ESI) m / z: 360.1 [M+H] + .

[0778] Step 3: tert-Butyl (4-(aminomethyl)thiazol-2-yl)carbamate

[0779] At room temperature, tert-butyl (4-((1,3-dioxoisoindolin-2-yl)methyl)thiazol-2-yl)carbamate (105 mg, 0.292 mmol) was dissolved in ethanol (3 mL). 80% hydrazine hydrate (146 mg, 2.34 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 18 hours. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. Ethanol was added again, and the mixture was filtered again. The filtrate was concentrated to dryness under reduced pressure to obtain the target compound (yellow solid, 60 mg, yield 89.6%). LC / MS (ESI) m / z: 230.0 [M+H] + .

[0780] Step 4: tert-Butyl (4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piper azin-1-yl)picolinamido)methyl)

[0781] thiazol-2-yl

[0782] At room temperature, tert-butyl (4-(aminomethyl)thiazol-2-yl)carbamate (20 mg, 0.087 mmol) and 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (38 mg, 0.096 mmol), N,N-diisopropylethylamine (56 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (3 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) was added to the reaction solution, and then the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to dryness to obtain an oil, and then ethyl acetate was added for slurrying to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0-10% methanol) to obtain the target compound (yellow solid, 20 mg, yield 37.9%). LC / MS (ESI) m / z: 605.3 [M+H] + .

[0783] Step 5: N-((2-Aminothiazol-4-yl)methyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naph thyridin-3-yl)methyl]piperazin-1-yl)picolinamide

[0784] Tert-butyl (4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylcarbamoyl)methyl)thiazol-2-yl (20 mg, 0.033 mmol) and methanol (1 mL) were added to a reaction flask. 4N hydrochloric acid dioxane (3 mL) solution was added to the mixture. The reaction solution gradually became clear and was stirred at room temperature for 18 hours. A solid precipitated out. The reaction solution was concentrated under reduced pressure to dryness, and then slurried with a mixed solvent (DCM / MeOH = 10 / 1, 20 mL) and dried to obtain the target compound (11 mg, yellow solid, yield 65.9%). LC / MS (ESI) m / z: 505.2 [M+H] + .

[0785] Step 6: 2”-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)picolinamidomethyl)thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2': 4',4”-bipyridine]-5'-carboxamide

[0786] N-((2-Aminothiazol-4-yl)methyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl)picolinamide (10 mg, 0.02 mmol), 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-terpyridine]-5'-carboxylic acid (7.75 mg, 0.02 mmol), and N-methylimidazole (9.8 mg, 0.12 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (1 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (8.34 mg, 0.03 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture. Then the reaction mixture was stirred at 70 °C for 1 hour. N-Methylimidazole (9.76 mg, 0.12 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (8.34 mg, 0.03 mmol) were added, and the reaction mixture was stirred at 70 °C for an additional 1 hour. The reaction mixture was filtered and purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, H2O solution with 20 - 95% acetonitrile and 0.1% TFA) to obtain the target compound (1 mg, white solid, yield 5.8%). 1 H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 8.39 (d, J = 1.6 Hz, 1H), 8.27 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.81 (dd, J = 15.6, 8.0 Hz, 2H), 7.73 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.38 - 7.34 (m, 1H), 7.29 - 7.24 (m, 1H), 6.84 (s, 1H), 6.64 (t, J = 55.3 Hz, 1H), 6.40 - 6.36 (m, 1H), 4.50 (s, 2H), 3.66 (s, 3H), 3.63 (s, 2H), 3.33 - 3.29 (m, 4H), 2.60 - 2.55 (m, 6H), 1.28 - 1.25 (m, 3H). LC / MS (ESI) (m / z): 878 [M + H] + .

[0787] Example 23: 2”-(Difluoromethyl)-N-(6-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl) methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2': 4',4”-terpyridine]-5'-carboxamide

[0788]

[0789] Step 1: tert-Butyl (6-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzothiazol-2-yl)carbamate amino)benzo[d]thiazol-2-yl)carbamate

[0790] At room temperature, (tert-butyl (6-aminobenzothiazol-2-yl)carbamate) (30 mg, 0.11 mmol), 4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzoic acid (44 mg, 0.11 mmol) and N-methylimidazole (28 mg, 0.33 mmol) were dissolved in acetonitrile (2 mL). After stirring at 70 °C for five minutes, N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (62 mg, 0.22 mmol) was added to the reaction solution. The reaction solution became basically clear, and then the reaction solution was stirred at 70 °C for 2 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 80 - 100% ethyl acetate) to obtain the target compound (yellow solid, 25 mg, yield 34.6%). LC / MS (ESI) m / z: 639 [M+H] + .

[0791] Step 2: N-(2-Aminobenzo[d]thiazol-6-yl)-4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7- yl)methyl)piperazin-1-yl)benzamide hydrochloride

[0792] tert-Butyl (6-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzothiazol-2-yl)carbamate (25 mg, 0.04 mmol) and methanol (1 mL) were added to a reaction flask. 4N hydrochloric acid dioxane (3 mL) solution was added to the mixture. The reaction solution gradually became clear and was stirred at room temperature for 24 hours. A solid precipitated out. The reaction solution was filtered, washed with ethyl acetate, and the filter cake was dried to obtain the target compound (20 mg, white solid, yield 89%). LC / MS (ESI) m / z: 539 [M+H]+.

[0793] Step 3: 2''-(Difluoromethyl)-N-(6-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)meth yl)piperazin-1-yl)benzamido)benzothiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4', 4''-terpyridine]-5'-carboxamide

[0794] At room temperature, N-(2-aminobenzothiazol-6-yl)-4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamide hydrochloride (20 mg, 0.034 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (12 mg, 0.034 mmol) and N-methylimidazole (9 mg, 0.10 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (0.5 mL). After stirring at 70 °C for 10 minutes, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (16 mg, 0.056 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 70 °C for 3 hours. The reaction mixture was filtered and separated by preparative HPLC (C18, H2O solution with 10 - 50% acetonitrile and 0.1% TFA) to obtain the target compound (white solid, 4.7 mg, yield 15.1%). 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 12.03 (s, 1H), 10.18 (s, 1H), 9.04 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 7.0 Hz, 1H), 7.81 - 7.77 (m, 3H), 7.77 - 7.72 (m, 2H), 7.62 - 7.55 (m, 1H), 7.40 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.16 - 6.88 (m, 3H), 6.48 - 6.39 (m, 1H), 4.53 - 4.47 (m, 2H), 4.09 - 4.02 (m, 2H), 3.74 (s, 3H), 3.51 - 3.40 (m, 2H), 3.30 - 3.19 (m, 2H), 3.16 - 3.06 (m, 2H), 2.58 - 2.53 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 912 [M + H] + .

[0795] Example 24: 2''-(Difluoromethyl)-N-(6-(5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7- yl)methyl)piperazin-1-yl)picolylamido)benzothiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2': 4',4''-bipyridine]-5'-carboxamide

[0796]

[0797] Step 1: Methyl 5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolinate methyl ester

[0798] To a solution of methyl 5-(piperazin-1-yl)picolinate hydrochloride (100 mg, 0.34 mmol) in acetonitrile (3 mL) was added 7-(chloromethyl)-3-ethylquinolin-2(1H)-one (82.9 mg, 0.37 mmol), sodium iodide (5.1 mg, 0.034 mmol) and N,N-diisopropylethylamine (439 mg, 3.40 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile and dried under reduced pressure to give the target compound (85 mg, yellow solid, yield 61.5%). LC / MS (ESI) m / z: 407.4 [M+H] + .

[0799] Step 2: 5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolinate

[0800] At room temperature, methyl 5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolinate (85 mg, 0.21 mmol) and tetrahydrofuran (3 mL) were added to a reaction flask, and a solution of lithium hydroxide hydrate (26 mg, 0.63 mmol) in water (1 mL) was added. The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was cooled to 0 °C, and the pH was adjusted to ~3 with 1 N hydrochloric acid. An oil separated out, which was concentrated to dryness under reduced pressure and triturated with acetonitrile to give the target compound (65 mg, yellow solid, yield 79.2%). LC / MS (ESI) m / z: 393.4 [M+H] + .

[0801] Step 3: (6-(5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picol ylamido)benzothiazol-2-yl)carbamate

[0802] At room temperature, 5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolinate (35 mg, 0.089 mmol), tert-butyl (6-aminobenzothiazol-2-yl)carbamate (23.7 mg, 0.089 mmol), and N-methylimidazole (43.9 mg, 0.54 mmol) were dissolved in acetonitrile (3 mL) and N,N-dimethylformamide (1 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (37.5 mg, 0.13 mmol) in acetonitrile (1 mL) was added to the reaction solution. Then the reaction solution was stirred at 70 °C for 2 hours. N-Methylimidazole (43.9 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (37.5 mg, 0.13 mmol) were added, and the reaction was stirred at 70 °C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain an oil, which was triturated with acetonitrile to give the target compound (yellow solid, 30 mg, yield 52.6%). LC / MS (ESI) m / z: 640.3 [M+H] + .

[0803] Step 4: N-(2-Aminobenzo[d]thiazol-6-yl)-5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7- yl)methyl)piperazin-1-yl)picolylamide hydrochloride

[0804] tert-Butyl (6-(5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolylamido)benzothiazol-2-yl)carbamate (35 mg, 0.055 mmol) and 30% hydrogen chloride in methanol (3 mL) were added to a reaction flask. The reaction solution gradually became clear and was stirred at room temperature for 18 hours. A solid precipitated out. The reaction solution was filtered, and the solid was rinsed with ethyl acetate and dried to give the target compound (30 mg, white solid, yield 94.7%). LC / MS (ESI) m / z: 540.3 [M+H] + .

[0805] Step 5: 2''-(Difluoromethyl)-N-(6-(5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)meth yl)piperazin-1-yl)picolylamido)benzothiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2': 4',4''-bipyridine]-5'-carboxamide

[0806] N-(2-Aminobenzo[d]thiazol-6-yl)-5-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)picolinamide hydrochloride (30 mg, 0.052 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (20.4 mg, 0.052 mmol), and N-methylimidazole (25.7 mg, 0.31 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (10 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (21.9 mg, 0.078 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture, and then the reaction mixture was stirred at 70 °C for 1 hour. After filtration, the reaction mixture was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, H2O solution with 20 - 95% acetonitrile and 0.1% TFA) to obtain the target compound (10 mg, white solid, yield 21.0%). 1 H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 12.03 (s, 1H), 10.53 (s, 1H), 9.04 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.93 - 7.87 (m, 2H), 7.79 - 7.74 (m, 4H), 7.60 - 7.56 (m, 2H), 7.40 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.01 (t, J = 55.1, 1H), 6.46 - 6.42 (m, 1H), 4.48 (s, 2H), 3.73 (s, 3H), 3.46 - 3.42 (m, 4H), 3.26 - 3.22 (s, 4H), 2.55 - 2.51 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 913 [M + H] + .

[0807] Example 25: 2''-(Difluoromethyl)-N-(6-(4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl) methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)benzothiazol-2-yl)-3-fluoro-5''-methoxy-2-ox o-2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0808]

[0809] Step 1: tert-Butyl (6-(4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3, 6-tetrahydropyridin-4-yl)benzamido)benzothiazol-2-yl)carbamate

[0810] Under nitrogen protection, 4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid (30 mg, 0.077 mmol), tert-butyl-(6-aminobenzothiazol-2-yl)carbamate (20 mg, 0.077 mmol) and N-methylimidazole (32 mg, 0.38 mmol) were dissolved in anhydrous acetonitrile (1 mL). Then, the mixture was stirred at 70 °C for 5 minutes, and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (43 mg, 0.15 mmol) was added. Subsequently, the reaction was stirred at 70 °C for 1 hour. After completion of the reaction, the target compound (white solid, 30 mg, yield 61.1%) was obtained by filtration. LC / MS (ESI) m / z: 636 [M+H] + .

[0811] Step 2: N-(2-aminobenzo[d]thiazol-6-yl)-4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7- yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0812] At room temperature, tert-butyl-(6-(4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)benzothiazol-2-yl)carbamate (30 mg, 0.047 mmol) was added to a reaction flask containing 4 M hydrochloric acid dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the target compound (white solid, 20 mg, yield 79.1%). LC / MS (ESI) m / z: 536 [M+H] + .

[0813] Step 3: 2''-(difluoromethyl)-N-(6-(4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)meth yl)-1,2,3,6-tetrahydropyridin-4-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo- 2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0814] Under nitrogen protection, N-(2-aminobenzothiazol-6-yl)-4-(1-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)benzamide (26 mg, 0.051 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (20 mg, 0.051 mmol) and N-methylimidazole (21 mg, 0.26 mmol) were dissolved in anhydrous acetonitrile (1 mL). Then it was stirred at 70 °C for 5 minutes, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (29 mg, 0.10 mmol) was added. Then it was stirred at 70 °C for 1 hour. After the reaction was completed, it was filtered, and the filtrate was purified by preparative HPLC (welch xbidge xb 5um 21.2*250mm, H2O solution of 20 - 95% methanol and 0.1% TFA) to obtain the target compound (white solid, 8.2 mg, yield 18.1%). 1 HNMR(400MHz, DMSO-d6) δ13.16(s, 1H), 12.02(s, 1H), 10.44(s, 1H), 9.04(s, 1H), 8.53(s, 1H), 8.47(s, 1H), 8.10(s, 1H), 8.03(d, J = 8.4Hz, 2H), 7.88(d, J = 7.0Hz, 1H), 7.81 - 7.77(m, 4H), 7.75(d, J = 8.1Hz, 1H), 7.66(d, J = 8.4Hz, 2H), 7.61 - 7.56(m, 1H), 7.43(s, 1H), 7.34(d, J = 8.1Hz, 1H), 7.02(t, J = 55.1Hz, 1H), 6.47 - 6.42(m, 1H), 6.35(s, 1H), 4.59 - 4.47(m, 2H), 3.93 - 3.84(m, 2H), 3.74(s, 3H), 3.39 - 3.30(m, 2H), 2.91 - 2.80(m, 2H), 2.57 - 2.53(m, 2H), 1.19(t, J = 7.4Hz, 3H). LC / MS(ESI)(m / z): 909[M + H] + .

[0815] Example 26: 2''-(difluoromethyl)-N-(3-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)phenyl)ethynyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo- 2H-[1,2':4',4''-terpyridine]-5'-carboxamide

[0816]

[0817] Step 1: tert-Butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylate

[0818] Under nitrogen protection, tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (500 mg, 1.29 mmol), trimethylsilylacetylene (252.98 mg, 2.58 mmol), triethylamine (5 mL, 35.97 mmol), copper(I) iodide (24.53 mg, 0.13 mmol), bis(triphenylphosphine)palladium(II) dichloride (45.20 mg, 0.064 mmol) and anhydrous N,N-dimethylformamide (2.5 mL) were added to a microwave reaction flask. Under nitrogen protection, the reaction was carried out at 100 °C for one hour by microwave. Triethylamine and N,N-dimethylformamide were removed by concentration under reduced pressure. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 5% ethyl acetate) to obtain the target compound (yellow solid, 430 mg, yield 93.1%). LC / MS (ESI) m / z: 359.5 [M+H] + .

[0819] Step 2: tert-Butyl 4-(4-ethynylphenyl)piperazine-1-carboxylate

[0820] At room temperature, tert-butyl 4-(4-((trimethylsilyl)ethynyl)phenyl)piperazine-1-carboxylate (430 mg, 1.2 mmol), potassium carbonate (829 mg, 6.0 mmol), anhydrous methanol (4 mL), and tetrahydrofuran (2 mL) were added to a reaction flask. The reaction was stirred at room temperature for 3 hours. Methanol and tetrahydrofuran were removed by concentration under reduced pressure. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed successively with water and saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 15% ethyl acetate) to obtain the target compound (yellow solid, 270 mg, yield 78.6%). LC / MS (ESI) m / z: 287.4 [M+H] + .

[0821] Step 3: tert-Butyl 4-(4-((5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)ethynyl)phenyl)piperazine- 1-carboxylate

[0822] Under nitrogen protection, tert-butyl 4-(4-ethynylphenyl)piperazine-1-carboxylate (240 mg, 0.84 mmol), tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (235 mg, 0.84 mmol), triethylamine (3 mL), copper(I) iodide (16 mg, 0.084 mmol), bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.042 mmol) and anhydrous N,N-dimethylformamide (3 mL) were added to a microwave reaction flask, and the mixture was irradiated with microwave at 100 °C for one hour under nitrogen protection. The reaction solution was concentrated under reduced pressure to remove triethylamine and N,N-dimethylformamide, water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate twice, the organic phases were combined, washed successively with water and saturated brine, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 0 - 3% methanol) to obtain the target compound (yellow solid, 250 mg, yield 61.4%). LC / MS (ESI) m / z: 486.2 [M+H] + .

[0823] Step 4: 3-((4-(piperazin-1-yl)phenyl)ethynyl)-1,2,4-thiadiazol-5-amine

[0824] Under an ice bath, tert-butyl 4-(4-((5-((tert-butoxycarbonyl)amino)-1,2,4-thiadiazol-3-yl)ethynyl)phenyl)piperazine-1-carboxylate (90 mg, 0.19 mmol) and dichloromethane (15 mL) were added to a reaction flask, and a solution of trimethylsilyl trifluoromethanesulfonate (412 mg, 1.85 mmol) in dichloromethane (5 mL) was added dropwise to the mixture. The reaction was stirred at room temperature for one hour. The reaction solution was concentrated to dryness under reduced pressure, the residue was triturated with dichloromethane, and the solid was collected by filtration and dried to obtain the target compound (33 mg, yellow solid, yield 62.4%). LC / MS (ESI) m / z: 286.2 [M+H] + .

[0825] Step 5: 7-((4-(4-((5-amino-1,2,4-thiadiazol-3-yl)ethynyl)phenyl)piperazin-1-yl)meth yl)-3-ethyl-1,5-naphthyridin-2(1H)-one

[0826] At room temperature, 3-((4-(piperazin-1-yl)phenyl)ethynyl)-1,2,4-thiadiazol-5-amine (60 mg, 0.21 mmol), 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (51.5 mg, 0.23 mmol), N,N-diisopropylethylamine (272 mg, 2.10 mmol), sodium iodide (3.15 mg, 0.021 mmol) and acetonitrile (5 mL) were added to a reaction flask. The reaction was stirred at 80 °C for 2 hours. The mixture was filtered to obtain the crude product, which was purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 10% methanol) to give the target compound (yellow solid, 19 mg, yield 19.2%). LC / MS (ESI) m / z: 472.2 [M+H] + .

[0827] Step 6: 2''-(difluoromethyl)-N-(3-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)phenyl)ethynyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5''-methoxy-2-oxo-2H- [1,2':4',4''-terpyridine]-5'-carboxamide

[0828] At room temperature, 7-((4-(4-((5-amino-1,2,4-thiadiazol-3-yl)ethynyl)phenyl)piperazin-1-yl)methyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (15 mg, 0.032 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridine]-5'-carboxylic acid (12 mg, 0.032 mmol), N-methylimidazole (16 mg, 0.19 mmol) were dissolved in acetonitrile (2 mL) and N,N-dimethylformamide (0.3 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (13 mg, 0.048 mmol) in acetonitrile (0.3 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for one hour. N-methylimidazole (1 mg, 0.191 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (13 mg, 0.048 mmol) were added, and the reaction was stirred at 70 °C for another hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was triturated with acetonitrile to obtain the crude product, which was further purified by preparative TLC and preparative HPLC (YMC-Actus Triart C18 250*21 mm, 20 - 95% acetonitrile in H2O solution and 0.1% NH4HCO3) to give the target compound (1.08 mg, white solid, yield 4.02%). 1HNMR(400MHz, DMSO-d6) δ 11.85 (s, 1H), 9.10 (s, 1H), 8.49 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.09 - 7.93 (m, 1H), 7.88 (d, J = 7.0 Hz, 1H), 7.76 (s, 1H), 7.71 - 7.69 (m, 1H), 7.64 (s, 1H), 7.59 - 7.52 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.14 - 6.85 (m, 3H), 6.44 - 6.40 (m, 1H), 3.67 (s, 3H), 3.60 (s, 2H), 3.49 - 3.44 (m, 4H), 3.29 - 3.27 (m, 4H), 2.56 - 2.53 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS(ESI) (m / z): 845 [M + H] + .

[0829] Example 27: 2''-(difluoromethyl)-N-(6-(4-(4((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1, 2':4',4''-terpyridine]-5'-carboxamide

[0830]

[0831] Step 1: tert-Butyl 6-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl) benzamido)benzo[d]thiazol-2-yl)carbamate

[0832] At room temperature, dissolve tert-butyl (6-aminobenzothiazol-2-yl)carbamate (30 mg, 0.11 mmol), 4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzoic acid (44 mg, 0.11 mmol) and N-methylimidazole (28 mg, 0.33 mmol) in acetonitrile (2 mL) solution. After stirring at 70 °C for five minutes, add N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (62 mg, 0.22 mmol) to the reaction solution. The reaction solution becomes basically clear, and then the reaction solution is stirred at 70 °C for 2 hours. Dilute the reaction solution with ethyl acetate, wash it successively with water and saturated brine, and concentrate it under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 80 - 100% ethyl acetate) to obtain the target compound (yellow solid, 25 mg, yield 34.6%). LC / MS(ESI) m / z: 640 [M + H] + .

[0833] Step 2: N-(2-aminobenzo[d]thiazol-6-yl)-4-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5- naphthyridin-3-yl)methyl)piperazin-1-yl)benzamide hydrochloride

[0834] tert-Butyl (6-(4-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)benzamido)benzothiazol-2-yl)carbamate (25 mg, 0.04 mmol) and dioxane (1 mL) were added to a reaction flask. To the mixture was added a 4N hydrochloric acid dioxane (3 mL) solution. The reaction solution gradually became clear. The reaction was stirred at room temperature for 24 hours, and a solid precipitated. The reaction solution was filtered, rinsed with ethyl acetate, and the filter cake was dried to obtain the target compound (20 mg, white solid, yield 89%). LC / MS (ESI) m / z: 540 [M+H]+.

[0835] Step 3: 2”-(Difluoromethyl)-N-(6-(4-(4((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)benzamido)benzothiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1, 2':4',4”-Terpyridine]-5'-carboxamide

[0836] At room temperature, N-(2-aminobenzothiazol-6-yl)-4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamide hydrochloride (20 mg, 0.034 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (12 mg, 0.034 mmol) and N-methylimidazole (9 mg, 0.10 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (0.5 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (16 mg, 0.056 mmol) in acetonitrile (0.5 mL) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 3 hours. The reaction solution was filtered and separated by preparative HPLC (C18, H2O solution with 10 - 50% acetonitrile and 0.1% TFA) to obtain the target compound (white solid, 1.1 mg, yield 3.5%). 11H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 12.21 (s, 1H), 10.17 (s, 1H), 9.04 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.45 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 7.0 Hz, 1H), 7.82 (s, 1H), 7.78 - 7.76 (m, 3H), 7.61 - 7.56 (m, 1H), 7.24 - 7.13 (m, 1H), 7.12 - 7.08 (m, 2H), 7.02 - 6.88 (m, 1H), 6.48 - 6.42 (m, 1H), 4.62 - 4.54 (m, 1H), 4.15 - 4.04 (m, 1H), 3.73 (s, 3H), 3.58 - 3.47 (m, 2H), 3.24 - 3.20 (m, 2H), 3.19 - 3.05 (m, 4H), 2.62 - 2.55 (m, 2H), 1.20 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 913 [M+H] + .

[0837] Example 28: 2”-(Difluoromethyl)-N-(3-(4-(5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphth yridin-3-yl)methyl)piperazin-1-yl)picolinamidobutyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2- oxo-2H-[1,2':4',4”-Terpyridine]-5'-carboxamide

[0838]

[0839] Step 1: tert-Butyl ((3-(4-((tert-Butoxycarbonyl)amino)but-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)amino)carboxylate Step 2: tert-Butyl ((3-(4-((tert-Butoxycarbonyl)amino)butyl)-1,2,4-thiadiazol-5-yl)amino)carboxylate

[0840] Under nitrogen protection, to a solution of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.714 mmol), N-BOC-3-butyn-1-amine (121 mg, 0.714 mmol) and triethylamine (6 mL) in N,N-dimethylformamide (10 mL) were successively added copper(I) iodide (13.6 mg, 0.071 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25.06 mg, 0.036 mmol). After addition, the mixture was stirred at 100 °C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, then ethyl acetate and water were added, and the ethyl acetate phase was separated, washed with water and saturated brine, and the organic phase 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 target compound (yellow solid, 240 mg, yield 91%). LC / MS (ESI) m / z: 369.2 [M+H] + .

[0841] Step 3: 3-(4-Aminobutyl)-1,2,4-thiadiazol-5-amine

[0842] Under nitrogen protection, platinum dioxide (30 mg, 0.132 mmol) was added to a solution of tert-butyl (3-(4-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (150 mg, 0.407 mmol) in methanol (20 mL). Subsequently, the reaction mixture was purged with hydrogen three times, and then stirred at room temperature for 18 hours under hydrogen protection. After the reaction was complete, it was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 25% ethyl acetate) to obtain the target compound (yellow oil, 110 mg, yield 66%). LC / MS (ESI) m / z: 373.2 [M+H] + .

[0843] Step 4: N-(4-(5-Amino-1,2,4-thiadiazol-3-yl)butyl)-5-(4-(((7-Ethyl-6-oxo-5,6-

[0844] At room temperature, hydrochloric acid in methanol (5 mL) was added to a reaction flask containing tert-butyl (3-(4-((tert-butoxycarbonyl)amino)butyl)-1,2,4-thiadiazol-5-yl)carbamate (130 mg, 0.310 mmol). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete, it was concentrated under reduced pressure, and the residue was triturated with ethyl acetate to obtain the target compound (white solid, 55 mg, yield 98%). LC / MS (ESI) (m / z): 173.3 [M+H] + .

[0845] dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide Step 5: 2”-(Difluoromethyl)-N-(3-(4-(5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-

[0846] At room temperature, 3-(4-aminobutyl)-1,2,4-thiadiazol-5-amine (30 mg, 0.144 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (57 mg, 0.144 mmol), and N,N-diisopropylethylamine (111 mg, 0.862 mmol) were dissolved in N,N-dimethylformamide (6 mL). 2-(7-Azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82 mg, 0.216 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure, triturated with acetonitrile to obtain the crude product, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 50 mg, yield 63.5%). LC / MS (ESI) m / z: 548.3 [M+H] + .

[0847] 3-yl)methyl)piperazin-1-yl)picolinamidobutyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo -2H-[1,2':4',4”-Terpyridine]-5'-carboxamide Example 29: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-

[0848] N-(4-(5-Amino-1,2,4-thiadiazol-3-yl)butyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide (50 mg, 0.091 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (36 mg, 0.091 mmol), and N-methylimidazole (45 mg, 0.548 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (5 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (38 mg, 0.137 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture. Then the reaction mixture was stirred at 70 °C for 18 hours. N-Methylimidazole (45 mg, 0.548 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (38 mg, 0.137 mmol) were added, and the reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness to obtain an oil, which was then slurried with acetonitrile to give the crude product. The crude product was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, H2O solution with 20 - 95% acetonitrile and 0.1% FA) to obtain the target compound (10 mg, white solid, yield 11.9%). 1 1H NMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H), 11.85 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.43 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 8.09 (s, 1H), 7.86 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.75 (s, 2H), 7.62 (s, 1H), 7.60 - 7.54 (m, 1H), 7.40 (dd, J = 8.9, 2.8 Hz, 1H), 7.00 (t, J = 55.1 Hz, 1H), 6.42 (td, J = 7.3, 4.7 Hz, 1H), 3.65 (s, 5H), 3.35 - 3.31 (m, 4H), 3.28 - 3.26 (m, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.57 - 2.50 (m, 6H), 1.78 - 1.73 (m, 2H), 1.60 - 1.55 (m, 2H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 921 [M + H] + .

[0849] 3-yl)methyl)piperazin-1-yl)picolinamidopentyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-Terpyridine]-5'-carboxamide Step 1: tert-Butyl ((3-(5-((tert-Butoxycarbonyl)amino)pent-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)amino)carboxylate

[0850]

[0851] Step 2: tert-Butyl ((3-(5-((tert-Butoxycarbonyl)amino)pentyl)-1,2,4-thiadiazol-5-yl)amino)carboxylate Step 3: 3-(5-Aminopentyl)-1,2,4-thiadiazol-5-amine

[0852] Under nitrogen protection, copper(I) iodide (13.60 mg, 0.071 mmol) and bis(triphenylphosphine)palladium(II) dichloride (25.06 mg, 0.036 mmol) were successively added to a solution of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (200 mg, 0.714 mmol), tert-butyl pent-4-yn-1-ylcarbamate (141 mg, 0.714 mmol) and triethylamine (6 mL) in N,N-dimethylformamide (10 mL). After the addition was complete, the reaction mixture was stirred at 100 °C for 2 h. The reaction solution was concentrated to dryness under reduced pressure, then ethyl acetate and water were added, the ethyl acetate phase was separated, washed with water and saturated brine, and the organic phase 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 target compound (yellow solid, 180 mg, yield 66.4%). LC / MS (ESI) m / z: 383.2 [M+H] + .

[0853] Step 4: N-(5-(5-Amino-1,2,4-thiadiazol-3-yl)pentyl)-5-(4-(((7-Ethyl-6-oxo-5,6-

[0854] At room temperature, methanol (20 mL) was added to a reaction flask containing tert-butyl (3-(5-((tert-butoxycarbonyl)amino)pent-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (180 mg, 0.474 mmol) and platinum(IV) oxide (30 mg, 0.132 mmol). The reaction mixture was stirred at room temperature for 18 h under hydrogen protection. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0–25% ethyl acetate) to obtain the target compound (yellow oil, 130 mg, yield 72.2%). LC / MS (ESI) m / z: 387.2 [M+H] + .

[0855] dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0856] At room temperature, 1,4-dioxane hydrochloride (5 mL) was added to a reaction flask containing tert-butyl (3-(5-((tert-butoxycarbonyl)amino)pentyl)-1,2,4-thiadiazol-5-yl)carbamate (130 mg, 0.337 mmol). The reaction solution was stirred at room temperature for 24 hours. After the reaction was complete, it was concentrated under reduced pressure, and the residue was triturated with ethyl acetate and filtered to obtain the target compound (white solid, 55 mg, yield 87.3%). LC / MS (ESI) (m / z): 187.3 [M+H] + .

[0857] ​ ​

[0858] At room temperature, 3-(5-aminopentyl)-1,2,4-thiadiazol-5-amine (30 mg, 0.144 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (57 mg, 0.144 mmol), and N,N-diisopropylethylamine (111 mg, 0.862 mmol) were dissolved in N,N-dimethylformamide (6 mL), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (82 mg, 0.216 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, triturated with acetonitrile to obtain the crude product, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 7% methanol) to obtain the target compound (yellow solid, 50 mg, yield 61.7%). LC / MS (ESI) m / z: 562.3 [M+H] + .

[0859] Step 5: 2”-(Difluoromethyl)-N-(3-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)picolinamido)pentyl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-methoxy-2-oxo -2H-[1,2':4',4”-tripyridine]-5'-carboxamide

[0860] N-(5-(5-Amino-1,2,4-thiadiazol-3-yl)pentyl)-5-(4-(((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide (50 mg, 0.089 mmol), 2"-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxylic acid (35 mg, 0.089 mmol), and N-methylimidazole (45 mg, 0.548 mmol) were dissolved in N,N-dimethylformamide (2 mL). After stirring at 70 °C for 10 minutes, N,N,N’,N’-tetramethylchloroformamidinium hexafluorophosphate (38 mg, 0.137 mmol) was added to the reaction solution, and then the reaction solution was stirred at 70 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure to obtain an oil, which was purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, H2O solution with 20 - 95% acetonitrile and 0.1% FA) to obtain the target compound (4 mg, white solid, yield 4.8%). 1 H NMR (400 MHz, CD3OD) δ 8.94 (s, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 10.9 Hz, 3H), 7.80 (s, 1H), 7.51 - 7.42 (m, 2H), 6.76 (t, J = 55.3 Hz, 1H), 6.53 - 6.45 (m, 1H), 4.56 (s, 2H), 3.68 (s, 3H), 3.63 (s, 2H), 3.47 (s, 4H), 3.40 (t, J = 6.8 Hz, 2H), 2.99 (s, 1H), 2.91 - 2.84 (m, 3H), 2.73 - 2.65 (m, 2H), 1.91 - 1.81 (m, 2H), 1.67 - 1.61 (m, 2H), 1.43 - 1.36 (m 2H), 1.30 - 1.28 (m 3H). LC / MS (ESI) (m / z): 935 [M+H] + .

[0861] Example 30: 2”-(Difluoromethyl)-N-(3-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naph thyridin-3-yl)methyl)piperazin-1-yl)picolinamido)but-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”- methoxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0862]

[0863] Step 1: 3-(4-Aminobut-1-yn-1-yl)-1,2,4-thiadiazol-5-amine

[0864] tert-Butyl (3-(4-((tert-butoxycarbonyl)amino)but-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.271 mmol) and dichloromethane (4 mL) were added to a reaction flask. A solution of trimethylsilyl trifluoromethanesulfonate (603 mg, 2.71 mmol) in dichloromethane (1 mL) was added dropwise to the mixture. The reaction solution gradually became clear, and the reaction was stirred at room temperature for one hour. The reaction solution was concentrated to dryness under reduced pressure, triturated with dichloromethane, and dried to obtain the target compound (100 mg, yellow solid, yield 62.4%). LC / MS (ESI) m / z: 169.2 [M+H] + .

[0865] Step 2: N-(4-(5-Amino-1,2,4-thiadiazol-3-yl)but-3-yn-1-yl)-5-(4-((7-ethyl-6-oxo -5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinamide

[0866] At room temperature, 3-(4-aminobut-1-yn-1-yl)-1,2,4-thiadiazol-5-amine (25 mg, 0.149 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (58 mg, 0.149 mmol), and N,N-diisopropylethylamine (115 mg, 0.892 mmol) were dissolved in N,N-dimethylformamide (2 mL). 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85 mg, 0.223 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, triturated with ethyl acetate to obtain the crude product, and then purified by silica gel column chromatography (eluent: dichloromethane / methanol, gradient: 2 - 10% methanol) to obtain the target compound (yellow solid, 15 mg, yield 18.6%). LC / MS (ESI) m / z: 544.2 [M+H] + .

[0867] Step 3: 2”-(Difluoromethyl)-N-(3-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin- 3-yl)methyl)piperazin-1-yl)picolinamido)but-1-yn-1-yl)-1,2,4-thiadiazol-5-yl)-3-fluoro-5”-meth oxy-2-oxo-2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0868] N-(4-(5-Amino-1,2,4-thiadiazol-3-yl)but-3-yn-1-yl)-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamide (15 mg, 0.028 mmol), 2'-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (10.8 mg, 0.028 mmol), and N-methylimidazole (14 mg, 0.166 mmol) were dissolved in acetonitrile (0.5 mL) and N,N-dimethylformamide (1 mL). After stirring at 70 °C for 1 minute, a solution of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (12 mg, 0.041 mmol) in acetonitrile (0.5 mL) was added to the reaction mixture. Then the reaction mixture was stirred at 70 °C for 1 hour. N-Methylimidazole (14 mg, 0.166 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (12 mg, 0.041 mmol) were added, and the reaction mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness to obtain an oil, which was then slurried with acetonitrile. The crude product was obtained by preparative TLC and purified by preparative HPLC (YMC-Actus Triart C18 250*21 mm, H2O solution of 20 - 95% acetonitrile and 0.1% NH4HCO3) to obtain the target compound (0.2 mg, white solid, yield 0.79%). 1 H NMR (400 MHz, DMSO-d6) δ 13.71 (s, 1H), 11.84 (s, 1H), 9.10 (s, 1H), 8.65 - 8.61 (m, 1H), 8.45 (s, 1H), 8.40 (d, J = 1.7 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H), 7.88 - 7.85 (m, 2H), 7.75 (s, 1H), 7.63 (s, 1H), 7.57 - 7.51 (m, 1H), 7.41 (dd, J = 9.0, 2.6 Hz, 1H), 7.11 - 6.84 (m, 3H), 6.41 - 6.38 (m, 1H), 3.65 (s, 2H), 3.63 (s, 3H), 3.53 - 3.47 (m, 4H), 3.32 - 3.30 (m, 2H), 2.70 - 2.68 (m, 4H), 2.56 - 2.48 (m, 4H), 1.18 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 917 [M + H] + .

[0869] Example 31: 2”-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- yl)methyl)piperazin-1-yl)picolinamidoethoxy)thiazol-2-yl)-3-fluoro-5”-methoxy-2-oxo- 2H-[1,2':4',4”-terpyridine]-5'-carboxamide

[0870]

[0871] Step 1: tert-Butyl-(4-hydroxythiazol-2-yl)carbamate

[0872] Under an ice bath, di-tert-butyl dicarbonate (16.5 g, 75.77 mmol) was added portionwise to a solution of 2-aminothiazol-4-ol (8 g, 68.9 mmol) and 4-dimethylaminopyridine (9 g, 75.8 mmol) in anhydrous tetrahydrofuran (2 mL). The reaction mixture was stirred at 40 °C under nitrogen for 16 hours. After completion of the reaction, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 40% ethyl acetate) to obtain the target compound (white solid, 3.5 g, yield 23.5%). LC / MS (ESI) m / z: 217 [M+H] + .

[0873] Step 2: tert-Butyl-(4-(2-((benzyloxy)carbonyl)amino)ethoxy)thiazol-2-yl)carbamate

[0874] Under nitrogen protection, tert-butyl-(4-hydroxythiazol-2-yl)carbamate (200 mg, 0.92 mmol), benzyl (3-hydroxypropyl)carbamate (180 mg, 0.92 mmol) and CMBP (446 mg, 1.84 mmol) were dissolved in anhydrous toluene (2 mL). The reaction mixture was purged with nitrogen three times and stirred at 100 °C under nitrogen for 16 hours. After completion of the reaction, ethyl acetate and water were added, the ethyl acetate layer 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: petroleum ether / ethyl acetate, gradient: 0 - 20% ethyl acetate) to obtain the target compound (white solid, 220 mg, yield 60.4%). LC / MS (ESI) m / z: 394 [M+H] + .

[0875] Step 3: Benzyl (2-((2-aminothiazol-4-yl)oxy)ethyl)carbamate

[0876] tert-Butyl-(4-(2-((benzyloxy)carbonyl)amino)ethoxy)thiazol-2-yl)carbamate (220 mg, 0.56 mmol) was added to a reaction flask containing anhydrous dichloromethane (3 mL), and then the reaction mixture was cooled to 0 ℃ , and trifluoroacetic acid (1 mL) was slowly added dropwise. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and the residue was adjusted to pH 8 - 9 with saturated aqueous sodium bicarbonate. Then it was extracted with dichloromethane three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 160 mg, yield 97.5%). LC / MS (ESI) m / z: 294 [M+H] + .

[0877] Step 4: Benzyl (2-((2-(2”-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”- bipyridine]-5'-carboxamido)thiazol-4-yl)oxy)ethyl)carbamate

[0878] Under nitrogen protection, benzyl (2-((2-aminothiazol-4-yl)oxy)ethyl)carbamate (50 mg, 0.13 mmol), 2"-(difluoromethyl)-3-fluoro-5"-methoxy-2-oxo-2H-[1,2':4',4"-bipyridine]-5'-carboxylic acid (37 mg, 0.13 mmol) and N-methylimidazole (52 mg, 0.64 mmol) were dissolved in anhydrous acetonitrile (2 mL). The mixture was stirred at 70 °C for 5 minutes, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (71 mg, 0.26 mmol) was added. The reaction solution was stirred at 70 °C for 1 hour. After the reaction was completed, a white solid product precipitated out. The target compound (white solid, 40 mg, yield 46.9%) was obtained by filtration. LC / MS (ESI) m / z: 667 [M+H] + .

[0879] Step 5: N-(4-(2-Aminoethoxy)thiazol-2-yl)-2'-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo -2H-[1,2':4',4”-bipyridine]-5'-carboxamide

[0880] Under nitrogen protection, benzyl (2-((2-(2"-(difluoromethyl)-3-fluoro-5'-methoxy-2-oxo-2H-[1,2':4',4"-bipyridine]-5"-carboxamido)thiazol-4-yl)oxy)ethyl)carbamate (40 mg, 0.060 mmol) was added to a reaction flask containing anhydrous dichloromethane (1 mL). Then the reaction solution was cooled to 0 °C, and trifluoroacetic acid (0.3 mL) was slowly added dropwise. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid. The residue was adjusted to pH 8 - 9 with saturated aqueous sodium bicarbonate. Then it was extracted three times with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 15 mg, yield 46.9%). LC / MS (ESI) m / z: 533 [M+H] + .

[0881] Step 6: 2”-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3- ((2-((((2-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-yl)carbonyl)amino)ethoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Example 32: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0882] Under nitrogen protection, N-(4-(2-aminoethoxy)thiazol-2-yl)-2'-(difluoromethyl)-3-fluoro-5”-methoxy-2-oxo-2H-[1,2':4',4”-bipyridine]-5'-carboxamide (15 mg, 0.028 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (11 mg, 0.028 mmol), and N-methylimidazole (11 mg, 0.14 mmol) were dissolved in anhydrous acetonitrile (1 mL). The mixture was stirred at 70 °C for 5 minutes, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (16 mg, 0.056 mmol) was added. The reaction solution was stirred at 70 °C for 1 hour. After the reaction was completed, the mixture was filtered and purified by preparative HPLC (Welch XBridge XB 5 μm 21.2 * 250 mm, H2O solution containing 20 - 95% methanol and 0.1% TFA) to obtain the target compound (white solid, 1.09 mg, yield 4.2%). 1 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.13 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.38 (s, 1H), 7.97 (d, J = 2.6 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.76 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 3.0 Hz, 2H), 7.55 - 7.50 (m, 1H), 7.24 - 7.19 (m, 1H), 6.98 (t, J = 55.1 Hz, 1H), 6.43 - 6.38 (m, 1H), 3.94 (s, 2H), 3.77 (s, 3H), 3.60 (s, 2H), 3.30 - 3.26 (m, 2H), 3.25 - 3.22 (m, 4H), 2.58 - 2.52 (m, 4H), 2.47 - 2.46 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 908 [M + H] + .

[0883] Example 32: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide ((2-((((2-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-yl)carbonyl)amino)ethoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Example 32: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0884]

[0885] Step 1: tert-Butyl (4-(3-((benzyloxy)carbonyl)amino)propoxy)thiazol-2-yl)carbamate

[0886] Under nitrogen protection, tert-butyl-(4-hydroxythiazol-2-yl)carbamate (200 mg, 0.92 mmol), benzyl (3-hydroxypropyl)carbamate (193 mg, 0.92 mmol) and cyanomethylenetributylphosphine (446 mg, 1.84 mmol) were dissolved in anhydrous toluene (2 mL). The reaction solution was purged with nitrogen three times and stirred at 100 °C for 16 h under nitrogen. After the reaction was completed, 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: petroleum ether / ethyl acetate, gradient: 0 - 20% ethyl acetate) to obtain the target compound (white solid, 270 mg, yield 71.6%). LC / MS (ESI) m / z: 408 [M+H] + .

[0887] Step 2: Benzyl (3-((2-aminothiazol-4-yl)oxy)propyl)carbamate

[0888] Under nitrogen protection, tert-butyl-(4-(3-((benzyloxy)carbonyl)amino)propoxy)thiazol-2-yl)carbamate (270 mg, 0.66 mmol) was added to a reaction flask containing anhydrous dichloromethane (3 mL), and then the reaction solution was cooled to 0 °C. Trifluoroacetic acid (1 mL) was slowly added dropwise. Then the reaction mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and the residue was adjusted to pH 8 - 9 with saturated aqueous sodium bicarbonate. Then it was extracted with dichloromethane three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 160 mg, yield 81.5%). LC / MS (ESI) m / z: 308 [M+H] + .

[0889] Step 3: Benzyl (3-((2-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamido)thiazol-4-yl)oxy)propyl)carbamate Step 4: N-(4-(3-aminopropoxy)thiazol-2-yl)-2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0890] Under nitrogen protection, benzyl (3-((2-aminothiazol-4-yl)oxy)propyl)carbamate (50 mg, 0.16 mmol), 2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxylic acid (64 mg, 0.16 mmol) and N-methylimidazole (67 mg, 0.82 mmol) were dissolved in anhydrous acetonitrile (2 mL), stirred at 70 °C for 5 min, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (91 mg, 0.32 mmol) was added. The reaction solution was stirred at 70 °C for 1 h. After the reaction was completed, the target compound was obtained by filtration (white solid, 50 mg, yield 45.1%). LC / MS (ESI) m / z: 681 [M+H] + .

[0891] Step 5: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Example 32: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0892] Under nitrogen protection, benzyl (3-((2-(2''-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamido)thiazol-4-yl)oxy)propyl)carbamate (40 mg, 0.059 mmol) was added to a reaction flask containing anhydrous dichloromethane (1 mL). Then the reaction solution was cooled to 0 °C, and trifluoroacetic acid (0.3 mL) was slowly added dropwise. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and the residue was adjusted to pH 8 - 9 with saturated aqueous sodium bicarbonate. Then it was extracted with dichloromethane three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (white solid, 20 mg, yield 62.2%). LC / MS (ESI) m / z: 547 [M+H] + .

[0893] Step 5: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide ((2-((((2-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-yl)carbonyl)amino)ethoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Example 32: 2''-(Difluoromethyl)-N-(4-(5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolylamino)propoxy)thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0894] Under nitrogen protection, N-(4-(3-aminopropoxy)thiazol-2-yl)-2'-(difluoromethyl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-bipyridine]-5'-carboxamide (20 mg, 0.037 mmol), 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinate (14 mg, 0.037 mmol), and N-methylimidazole (15 mg, 0.18 mmol) were dissolved in anhydrous acetonitrile (1 mL). The mixture was stirred at 70 °C for 5 minutes, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (21 mg, 0.074 mmol) was added. The reaction solution was stirred at 70 °C for 1 hour. After the reaction was completed, it was filtered and purified by preparative HPLC (welch xbidge xb 5um 21.2*250mm, 20 - 95% methanol in H2O solution and 0.1% TFA) to obtain the target compound (white solid, 4.67 mg, yield 13.8%). 11H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.15 (s, 1H), 8.50 (s, 1H), 8.42 - 8.38 (m, 2H), 8.21 (d, J = 2.7 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.54 - 7.49 (m, 1H), 7.35 (dd, J = 8.9, 2.7 Hz, 1H), 6.99 (t, J = 55.1 Hz, 1H), 6.43 - 6.37 (m, 1H), 4.03 (s, 2H), 3.80 (s, 3H), 3.64 (s, 2H), 3.49 (s, 2H), 3.30 - 3.26 (m, 4H), 3.24 - 3.18 (m, 2H), 2.58 - 2.52 (m, 4H), 1.71 - 1.68 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H). LC / MS (ESI) (m / z): 922 [M + H] + .

[0895] Example 33: 2''-(Difluoromethyl)-N-(5-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Step 1: tert-Butyl (5-nitrobenzo[d]thiazol-2-yl)carbamate Step 2: tert-Butyl (5-aminobenzo[d]thiazol-2-yl)carbamate

[0896]

[0897] Step 3: tert-Butyl 5-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)carbamate

[0898] Under nitrogen protection, 5-nitrobenzo[d]thiazol-2-amine (900 mg, 4.61 mmol), di-tert-butyl dicarbonate (1001 mg, 4.61 mmol) and 4-dimethylaminopyridine (0.92 g, 0.92 mmol) were dissolved in anhydrous tetrahydrofuran (9 mL). The reaction mixture was stirred at 40 °C under nitrogen for 16 hours. After completion of the reaction, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, gradient: 0 - 40% ethyl acetate) to obtain the target compound (white solid, 1.0 g, yield 73.4%). LC / MS (ESI) m / z: 296 [M + H] + .

[0899] Step 4: N-(2-aminobenzo[d]thiazol-5-yl)-4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamide

[0900] Under nitrogen protection, 20% palladium hydroxide on carbon (200 mg) was added to a methanol (10 mL) solution of tert-butyl-(5-nitrobenzo[d]thiazol-2-yl)carbamate (1 g, 3.39 mmol). The reaction mixture was purged with hydrogen three times and stirred at room temperature under a hydrogen balloon for 2 hours. After the reaction was complete, the reaction solution was filtered and concentrated under reduced pressure to obtain the target compound (white solid, 800 mg, yield 89.0%). LC / MS(ESI) m / z: 266 [M+H] + .

[0901] Step 5: 2''-(Difluoromethyl)-N-(5-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide Step 5: 2''-(Difluoromethyl)-N-(5-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzamido)benzo[d]thiazol-2-yl)-3-fluoro-5''-methoxy-2-oxo-2H-[1,2':4',4''-terpyridin]-5'-carboxamide

[0902] Under nitrogen protection, tert-butyl-(5-aminobenzo[d]thiazol-2-yl)carbamate (24 mg, 0.092 mmol), 4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)benzoic acid (30 mg, 0.077 mmol) and N-methylimidazole (31 mg, 0.38 mmol) were dissolved in anhydrous acetonitrile (2 mL), stirred at 70 °C for 5 minutes, and then N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (43 mg, 0.15 mmol) was added. The reaction solution was stirred at 70 °C for 1 hour. After the reaction was completed, the target compound was obtained by filtration (white solid, 30 mg, yield 61.3%). LC / MS(ESI) m / z: 639 [M+H] + .

[0903] Step 5: 2''-(Difluoromethyl)-N-(5-(4-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3; X 1 and X 2 are independently N or CH; Each R 2 is independently deuterium, halogen, cyano, amino, hydroxy, -COOR 2-7 , -C(O)R 2-8 , -C(O)N(R 2-9 )2, -N(R 2-12 )2, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy, unsubstituted or substituted by one or more R 2-3 substituted C 2-6 alkenyl, unsubstituted or substituted by one or more R 2-4 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 2-5 substituted C 3-10 cycloalkyl, unsubstituted or substituted by one or more R 2-6 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 2-13 substituted 4- to 12-membered heterocycloalkenyl; 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 hydroxyl group, a cyano group or a halogen; Each R 2-7 、R 2-8 、R 2-9 and R 2-12 is independently hydrogen or a C 1-6 alkyl group; Each R 2-10 and R 2-11 are independently a hydroxyl group or a C 1-6 alkyl group; or two Rs 2-11 together with the P atom to which they are attached form a 5- to 10-membered alkane heterocycle, the heteroatom in the 5- to 10-membered alkane heterocycle being P and the number of heteroatoms being 1; Each R 3 is independently -N(R 3-7 )2, -C(O)N(R 2-9 )2, -O-5- to 12-membered heteroaryl, C 3-1 alkyl which is unsubstituted or substituted by one or more R 1-6 , C 3-2 alkenyl which is unsubstituted or substituted by one or more R 2-6 , C 3-3 alkynyl which is unsubstituted or substituted by one or more R 2-6 , C 3-4 cycloalkyl which is unsubstituted or substituted by one or more R 3-6 , 3- to 12-membered heterocycloalkyl which is unsubstituted or substituted by one or more R 3-5 , 4- to 12-membered heterocycloalkenyl which is unsubstituted or substituted by one or more R 3-9 , 5- to 12-membered heteroaryl which is unsubstituted or substituted by one or more R 3-6 or C 3-10 aryl which is unsubstituted or substituted by one or more R 6-12 ; Each R 3-1 , R 3-2 and R 3-3 is independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 3-1-2 substituted 5- to 12-membered heteroaryl; Each R 3-4 、R 3-5 and R 3-9 are independently an oxo group, a halogen, a cyano group, a hydroxyl group, -N(R 3-5-3 )2, an unsubstituted or one or more R 3-5-1 -substituted C 1-6 alkyl, an unsubstituted or one or more R 3-5-2 -substituted C 1-6 alkoxy, an unsubstituted or one or more R 3-5-5 -substituted C 3-6 cycloalkyl or an unsubstituted or one or more R 3-5-6 -substituted 3- to 12-membered heterocycloalkyl; Each R 3-6 and R 3-10 are independently an oxo group, a halogen, a cyano group, a hydroxy group, -N(R 3-6-3 )2, an unsubstituted or one or more R 3-6-1 substituted C 1-6 alkyl, an unsubstituted or one or more R 3-5-2 substituted C 1-6 alkoxy, an unsubstituted or one or more R 3-5-5 substituted C 3-6 cycloalkyl, an unsubstituted or one or more R 3-6-2 substituted 3- to 12-membered heterocycloalkyl; Each R 3-7 is independently hydrogen, unsubstituted or substituted by one or more R 3-7-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-8-1 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 3-7-2 substituted 5- to 12-membered heteroaryl; Each R 3-8 is independently unsubstituted or substituted by one or more R 3-7-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-8-1 substituted 3- to 12-membered heterocycloalkyl or unsubstituted or substituted by one or more R 3-7-2 substituted 5- to 12-membered heteroaryl; Each R 3-1-1 and R 3-1-2 are independently a hydroxyl group, a cyano group, a halogen, or a C 1-6 alkyl group; Each R 3-1-3 is independently an unsubstituted or R-substituted 3- to 12-membered heterocycloalkyl; 3-1-3-1 ​ Each R 3-1-3-1 is independently a hydroxyl group, a cyano group, a halogen, or a C 1-6 alkyl group; Each R 3-4-1 、R 3-5-3 and R 3-6-3 is independently hydrogen or a C 1-6 alkyl group; Each R 3-5-1 , R 3-5-2 and R 3-7-1 is independently deuterium, a hydroxyl group, a cyano group or a halogen; Each R 3-5-4 and R 3-7-3 are independently C 1-6 alkyl or C 3-6 cycloalkyl; Each R 3-5-5 , R 3-5-6 and R 3-6-2 is independently a hydroxyl group, a cyano group, a halogen, or a C 1-6 alkyl group; Each R 3-6-1 is independently a hydroxyl group, a cyano group, a halogen, or a C 1-6 alkoxy group; Each R 3-7-2 and R 3-8-1 are independently a hydroxyl group, a cyano group, a halogen, or a C 1-6 alkyl group; Ring A is a 5- to 12-membered heteroaryl ring; R 1 is hydrogen, deuterium, cyano, hydroxy, halogen, -NHC(O)R b , -NHS(O)2R c , -S(O)2NHR d , -NHR f , -C(O)NHR g , -OR h , -SR i , -C(O)R j , -S(O)2R k , -C(O)N(R m )2, -NH2, -SF5, unsubstituted or substituted by one or more R 1-3 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 1-4 substituted C 1-6 alkoxy, unsubstituted or substituted by one or more R 1-5 substituted C 3-10 cycloalkyl, unsubstituted or substituted by one or more R 1-6 substituted 3- to 12-membered heterocycloalkyl, unsubstituted or substituted by one or more R 1-7 substituted C 6-12 aryl or unsubstituted or substituted by one or more R 1-8 substituted 5- to 12-membered heteroaryl; R b 、R c 、R d 、R f 、R g 、R h 、R i 、R j 、R k and R m are independently unsubstituted or substituted by one or more R 1-9 substituted cycloalkyl, unsubstituted or substituted by one or more R 3-10 substituted 3- to 12-membered heterocycloalkyl, unsubstituted or substituted by one or more R 1-10 substituted aryl, unsubstituted or substituted by one or more R 1-11 substituted 5- to 12-membered heteroaryl or unsubstituted or substituted by one or more R 6-12 substituted C 1-12 alkyl; 1-13 substituted C 1-6 alkyl; Each R 1-3 、R 1-4 、R 1-5 、R 1-6 、R 1-7 、R 1-8 、R 1-9 、R 1-10 、R 1-11 、R 1-12 and R 1-13 are independently halogen, C 1-6 alkyl, -S(O)2C 1-6 alkyl or -P(O)(C 1-6 alkyl)2; Ring E is an unsubstituted or one or more R-substituted benzene ring or an unsubstituted or one or more R-substituted 5- to 12-membered heteroaromatic ring; e-1 Ring E is an unsubstituted or one or more R-substituted benzene ring or an unsubstituted or one or more R-substituted 5- to 12-membered heteroaromatic ring; e-1 Ring E is an unsubstituted or one or more R-substituted benzene ring or an unsubstituted or one or more R-substituted 5- to 12-membered heteroaromatic ring; Ring F is unsubstituted or substituted by one or more R e-2 to form a 4- to 12-membered heteroalkene ring; Each R e-1 is independently halogen or an unsubstituted or R-substituted C 2-1 alkyl; 1-6 ​ Each R e-2 is independently an oxo group, a halogen, or an unsubstituted or R 2-1 -substituted C 1-6 alkyl; L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 -,-L 5 -L 6 -,-L 2 -L 4 -L 5 -L 6 -,-L 1 -L 2 -L 3 -L 5 -L 6 - or -L 2 -L 3 -L 5 -L 6 -;(L in L 6 is connected to ring E, and the other end of L is connected to ring A) Each - L 1 - independently is Each R P1 independently deuterium, a halogen or C 1-6 alkyl, or two Rs P1 together with the carbon atom to which they are attached form C 3-10 subcycloalkyl or 3 - 12 - membered heterocycloalkyl; ring G is independently a 3 - 12 - membered alkheterocycle; Each - L 2 - independently is unsubstituted or substituted by one or more R P2 alkylene, unsubstituted or substituted by one or more R 1-14 substituted C P2 alkynylene, unsubstituted or substituted by one or more R 2-14 substituted C P2 cycloalkylene, unsubstituted or substituted by one or more R 3-10 substituted 3 - 12 - membered heterocycloalkylene or unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroarylene; each said C P2 alkylene and C 1-14 alkynylene, one or more methylene units in 2-14 which are independently optionally replaced by R P3 each R P3 independently is C 3-10 cycloalkylene or 3 - 12 - membered heterocycloalkylene; Each - L 3 - independently is each - L 4 - independently is unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered arylene, unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroarylene or unsubstituted or substituted by one or more R P2 substituted C 3-10 subcycloalkyl; Ring H is a 5- to 12-membered heteroaryl ring, and t1 is 0, 1, 2, 3 or 4; Each - L 5 - independently is unsubstituted or substituted by one or more R P2 substituted 3 - 12 - membered heteroalkyl, unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted 4 - 12 - membered heteroalkenyl; ring P is independently a 5 - 12 - membered heteroaromatic ring; ring Q is independently a 3 - 12 - membered alkheterocyclic ring; n1 and n2 are independently 0, 1 or 2; each - L 6 - independently unsubstituted or substituted by one or more R P2 - alkylene 1-14 ; Each R P2 is independently a halogen; Each of the 3- to 12-membered heterocycloalkyl, 3- to 12-membered alkheterocycle, 4- to 12-membered heterocycloalkenyl, 4- to 12-membered alkenheterocycle, 4- to 12-membered subheterocycloalkenyl, 5- to 12-membered heteroaryl, -O-5- to 12-membered heteroaryl, 5- to 12-membered heteroaryl ring, 3- to 12-membered subheterocycloalkyl and 5- to 10-membered subheteroaryl has heteroatoms independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

2. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein It satisfies one or more of the following conditions: (1) Each of the halogens is independently fluorine, chlorine, bromine or iodine; (2) Each of the C 1-6 alkyl groups is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) Each of the C 1-6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (4) Each of the C 2-6 alkenyl groups is independently vinyl, propenyl or allyl; (5) Each of the C 2-6 alkynyl groups is independently ethynyl, propynyl or propargyl; (6) Each of the C 3-10 cycloalkyl group and each of the C 3-6 cycloalkyl groups is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (7) Each of the 3- to 12-membered heterocycloalkyl is independently a 3- to 9-membered heterocycloalkyl, such as a 3- to 6-membered heterocycloalkyl or a 5- to 9-membered heterocycloalkyl; (8) Each of the 3- to 12-membered heterocycloalkyl is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2; the monocyclic ring can be a 3- to 6-membered monocyclic heterocycloalkyl or a 5- to 9-membered monocyclic heterocycloalkyl; the fused ring can be a 5- to 9-membered fused heterocycloalkyl, such as a 3-membered fused 6-membered heterocyclic group; (9) The heteroatoms in each of the 3- to 12-membered heterocycloalkyl are independently selected from one or two of N and O, and the number of heteroatoms can be independently 1 or 2; (10) Each of the 4- to 12-membered heterocycloalkenyl is independently a 5- to 6-membered heterocycloalkenyl; (11) The heteroatom of each of the 4- to 12-membered heterocycloalkenyl is N, and the number of heteroatoms can be independently 1 or 2; (12) The number of double bonds in each of the 4- to 12-membered heterocycloalkenyl is independently 1 or 2, such as 2; (13) Each of the 5- to 12-membered heteroaryl is independently a monocyclic or fused ring, and the number of rings in the fused ring can be 2; (14) Each of the 5- to 12-membered heteroaryl is independently a 5- to 6-membered heteroaryl; (15) The heteroatoms in each of the 5- to 12-membered heteroaryl are independently selected from one or two of N and O, and the number of heteroatoms can be independently 1, 2 or 3; (16) Each of the C 6-12 aryl groups is independently phenyl or naphthyl; (17) Each of the 5- to 12-membered heteroaryl rings is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2; (18) Each of the 5- to 12-membered heteroaryl rings is independently a 5- to 10-membered heteroaryl ring, such as a 5- to 6-membered heteroaryl ring or an 8- to 10-membered heteroaryl ring; (19) Each of the 3- to 12-membered subheterocycloalkyl is independently a monocyclic, bridged, spiro or fused ring; the number of rings in the bridged, spiro or fused ring can be 2; preferably a monocyclic ring; (20) Each of the 3- to 12-membered subheterocycloalkyl is independently a 3- to 8-membered subheterocycloalkyl, such as a 3- to 6-membered subheterocycloalkyl; (21) The heteroatoms in each of the 3- to 12-membered subheterocycloalkyl are independently selected from one or two of N and O, and the number of heteroatoms can be independently 1 or 2; (22) Each of the 5- to 10-membered heteroarylene groups is independently a 5- to 6-membered heteroarylene group or an 8- to 10-membered heteroarylene group; (23) Each of the 5- to 10-membered heteroarylene groups is independently a monocyclic or fused ring, and the number of rings in the fused ring can be 2; (24) The heteroatoms in each of the 5- to 10-membered heteroarylene groups are N, and the number of heteroatoms can independently be 1, 2, or 3; (25) Each of said C 3-10 The subcycloalkyl group is independently C 3-6 The subcycloalkyl group or C 5-10 The subcycloalkyl group; (26) Each of the C 3-10 The subcycloalkyl group is independently a monocyclic, bridged, spiro or fused ring; the number of rings in the bridged, spiro or fused ring can be 2; the monocyclic ring can be C 3-6 Monocyclic subcycloalkyl group, such as cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene; the bridged ring can be C 5-10 Bridged subcycloalkyl group, such as 4-membered bridge 4-membered subcycloalkyl group, 4-membered bridge 5-membered subcycloalkyl group or 4-membered bridge 6-membered subcycloalkyl group; the fused ring can be C 5-10 Fused subcycloalkyl group, such as 4-membered fused 5-membered subcycloalkyl group, 4-membered fused 6-membered subcycloalkyl group, 5-membered fused 5-membered subcycloalkyl group, 5-membered fused 6-membered subcycloalkyl group or 6-membered fused 6-membered subcycloalkyl group; the spiro ring can be C 5-10 Spiro subcycloalkyl group, such as 4-membered spiro 4-membered subcycloalkyl group, 4-membered spiro 5-membered subcycloalkyl group, 4-membered spiro 6-membered subcycloalkyl group, 5-membered spiro 4-membered subcycloalkyl group, 5-membered spiro 5-membered subcycloalkyl group, 5-membered spiro 6-membered subcycloalkyl group, 6-membered spiro 4-membered subcycloalkyl group or 6-membered spiro 5-membered subcycloalkyl group; (27) Each of the 3- to 12-membered alkheterocyclic rings is a monocyclic ring; (28) Each of the 3- to 12-membered alkheterocyclic rings is independently a 3- to 6-membered alkheterocyclic ring; (29) The heteroatoms in each of the 3- to 12-membered alkheterocyclic rings are N, and the number of heteroatoms can independently be 1 or 2; (30) Each of the "each of the plurality of" is independently 2, 3, 4, or 5, such as 2 or 3; Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine or chlorine; (2)R e-1 、R 2-1 、R 3-9 、R 1 、R P1 and R P2 wherein the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine; (3)R e-2 Among them, each C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl or ethyl; (4)R 2 、R 3 、R 2-9 、R 3-9 、R 3-5 、R 3-6 、R 1 and R P1 among them, each C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl; (5)R 2-11 Among them, each C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as ethyl; (6)R 2-11 In which, two Rs 2-11 together with the P atom to which they are attached form a 5- or 6-membered alkanheterocycle, the heteroatom in the 5- or 6-membered alkanheterocycle is P, and the number of heteroatoms is 1; for example is (7)R 1 and R 2 In, each of the C 1-6 alkoxy groups is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, such as methoxy; (8)R 1 Among them, each C 3-10 cycloalkyl group is independently a C 3-6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and for another example, cyclopropyl; (9)R 3 Among them, each C 2-6 alkynyl group is independently ethynyl, propynyl or propargyl, such as ethynyl; (10)R 3 In which, each of said 3- to 12-membered heterocycloalkyl groups is independently a 3- to 9-membered heterocycloalkyl group, such as a 3- to 6-membered heterocycloalkyl group or a 5- to 9-membered heterocycloalkyl group; (11)R 3 In which, each of the 3- to 12-membered heterocycloalkyl groups is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2; the monocyclic ring can be a 3- to 6-membered monocyclic heterocycloalkyl group or a 5- to 9-membered monocyclic heterocycloalkyl group; the fused ring can be a 5- to 9-membered fused heterocycloalkyl group, such as a 3-membered fused 6-membered heterocycloalkyl group; (12)R 3 Among them, the heteroatoms in each 3- to 12-membered heterocycloalkyl group are independently selected from one or two of N and O, and the number of heteroatoms can independently be 1 or 2; (13)R 3 Among them, each 4-12-membered heteroalkenyl is independently a 5-6-membered heteroalkenyl; (14)R 3 Among them, the heteroatom of each 4- to 12-membered heteroalkenyl group is N, and the number of heteroatoms can independently be 1 or 2; (15)R 3 In the formula, the number of double bonds in each 4- to 12-membered heterocyclic alkenyl group is independently 1 or 2, for example, 2; (16)R 3 wherein each of the 5- to 12-membered heteroaryl groups is independently monocyclic or fused-ring, and the number of rings of the fused-ring may be 2; (17)R 3 wherein each of said 5- to 12-membered heteroaryl groups is independently a 5- to 6-membered heteroaryl group; (18)R 3 Among them, the heteroatoms of each 5- to 12-membered heteroaryl are independently selected from one or both of N and O, and the number of heteroatoms can independently be 1, 2, or 3; (19)R 3-3 Among them, each 3- to 12-membered heterocycloalkyl group is independently a 3- to 9-membered heterocycloalkyl group, such as a 3- to 6-membered heterocycloalkyl group or a 5- to 9-membered heterocycloalkyl group; (20)R 3-3 In which, each of the 3- to 12-membered heterocycloalkyl groups is independently a monocyclic or fused ring; the number of rings in the fused ring may be 2; the monocyclic ring may be a 3- to 6-membered monocyclic heterocycloalkyl group or a 5- to 9-membered monocyclic heterocycloalkyl group; the fused ring may be a 5- to 9-membered fused heterocycloalkyl group, such as a 3-membered fused 6-membered heterocyclic group; (21)R 3-3 wherein the heteroatoms in each of the 3- to 12-membered heterocycloalkyl groups are independently selected from one or two of N and O, and the number of heteroatoms can independently be 1 or 2; (22) In ring A, each of the 5- to 12-membered heteroaromatic rings is independently a monocyclic or fused ring; the number of rings in the fused ring can be 2; (23) In ring A, each of the 5- to 12-membered heteroaromatic rings is independently a 5- to 10-membered heteroaromatic ring, such as a 5- to 6-membered heteroaromatic ring or an 8- to 10-membered heteroaromatic ring; (24) In ring A, the heteroatoms of each of the 5- to 12-membered heteroaromatic rings are selected from one or both of N and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; (25) In ring F, each of the 4- to 12-membered enheterocyclic rings is independently a 5- to 6-membered enheterocyclic ring; (26) In ring F, the heteroatoms of each of the 4- to 12-membered enheterocyclic rings are N, and the number of heteroatoms can be 1 or 2; (27) In ring F, the number of double bonds in each of the 4- to 12-membered enheterocyclic rings is 1 or 2; (28) In rings E and P, each of the 5- to 12-membered heteroaromatic rings is independently a monocyclic ring; (29) In rings E and P, each of the 5- to 12-membered heteroaromatic rings is independently a 5- to 10-membered heteroaromatic ring, such as a 5- to 6-membered heteroaromatic ring; (30) In rings E and P, the heteroatoms of each of the 5- to 12-membered heteroaromatic rings are N, and the number of heteroatoms can be 1, 2, or 3; (31) In ring Q, each of the 3- to 12-membered alkheterocyclic rings is a monocyclic ring; (32) In ring Q, each of the 3- to 12-membered alkheterocyclic rings is independently a 3- to 6-membered alkheterocyclic ring; (33) In ring Q, the heteroatoms of each of the 3- to 12-membered alkheterocyclic rings are N, and the number of heteroatoms can be 1 or 2; (34)R P1 Among them, the C 3-10 subcycloalkyl groups are independently C 3-6 monocyclic subcycloalkyl groups, such as subcyclopropyl groups, and for another example (35)R P1 wherein the 3- to 12-membered heteroalicyclic group is independently a 3- to 6-membered monocyclic heteroalicyclic group, the heteroatom of the 3- to 6-membered monocyclic heteroalicyclic group may be independently selected from one or two of N and O, the number of heteroatoms may be 1 or 2, such as oxetanyl or azetidinyl, and for another example In ring G, the 3- to 12-membered alicyclic heterocycle is independently a 3- to 6-membered monocyclic alicyclic heterocycle. The heteroatom of the 3- to 6-membered monocyclic alicyclic heterocycle is N, and the number of heteroatoms is 1. For example is (37)L 2 Among them, each C 1-14 alkylene group is independently a C 1-8 alkylene group, and the C 1-8 alkylene group can be a straight-chain alkylene group, for example (38)L 2 Among them, each C 2-14 alkynylene group is independently a C 2-6 alkynylene group, and the C 2-6 alkynylene group can be a straight-chain alkynylene group, for example For another example For still another example (39)L 2 and R P3 in which each C 3-10 subcycloalkyl group is independently a C 3-6 subcycloalkyl group or a C 5-10 subcycloalkyl group; (40)L 2 and R P3 wherein each C 3-10 subcycloalkyl group is independently a monocyclic, bridged, spiro or fused ring; the number of rings in the bridged, spiro or fused ring may be 2; the monocyclic ring may be a C 3-6 monocyclic subcycloalkyl group, such as a cyclopropylidene, cyclobutylidene, cyclopentylidene or cyclohexylidene group; the bridged ring may be a C 5-10 bridged subcycloalkyl group, such as a 4-membered bridged 4-membered subcycloalkyl group, a 4-membered bridged 5-membered subcycloalkyl group or a 4-membered bridged 6-membered subcycloalkyl group; the fused ring may be a C 5-10 fused subcycloalkyl group, such as a 4-membered fused 5-membered subcycloalkyl group, a 4-membered fused 6-membered subcycloalkyl group, a 5-membered fused 5-membered subcycloalkyl group, a 5-membered fused 6-membered subcycloalkyl group or a 6-membered fused 6-membered subcycloalkyl group; the spiro ring may be a C 5-10 spiro subcycloalkyl group, such as a 4-membered spiro 4-membered subcycloalkyl group, a 4-membered spiro 5-membered subcycloalkyl group, a 4-membered spiro 6-membered subcycloalkyl group, a 5-membered spiro 4-membered subcycloalkyl group, a 5-membered spiro 5-membered subcycloalkyl group, a 5-membered spiro 6-membered subcycloalkyl group, a 6-membered spiro 4-membered subcycloalkyl group or a 6-membered spiro 5-membered subcycloalkyl group; (41)L 2 and R P3 wherein each of said 3- to 12-membered heteroalkyl rings is independently a monocyclic, bridged, spiro or fused ring; the number of rings in said bridged, spiro or fused ring may be 2, preferably a monocyclic ring; (42)L 2 and R P3 wherein each of said 3- to 12-membered heteroalkylidene groups is independently a 3- to 8-membered heteroalkylidene group, such as a 3- to 6-membered heteroalkylidene group; (43)L 2 and R P3 wherein, the heteroatoms of each 3- to 12-membered heteroalkyl group are independently selected from one or both of N and O, and the number of heteroatoms may independently be 1 or 2; (44)L 2 wherein each of said 5- to 10-membered heteroarylene groups is independently a 5- to 6-membered heteroarylene group or an 8- to 10-membered heteroarylene group; (45)L 2 wherein each of the 5- to 10-membered heteroarylene groups is independently a monocyclic or fused ring, and the number of rings of the fused ring may be 2; (46)L 2 Among them, the heteroatom in each 5- to 10-membered heteroarylene group is N, and the number of heteroatoms can independently be 1, 2, or 3; (47)L 4 Among them, each 5- to 10-membered arylene group is a phenylene group or a naphthylene group, such as a phenylene group; (48)L 4 wherein each of said 5- to 10-membered heteroarylene groups is independently a 5- or 6-membered heteroarylene group or an 8- to 10-membered heteroarylene group; (49)L 4 In which, each of the 5- to 10-membered heteroarylene groups is independently a monocyclic or fused ring, and the number of rings of the fused ring can be 2; (50)L 4 Among them, the heteroatom in each 5- to 10-membered heteroarylene is N, and the number of heteroatoms can be 1, 2, or 3; (51)L 4 Among them, each C 3-10 Subcycloalkyl is independently C 3-6 Subcycloalkyl, such as cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene or bicyclo[1.1.1]pentylidene, for example bicyclo[1.1.1]pentylidene, and for another example (52) In ring H, the 5- to 10-membered heteroarylene group is a 5- to 6-membered heteroaromatic ring, the heteroatoms in the 5- to 6-membered heteroaromatic ring are selected from N, and the number of heteroatoms is 1, 2, or 3, such as a pyridine ring; (53)L 5 In which, each of the 3- to 12-membered heteroalkyl rings is independently a monocyclic, bridged, spiro or fused ring; the number of rings in the bridged, spiro or fused ring can be 2, preferably a monocyclic ring; (54)L 5 In which, each of said 3-12 membered heteroalkylidene groups is independently a 3-8 membered heteroalkylidene group, such as a 3-6 membered heteroalkylidene group; (55)L 5 Among them, the heteroatoms of each 3- to 12-membered heteroalkyl group are independently selected from one or two of N and O, and the number of heteroatoms can independently be 1 or 2; (56)L 5 Wherein each of said 5- to 10-membered heteroarylene groups is independently a 5- or 6-membered heteroarylene group or an 8- to 10-membered heteroarylene group; (57)L 5 In which, each of the 5- to 10-membered heteroarylene groups is independently a monocyclic or fused ring, and the number of rings of the fused ring can be 2; (58)L 5 Among them, the heteroatom in each 5- to 10-membered heteroarylene is N, and the number of heteroatoms can be 1, 2, or 3; (59)L 5 wherein each of the 4- to 12-membered heteroalkenyl groups is independently a 5- to 6-membered heteroalkenyl group, the heteroatom of the 5- to 6-membered heteroalkenyl group may be N, the number of heteroatoms may be 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl group may be 1 or 2. For example Another example is (60)L 6 Among them, each C 1-14 alkylene group is independently a C 1-8 alkylene group, and the C 1-8 alkylene group may be a straight-chain alkylene group, such as For another example Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1)R 2 in which the C 2-1 alkyl substituted by one or more R 1-6 is (2)R 3 Among them, each 3- to 12-membered heterocycloalkyl is a 3- to 9-membered heterocycloalkyl, the heteroatom of the 3- to 9-membered heterocycloalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the 3- to 9-membered heterocycloalkyl is a monocyclic or fused ring, and the number of rings in the fused ring is 2; for example, morpholinyl, piperazinyl or For another example (3)R 3 Among them, each 4- to 12-membered heteroalkenyl is independently a 5- to 6-membered heteroalkenyl. The heteroatom of the 5- to 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl is 1 or 2. For example For another example (4)R 3 wherein each of said 5- to 12-membered heteroaryl groups is independently a 5- to 6-membered monocyclic heteroaryl group, and the heteroatoms of said 5- to 6-membered monocyclic heteroaryl group are selected from one or two of N and O, and the number of heteroatoms is 1, 2 or 3; for example, Scheme 1 or Scheme 2: Scheme 1: is For another example Scheme 2: is For example (5) The R 3-3 Among them, each of the 3- to 12-membered heterocycloalkyl groups is independently a 3- to 6-membered monocyclic heterocycloalkyl group. The heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl group are selected from one or two of N and O, and the number of heteroatoms is 1 or 2. For example, oxetanyl, and for another example In ring A, the 5-12 membered heteroaryl ring is independently a 5-10 membered heteroaryl ring; the 5-10 membered heteroaryl ring is a monocyclic or fused ring, and the number of rings in the fused ring is 2; the heteroatoms in the 5-10 membered heteroaryl ring are selected from one or two of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; for example (7) In ring E, the benzene ring substituted by one or more Rs e-1 is In the ring F, each 4-12 membered heteroalkene ring is a 5-6 membered heteroalkene ring. The heteroatom of the 5-6 membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of olefinic bonds is 1 or 2. For example (9) In rings E and P, the 5- to 12-membered heteroaromatic ring is independently a 5- to 6-membered monocyclic heteroaromatic ring, the heteroatoms in the 5- to 6-membered monocyclic heteroaromatic ring are N, and the number of heteroatoms is 1 or 2; such as a pyridine ring; In ring Q, the 3- to 12-membered alicyclic heterocycle is a 3- to 6-membered monocyclic alicyclic heterocycle. The heteroatom of the 3- to 6-membered monocyclic alicyclic heterocycle is N, and the number of heteroatoms is 1 or 2. For example, a piperazine ring, and for another example is (11) substituted by one or more R P2 substituted C 1-14 The alkylene group is (12)L 2 and R P3 in which each C 3-10 subcycloalkylidene is independently a subcyclopropylidene, subcyclobutylidene, subcyclohexylidene, 5-membered fused 5-membered subcycloalkylidene, 4-membered bridged 6-membered subcycloalkylidene or 4-membered spiro 4-membered subcycloalkylidene, for example (13)L 2 and R P3 wherein each of said 3- to 12-membered heteroalkyl groups is independently a 3- to 6-membered monocyclic heteroalkyl group, the heteroatoms of said 3- to 6-membered monocyclic heteroalkyl group are independently selected from one or two of N and O, the number of heteroatoms is independently 1 or 2, such as azetidinyl or piperidinyl, and further such as (14)L 2 Among them, each 5- to 10-membered heteroarylene is independently a 5- to 6-membered monocyclic heteroarylene, the heteroatom of the 5- to 6-membered monocyclic heteroarylene is N, and the number of heteroatoms is independently 1, 2, or 3, such as imidazolylene or pyrazolylene, and for another example (15)L 4 Among them, each 5- to 10-membered heteroarylene is independently a 5- to 6-membered monocyclic heteroarylene, the heteroatom of the 5- to 6-membered monocyclic heteroarylene is N, and the number of heteroatoms is independently 1, 2 or 3. For example, pyridinylene, and for another example For another example (16)L 5 wherein each of the 3- to 12-membered heteroalkyl groups is independently a 3- to 6-membered monocyclic heteroalkyl group, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group are independently selected from one or two of N and O, and the number of heteroatoms is independently 1 or 2, such as piperazinyl, and for another example (17)L 5 wherein each 5- to 10-membered heteroarylene is independently monocyclic or polycyclic, the number of rings of the polycyclic ring is 2, the heteroatom of each 5- to 10-membered heteroarylene is N, and the number of heteroatoms is independently 1, 2, or 3, such as pyridinylene or For another example Preferably, the compound of formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) The R 3-3 In, the 3- to 12-membered heterocycloalkyl group substituted by one or more R 3-1-1 is (2) In ring F, the 4- to 12-membered heteroalkene ring substituted by one or more R e-2 is (3)L 4 wherein the 5- to 10-membered heteroarylene group substituted by one or more R P2 is (4)L 4 wherein the 5- to 10-membered arylene group substituted by one or more Rs P2 is 3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1)X 1 is N; (2)X 2 is N; (3) m is 1, 2, 3 or 4, such as 2 or 3; (4) n is 1, 2 or 3; such as 1; (5) Each R 2 is independently deuterium, a halogen, an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl or an unsubstituted or one or more R 2-2 substituted C 1-6 alkoxy; preferably, each R 2 is independently deuterium, an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl or an unsubstituted or one or more R 2-2 substituted C 1-6 alkoxy; (6) Each R 2-1 and R 2-2 is independently a halogen; (7) Each R 3 is independently -C(O)N(R 2-9 )2, unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-3 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 3-5 substituted 3- to 12-membered heterocycloalkyl, unsubstituted or substituted by one or more R 3-9 substituted 4- to 12-membered heterocycloalkenyl or unsubstituted or substituted by one or more R 3-6 substituted 5- to 12-membered heteroaryl; preferably, each R 3 is independently -C(O)N(R 2-9 )2, unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-3 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 3-5 substituted 3- to 9-membered heterocycloalkyl, unsubstituted or substituted by one or more R 3-9 substituted 5- to 6-membered heterocycloalkenyl or unsubstituted or substituted by one or more R 3-6 substituted 5- to 6-membered monocyclic heteroaryl; the heteroatoms of the 3- to 9-membered heterocycloalkyl are selected from one or both of N and O, the number of heteroatoms is 1 or 2, the 3- to 9-membered heterocycloalkyl is monocyclic or fused-ring, and the number of rings in the fused-ring is 2; the heteroatom of the 5- to 6-membered heterocycloalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heterocycloalkenyl is 1 or 2; the heteroatoms of the 5- to 6-membered monocyclic heteroaryl are selected from one or both of N and O, and the number of heteroatoms is 1, 2, or 3; more preferably, each R 3 is independently unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- to 6-membered heterocycloalkenyl, the heteroatom of the 5- to 6-membered heterocycloalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heterocycloalkenyl is 1 or 2; most preferably, each R 3 is independently unsubstituted or substituted by one or more R 3-9 substituted 5- to 6-membered heterocycloalkenyl; the heteroatom of the 5- to 6-membered heterocycloalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heterocycloalkenyl is 1 or 2; (8) Each R 2-9 is independently hydrogen or C 1-6 alkyl; (9) Each R 3-1 and R 3-3 is independently an unsubstituted or one or more R 3-1-1 substituted 3- to 12-membered heterocycloalkyl; preferably, each R 3-1 and R 3-3 is independently an unsubstituted or one or more R 3-1-1 substituted 3- to 6-membered monocyclic heterocycloalkyl, the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl being selected from one or both of N and O, and the number of heteroatoms being 1 or 2; (10) Each R 3-1-1 is a hydroxyl group; (11) Each R 3-5 is independently an oxo group, a halogen, or an unsubstituted or R-substituted C 3-5-1 alkyl; preferably, each R 1-6 is independently an oxo group, a halogen, or a C 3-9 alkyl; more preferably, each R 1-6 is independently an oxo group or a C 3-5 alkyl; 1-6 ​ (12) Each R 3-5-1 independently is deuterium or a halogen; (13) Each R 3-9 is independently an oxo group, a halogen, or an unsubstituted or one or more R 3-5-1 substituted C 1-6 alkyl; preferably, each R 3-9 is independently an oxo group, a halogen, or C 1-6 alkyl; more preferably, each R 3-9 is independently an oxo group or a halogen; (14) Each R 3-6 is independently unsubstituted or substituted by one or more R 3-6-1 alkyl; preferably, each R 1-6 is independently unsubstituted C 3-6 alkyl; 1-6 ​ (15) Each R 3-6-1 independently is a halogen; (16) Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; (17)R 1 for hydrogen, deuterium, cyano, halogen, -NH2, -SF5, unsubstituted or replaced by one or more R 1-3 Substituted C 1-6 Alkyl, unsubstituted or substituted with one or more R 1-4 Substituted C 1-6 Alkoxy is unsubstituted or substituted with one or more R 1-5 Substituted C 3-10 Cycloalkyl, preferably, the C 3-10 Cycloalkyl is C 3-6 Cycloalkyl; more preferably, R 1 is hydrogen, deuterium or halogen, preferably, R 1 is hydrogen or deuterium; (18) Each R 1-3 , R 1-4 and R 1-5 is independently halogen or C 1-6 alkyl; (19) Each R 2-11 is independently C 1-6 alkyl; or two Rs 2-11 together with the P atom to which they are attached form a 5- to 10-membered alkanheterocycle, the heteroatom in the 5- to 10-membered alkanheterocycle being P and the number of heteroatoms being 1; preferably, the 5- to 10-membered alkanheterocycle is a 5- to 6-membered alkanheterocycle; (20) Ring E is independently unsubstituted or substituted by one or more Rs e-1 substituted benzene ring or unsubstituted or substituted by one or more Rs e-1 substituted 5- or 6-membered monocyclic heteroaromatic ring, the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring being N and the number of heteroatoms being 1 or 2; preferably, Ring E is independently an unsubstituted 5- or 6-membered monocyclic heteroaromatic ring; (21) Each R e-1 is independently a halogen or a C 1-6 alkyl group; (22) Ring F is independently a 4- to 12-membered heteroalkene ring substituted by one or more Rs e-2 Preferably, the 4- to 12-membered heteroalkene ring is a 5- to 6-membered heteroalkene ring, the heteroatoms of the 5- to 6-membered heteroalkene ring are N, the number of heteroatoms is one or two, and the number of double bonds is one or two; (23) Each R e-2 is independently an oxo group or an unsubstituted or R-substituted C 2-1 alkyl group; preferably, each R 1-6 is independently an oxo group or an unsubstituted C e-2 alkyl group; 1-6 ​ (24) L is selected from any of the following options: Solution 1: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L 6 -、-L 5 -L 6 -、-L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; Solution 2: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 -,-L 5 -L 6 -,-L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; Solution 3: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 -; Solution 4: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -; Solution 5: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 -; Solution 6: L is -L 5 -L 6 -; Solution 7: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -; Scheme 8: L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 -, -L 2 -L 4 -L 5 -L 6 - or -L 5 -L 6 -; (25) Each -L 1 - independently is Each R P1 independently is deuterium, a halogen or C 1-6 alkyl, or two Rs P1 together with the carbon atom to which they are attached form C 3-6 monocyclic cycloalkyl or 3- to 6-membered monocyclic heterocycloalkyl; the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; ring G is independently 3- to 6-membered monocyclic heterocycloalkane, the heteroatom of the 3- to 6-membered monocyclic heterocycloalkane is N, and the number of heteroatoms is 1; preferably, each -L 1 - independently is More preferably, is (26) Each -L 2 - Independently unsubstituted or substituted with one or more R P2 Substituted C 1-8 Alkylene, unsubstituted or substituted with one or more R P2 Substituted C 2-6 Alkyne, unsubstituted or substituted with one or more R P2 Substituted C 3-10 Cycloalkylene, unsubstituted or substituted with one or more R P2 Substituted 3-6 membered monocyclic heterocycloalkylene or unsubstituted or replaced by one or more R P2 substituted 5-6 membered monocyclic heteroarylene group; the heteroatom of the 3-6 membered monocyclic heterocycloalkylene group is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered monocyclic heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; each C 1-8 Alkylene and C 2-6 One or more methylene units in the alkynylene group are optionally replaced by R P3 Replace, each R P3 Independently C 3-10 Cycloalkylene or 3-6 membered monocyclic heterocycloalkylene; Preferably, each -L 2 - is unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene, unsubstituted or substituted by one or more R P2 substituted C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 substituted C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3- to 6-membered monocyclic heteroalkyl, unsubstituted or substituted by one or more R P2 substituted 5- to 6-membered monocyclic heteroaryl or wherein, Z 1 is independently a single bond or O, Z 2 is independently a single bond, O, C 3-10 cycloalkylene or 3- to 6-membered monocyclic heteroalkyl (Z 1 and Z 2 are not simultaneously a single bond); m1 is independently 0, 1 or 2; m2 is independently 0, 1 or 2; m3 is independently 0, 1 or 2; the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2 (m1, m2 and m3 are not simultaneously 0); the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; Preferably, each -L 2 - is independently unsubstituted or substituted by one or more R P2 -substituted C 1-8 -alkylene, unsubstituted or substituted by one or more R P2 -substituted C 2-6 -alkynylene, unsubstituted or substituted by one or more R P2 -substituted C 3-10 -cycloalkylene, unsubstituted or substituted by one or more R P2 -substituted 3- to 6-membered monocyclic heterocycloalkylene or unsubstituted, substituted by one or more R P2 -substituted 5- to 6-membered heteroaryl or wherein, Z 1 is independently O, Z 2 is independently a single bond or O, and Z 1 and Z 2 are not simultaneously a single bond; m1 is independently 0, 1 or 2; m2 is independently 0, 1 or 2; m3 is independently 0, 1 or 2; m1, m2 and m3 are not simultaneously 0; the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5- to 6-membered heteroaryl are N, and the number of heteroatoms is 1, 2 or 3; More preferably, each -L 2 - is independently unsubstituted or substituted by one or more R P2 -substituted C 1-8 -alkylidene, unsubstituted or substituted by one or more R P2 -substituted C 3-10 -cycloalkylidene, unsubstituted or substituted by one or more R P2 -substituted 3- to 6-membered monocyclic heteroalkylidene or unsubstituted or substituted by one or more R P2 -substituted 5- to 6-membered monocyclic heteroaryl, wherein the heteroatom of the 3- to 6-membered monocyclic heteroalkylidene is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; Optimally, each -L 2 - is independently unsubstituted or substituted with one or more R P2 Substituted C 1-8 Alkylene, unsubstituted or substituted with one or more R P2 Substituted 3-6 membered monocyclic heterocycloalkylene or unsubstituted or replaced by one or more R P2 A substituted 5-6 membered monocyclic heteroarylene group; the heteroatom of the 3-6 membered monocyclic heterocycloalkylene group is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered monocyclic heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; Even more preferably, each -L 2 - is independently an unsubstituted C 1-8 alkylene or an unsubstituted or one or more R P2 substituted 3- to 6-membered monocyclic heterocycloalkyl; the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2; (27) Each - L 3 - independently is (28) Each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene, unsubstituted or substituted by one or more R P2 substituted 5-6 membered monocyclic heteroaryl or unsubstituted or substituted by one or more R P2 substituted C 3-10 subcycloalkyl; the heteroatom of the 5-6 membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; ring H is a 5-6 membered heteroaromatic ring, and the heteroatoms in the 5-6 membered heteroaromatic ring are selected from N, and the number of heteroatoms is 1, 2 or 3, t1 is 0, 1, 2, 3 or 4; preferably, each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene or unsubstituted or substituted by one or more R P2 substituted 5-6 membered heteroaryl, the heteroatom of the 5-6 membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; preferably, each -L 4 - independently is Scheme 1 or Scheme 2. Scheme 1: Each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted 5-6 membered monocyclic heteroaryl, the heteroatom of the 5-6 membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; more preferably, it is an unsubstituted 5-6 membered monocyclic heteroaryl; Scheme 2: Each -L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene or unsubstituted 5-6 membered heteroaryl; (29) Each -L 5 - independently is unsubstituted or substituted by one or more R P2 substituted 3-6 membered monocyclic heteroalkyl, unsubstituted or substituted by one or more R P2 substituted 5-10 membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted 5-6 membered heteroalkenyl; each of the 5-10 membered heteroaryl is monocyclic or fused ring, the number of fused rings is 2, the heteroatoms of each of the 5-10 membered heteroaryl are N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5-6 membered heteroalkenyl are N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-6 membered heteroalkenyl is 1 or 2; ring P is independently a 5-6 membered monocyclic heteroaromatic ring, the heteroatoms in the 5-6 membered monocyclic heteroaromatic ring are N, and the number of heteroatoms is 1 or 2; ring Q is independently a 3-6 membered monocyclic heterocycloalkane, the heteroatoms of the 3-6 membered monocyclic heterocycloalkane are N, and the number of heteroatoms is 1 or 2; preferably, each -L 5 - independently is unsubstituted 3-6 membered monocyclic heteroalkyl or unsubstituted 5-6 membered heteroalkenyl, the heteroatoms of the 3-6 membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5-6 membered heteroalkenyl are N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-6 membered heteroalkenyl is 1 or 2; preferably, each -L 5 - independently is unsubstituted 3-6 membered monocyclic heteroalkyl, the heteroatoms of the 3-6 membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; preferably, the heteroatoms of the 3-6 membered monocyclic heteroalkyl are N, and the number of heteroatoms is 1 or 2; (30) each - L 6 - independently unsubstituted or substituted by one or more R P2 alkylene, preferably unsubstituted C 1-8 alkylene; 1-8 alkylene; (31) Each R P2 is independently a halogen; (32) n1 and n2 are independently 0, 1 or 2; (33) The compound represented by formula I is not any of the following compounds: Preferably, the compound represented by formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) Ring A is a single ring, and L is -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -; (2) Ring A is a fused ring, and L is -L 5 -L 6 -; (3) Each -L 1 - independently is Preferably, it is a single bond, where the 1-position is connected to ring A or ring C, and the 2-position is connected to L 2 connected; more preferably, it is where the 1-position is connected to ring A or ring C, and the 2-position is connected to L 2 connected; most preferably, it is where the 1-position is connected to ring A or ring C, and the 2-position is connected to L 2 connected; (4) Each -L 2 - Independently is Option 1 or Option 2, Option 1: Each -L 2 - Independently is Preferably, each -L 2 - is independently wherein bit 1 is connected to L 1 and bit 2 is connected to L 3 connected; More preferably, it is wherein the 1-bit is connected to L 1 and the 2-bit is connected to L 3 connected; More preferably, each -L 2 - is independently One of them is connected to L 1 and the other is connected to L 3 ; Optimally, each -L 2 - independently for where bit 1 is connected to L 1 and bit 2 is connected to L 3 connected; Solution 2: Each -L 2 - independently for Preferably, it is where the 1-bit is connected to L 1 and the 2-bit is connected to L 3 ; More preferably, it is where the 1-bit is connected to L 1 and the 2-bit is connected to L 3 ; Most preferably, it is where the 1-bit is connected to L 1 and the 2-bit is connected to L 3 ; (5) Each - L 3 - Independently is Preferably, is Wherein bit 1 is connected to L 2 And bit 2 is connected to L 4 Connected; more preferably, is Wherein bit 1 is connected to L 2 And bit 2 is connected to L 4 Connected; (6) Each -L 4 - Independently being Option 1 or Option 2: Solution 1: Each -L 4 - independently for Preferably, it is where bit 1 is connected to L 3 and bit 2 is connected to L 5 ; More preferably, it is where bit 1 is connected to L 3 and bit 2 is connected to L 5 ; Most preferably, it is where bit 1 is connected to L 3 and bit 2 is connected to L 5 ; Solution 2: Each -L 4 - independently for Preferably, each -L 4 - is independently One of them is connected to L 3 and the other is connected to L 5 ; More preferably, each -L 4 - is independently selected from Option A or Option B: Solution A: Each -L 4 - independently for where one bit is connected to L 3 and the second bit is connected to L 5 connected; Solution B: Each -L 4 - independently for where one bit is connected to L 3 and the second bit is connected to L 5 connected; (7) Each -L 5 - Independently is Option 1 or Option 2. Option 1: Each -L 5 - Independently is Preferably, it is where the 1-bit is connected to L 4 and the 2-bit is connected to L 6 connected; More preferably, it is where the 1-bit is connected to L 4 and the 2-bit is connected to L 6 connected; Option 2: Each -L 5 - Independently is Preferably, it is where the 1-bit is connected to L 4 and the 2-bit is connected to L 6 connected; More preferably, it is where the 1-bit is connected to L 4 and the 2-bit is connected to L 6 connected; (8) Each -L 6 - is (9) Ring A is Preferably, ring A is Preferably, ring A is More preferably, it is (10)R 1 is hydrogen, fluorine, methyl, methoxy, cyano, amino, -SF5, cyclopropyl, Preferably, R 1 is hydrogen; (11) Each R 2 is independently Cl or F; preferably, is (12) Each R 3 is independently methyl, Preferably, Each R 3 is independently methyl, such as methyl or for another example (13) For (14) For (15) Among them, is Preferably, More preferably, it is Preferably, the compound represented by formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) L is Option 1 or Option 2, Solution 1: L is Among them, the 1-position is connected to ring A, and the 2-position is connected to ring E; Preferably, it is wherein the 1-position is connected to ring A, and the 2-position is connected to ring E; More preferably, selected from Option 1 or Option 2, Solution 1: L is wherein the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; Solution 2: Option 2: L is Among them, the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; preferably, it is Among them, the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; more preferably, it is selected from Scheme 1 or Scheme 2. Scheme 1: Among them, the 1-position is connected to ring A or ring C, and the 2-position is connected to ring E; Scheme 2: (2) For Preferably, for wherein the 1-position is connected to NH and the 2-position is connected to L; preferably, for wherein the 1-position is connected to NH and the 2-position is connected to L; More preferably, For Scheme 1 or Scheme 2. Scheme 1: is wherein the 1-position is connected to NH and the 2-position is connected to L. Preferably, is wherein the 1-position is connected to NH and the 2-position is connected to L; Scheme 2: is wherein the 1-position is connected to NH and the 2-position is connected to L; Preferably, in the compound of formula I or a pharmaceutically acceptable salt thereof, is wherein the 1-position is connected to NH and the 2-position is connected to L; more preferably, it is wherein the 1-position is connected to NH and the 2-position is connected to L, and most preferably, it is wherein the 1-position is connected to NH and the 2-position is connected to L.

4. The compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein m is 1, 2, 3 or 4; n is 1, 2 or 3; X 1 and X 2 is independently N; Each R 2 is independently deuterium, a halogen, an unsubstituted or one or more R 2-1 substituted C 1-6 alkyl or an unsubstituted or one or more R 2-2 substituted C 1-6 alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 is independently -C(O)N(R 2-9 )2, unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 3-3 substituted C 2-6 alkynyl, unsubstituted or substituted by one or more R 3-5 substituted 3-9 membered heterocycloalkyl, unsubstituted or substituted by one or more R 3-9 substituted 5-6 membered heterocycloalkenyl or unsubstituted or substituted by one or more R 3-6 substituted 5-6 membered monocyclic heteroaryl; the heteroatoms of the 3-9 membered heterocycloalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered heterocycloalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5-6 membered heterocycloalkenyl is 1 or 2; the heteroatoms of the 5-6 membered monocyclic heteroaryl are selected from one or two of N and O, and the number of heteroatoms is 1, 2 or 3; Each R 2-9 is independently hydrogen or C 1-6 alkyl; Each R 3-1 and R 3-3 are independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 6-membered monocyclic heterocycloalkyl groups, the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl groups being selected from one or both of N and O, and the number of heteroatoms being 1 or 2; Each R 3-1-1 is a hydroxyl group; Each R 3-5 is independently an oxo group, a halogen, or an unsubstituted or R 3-5-1 -substituted C 1-6 alkyl; Each R 3-5-1 is independently deuterium or a halogen; Each R 3-9 is independently an oxo group, a halogen, or an unsubstituted or R 3-5-1 -substituted C 1-6 alkyl; Each R 3-6 is independently unsubstituted or substituted by one or more R 3-6-1 substituted C 1-6 alkyl; Each R 3-6-1 is independently a halogen; Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; R 1 is hydrogen, deuterium, cyano, halogen, -NH2, -SF5, unsubstituted or substituted by one or more R 1-3 substituted C 1-6 alkyl, unsubstituted or substituted by one or more R 1-4 substituted C 1-6 alkoxy or unsubstituted or substituted by one or more R 1-5 substituted C 3-6 cycloalkyl; Each R 1-3 、R 1-4 and R 1-5 is independently a halogen or a C 1-6 alkyl group; Each R 2-11 is independently C 1-6 alkyl; or two Rs 2-11 together with the P atom to which they are attached form a 5- or 6-membered alkanheterocycle, the heteroatom in the 5- or 6-membered alkanheterocycle being P and the number of heteroatoms being 1; Each ring E is independently an unsubstituted or one or more R e-1 substituted benzene ring or an unsubstituted or one or more R e-1 substituted 5- or 6-membered monocyclic heteroaromatic ring, wherein the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; Each R e-1 is independently a halogen or a C 1-6 alkyl group; Each ring F is independently a 5- or 6-membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom of the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of olefinic bonds is 1 or 2; Each R e-2 is independently an oxo group or an unsubstituted or R-substituted 2-1 C 1-6 alkyl; L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 -,-L 5 -L 6 -,-L 2 -L 4 -L 5 -L 6 -,-L 1 -L 2 -L 3 -L 5 -L 6 - or -L 2 -L 3 -L 5 -L 6 -;(in each L, L 6 is connected to ring E, and the other end of L is connected to ring A); Each - L 1 - independently is Each R P1 independently is deuterium, a halogen or C 1-6 alkyl, or two Rs P1 together with the carbon atom to which it is attached form C 3-6 monocyclic subcycloalkyl or 3 - 6 - membered monocyclic subheterocycloalkyl, the heteroatoms of the 3 - 6 - membered monocyclic subheterocycloalkyl being selected from one or two of N and O, the number of heteroatoms being 1 or 2; ring G is independently a 3 - 6 - membered monocyclic alkheterocycle, the heteroatom of the 3 - 6 - membered monocyclic alkheterocycle being N, the number of heteroatoms being 1; each - L 2 - independently is unsubstituted or substituted by one or more R P2 C 1-8 alkylene, unsubstituted or substituted by one or more R P2 C 2-6 alkynylene, unsubstituted or substituted by one or more R P2 C 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heterocycloalkylene or unsubstituted or substituted by one or more R P2 substituted 5 - 6 - membered monocyclic heteroaryl; the heteroatoms of the 3 - 6 - membered monocyclic heterocycloalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5 - 6 - membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; each C 1-8 alkylene and C 2-6 one or more methylene units in alkynylene are optionally replaced by R P3 each R P3 independently is C 3-10 cycloalkylene or 3 - 6 - membered monocyclic heterocycloalkylene; Each - L 3 - independently is Each - L 4 - independently is unsubstituted or substituted by one or more R P2 substituted phenylene, unsubstituted or substituted by one or more R P2 substituted 5-6 membered monocyclic heteroaryl or unsubstituted or substituted by one or more R P2 substituted C 3-10 subcycloalkyl; the heteroatom of the 5-6 membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; ring H is a 5-6 membered heteroaromatic ring, the 5-6 membered heteroaromatic ring, the heteroatoms in the 5-6 membered heteroaromatic ring are selected from N, and the number of heteroatoms is 1, 2 or 3, t1 is 0, 1, 2, 3 or 4; Each -L 5 - independently is unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heteroalkyl, unsubstituted or substituted by one or more R P2 substituted 5 - 10 - membered heteroaryl or unsubstituted or substituted by one or more R P2 substituted 5 - 6 - membered heteroalkenyl; each of the 5 - 10 - membered heteroaryl is monocyclic or fused - ring, the number of rings of the fused - ring is 2, the heteroatom of each of the 5 - 10 - membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; the heteroatom of the 5 - 6 - membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5 - 6 - membered heteroalkenyl is 1 or 2; ring P is independently a 5 - 6 - membered monocyclic heteroaromatic ring, the heteroatom in the 5 - 6 - membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; ring Q is independently a 3 - 6 - membered monocyclic alkanheterocyclic ring, the heteroatom of the 3 - 6 - membered monocyclic alkanheterocyclic ring is N, and the number of heteroatoms is 1 or 2; n1 and n2 are independently 0, 1 or 2; each - L 6 - independently unsubstituted or substituted by one or more R P2 -substituted C 1-8 -alkylene; Each R P2 is independently a halogen; Preferably, in the compound represented by formula I or a pharmaceutically acceptable salt thereof, m is 1, 2, 3 or 4; n is 1; X 1 and X 2 are each independently N; Each R 2 is independently deuterium, unsubstituted or substituted by one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 2-2 substituted C 1-6 alkoxy; Each R 2-1 and R 2-2 is independently a halogen; Each R 3 is independently unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2; Each R 3-1 is independently unsubstituted or substituted by one or more R 3-1-1 substituted 3- to 6-membered monocyclic heterocycloalkyl, wherein the heteroatom of the 3- to 6-membered monocyclic heterocycloalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; Each R 3-1-1 is a hydroxyl group; Each R 3-9 is independently an oxo group, a halogen, or an unsubstituted or R 3-5-1 -substituted C 1-6 alkyl; Each R 3-5-1 is independently deuterium or a halogen; Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; R 1 is hydrogen, deuterium or a halogen; Each ring E is independently an unsubstituted or substituted benzene ring by one or more R e-1 or an unsubstituted or substituted 5- or 6-membered monocyclic heteroaromatic ring by one or more R e-1 wherein the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N and the number of heteroatoms is 1 or 2; Each R e-1 is independently a halogen or a C 1-6 alkyl group; Each ring F is independently a 5-6 membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom of the 5-6 membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of olefinic bonds is 1 or 2; Each R e-2 is independently an oxo group or an unsubstituted or R-substituted C 2-1 alkyl group; 1-6 ​ L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 - or -L 2 -L 3 -L 4 -L 5 -L 6 - or -L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 - or -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; (in each L, L is connected to ring E, and the other end of L is connected to ring A); 6 ​ Each - L 1 - independently is Each -L 2 - is independently unsubstituted or substituted with one or more R P2 Substituted C 1-8 Alkylene, unsubstituted or substituted with one or more R P2 Substituted C 3-10 Cycloalkylene, unsubstituted or substituted with one or more R P2 Substituted 3-6 membered monocyclic heterocycloalkylene or unsubstituted or replaced by one or more R P2 A substituted 5-6 membered monocyclic heteroarylene group; the heteroatom of the 3-6 membered monocyclic heterocycloalkylene group is selected from one or both of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5-6 membered monocyclic heteroarylene group is N, and the number of heteroatoms is 1, 2 or 3; Each - L 3 - independently is Each -L 4 - independently unsubstituted or substituted by one or more R P2 - substituted 5- or 6-membered monocyclic heteroaryl; the heteroatom of the 5- or 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; Each - L 5 - independently is a 3- to 6-membered monocyclic heteroalkyl, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; each - L 6 - independently unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene; Each R P2 is independently a halogen.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein The compound represented by formula I is the following Option 1, Option 2, Option 3 or Option 4: Option 1: For m is 1, 2, 3 or 4; X 1 and X 2 are each independently N; Each R 2 is independently deuterium, unsubstituted or substituted by one or more R 2-1 alkyl or unsubstituted or substituted by one or more R 1-6 alkoxy; 2-2 substituted C 1-6 alkyl; Each R 2-1 and R 2-2 are independently halogen; R 3 independently unsubstituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2; Each R 3-9 is independently an oxo group or a halogen; Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2 or 3; R 1 is hydrogen or deuterium; Each ring E is independently an unsubstituted 5- to 6-membered monocyclic heteroaromatic ring, and the heteroatom in the 5- to 6-membered monocyclic heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; Each ring F is independently a 5- or 6-membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom of the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2; Each R e-2 is independently an oxo group or an unsubstituted C 1-6 alkyl group; L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 - or -L 2 -L 3 -L 4 -L 5 -L 6 - or -L 3 -L 4 -L 5 -L 6 - or -L 4 -L 5 -L 6 -; (in each L, L 6 is connected to ring E, and the other end of L is connected to ring A); Each - L 1 - independently is Each - L 2 - Independently unsubstituted C 1-8 alkylene or unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heterocycloalkyl; the heteroatoms of the 3 - 6 - membered monocyclic heterocycloalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; Each - L 3 - independently is Each -L 4 - independently is an unsubstituted 5- or 6-membered monocyclic heteroaryl group; the heteroatom of the 5- or 6-membered monocyclic heteroaryl group is N, and the number of heteroatoms is 1, 2, or 3; Each -L 5 - independently is a substituted 3- to 6-membered monocyclic heteroalkyl, wherein the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; Each - L 6 - independently unsubstituted C 1-8 alkylene; Each R P2 is independently a halogen; Option 2: m is 1, 2, 3 or 4; n is 1; X 1 and X 2 are each independently N; Each R 2 is independently deuterium, unsubstituted or substituted with one or more R 2-1 substituted C 1-6 alkyl or unsubstituted or substituted with one or more R 2-2 substituted C 1-6 alkoxy; Each R 2-1 and R 2-2 are independently halogen; Each R 3 is independently an unsubstituted or one or more R 3-9 -substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2; Each R 3-9 is independently an oxo group or a halogen; Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; R 1 is hydrogen, deuterium or a halogen; Each ring E is independently an unsubstituted or substituted benzene ring by one or more R e-1 or an unsubstituted or substituted 5- or 6-membered monocyclic heteroaromatic ring by one or more R e-1 wherein the heteroatom in the 5- or 6-membered monocyclic heteroaromatic ring is N and the number of heteroatoms is 1 or 2; Each R e-1 is independently halogen or C 1-6 alkyl; Each ring F is independently a 5- or 6-membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom of the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is one or two, and the number of olefinic bonds is one or two; Each R e-2 is independently an oxo group or an unsubstituted or R-substituted C 2-1 alkyl group; 1-6 ​ L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -,-L 2 -L 3 -L 4 -L 5 -L 6 -,-L 4 -L 5 -L 6 -,-L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -;(in each L, L 6 is connected to ring E, and the other end of L is connected to ring A); Each - L 1 - independently is Each - L 2 - independently unsubstituted or substituted by one or more R P2 - alkylene, unsubstituted or substituted by one or more R 1-8 - 3- to 6-membered monocyclic heterocycloalkyl, unsubstituted or substituted by one or more R P2 - or 5- to 6-membered monocyclic heteroaryl, unsubstituted or substituted by one or more R P2 ; the heteroatoms of the 3- to 6-membered monocyclic heterocycloalkyl are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; Each - L 3 - independently is Each -L 4 - independently unsubstituted or substituted by one or more R P2 - substituted 5- or 6-membered monocyclic heteroaryl; the heteroatom of the 5- or 6-membered monocyclic heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; Each -L 5 - independently is a 3- to 6-membered monocyclic heteroalkyl group, the heteroatoms of the 3- to 6-membered monocyclic heteroalkyl group are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; each - L 6 - independently unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene; Each R P2 is independently a halogen; And ring A and L satisfy the following situation (1) or situation (2) Case (1): Ring A is a single ring, and L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 2 -L 3 -L 4 -L 5 -L 6 -, -L 4 -L 5 -L 6 - or -L 2 -L 4 -L 5 -L 6 -; Case (2): Ring A is a fused ring and L is -L 5 -L 6 -; Option 3: The compound represented by formula I is the compound represented by formula I-1, Option 4: m is 1, 2, 3 or 4; n is 1; X 1 and X 2 are each independently N; Each R 2 is independently deuterium, unsubstituted or substituted by one or more R 2-1 alkyl or unsubstituted or substituted by one or more R 1-6 alkoxy; 2-2 substituted C 1-6 alkoxy; Each R 2-1 and R 2-2 is independently a halogen; R 3 is unsubstituted or substituted by one or more R 3-1 substituted C 1-6 alkyl or unsubstituted or substituted by one or more R 3-9 substituted 5- or 6-membered heteroalkenyl; the heteroatom of the 5- or 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- or 6-membered heteroalkenyl is 1 or 2; Each R 3-1 is independently an unsubstituted or one or more R 3-1-1 -substituted 3- to 6-membered monocyclic heterocycloalkyl group, the heteroatom of the 3- to 6-membered monocyclic heterocycloalkyl group being selected from one or both of N and O, and the number of heteroatoms being 1 or 2; Each R 3-1-1 is a hydroxyl group; Each R 3-9 is independently an oxo group, a halogen, or an unsubstituted or R 3-5-1 -substituted C 1-6 alkyl; Each R 3-5-1 is independently deuterium or a halogen; Ring A is a 5- to 10-membered heteroaromatic ring, the 5- to 10-membered heteroaromatic ring being a monocyclic or fused ring, and the heteroatoms in the 5- to 10-membered heteroaromatic ring are selected from one or more of N and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; R 1 is hydrogen, deuterium or a halogen; Each ring E is independently an unsubstituted or one or more R e-1 substituted benzene ring or an unsubstituted or one or more R e-1 substituted 5- or 6-membered heteroaromatic ring, wherein the heteroatom in the 5- or 6-membered heteroaromatic ring is N, and the number of heteroatoms is 1 or 2; Each R e-1 is independently a halogen or a C 1-6 alkyl group; Each ring F is independently a 5- or 6-membered heteroalkene ring substituted by one or more R e-2 wherein the heteroatom of the 5- or 6-membered heteroalkene ring is N, the number of heteroatoms is 1 or 2, and the number of double bonds is 1 or 2; Each R e-2 is independently an oxo group or an unsubstituted or R-substituted C 2-1 alkyl group; 1-6 ​ L is independently -L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -、-L 2 -L 3 -L 4 -L 5 -L 6 -、-L 3 -L 4 -L 5 -L 6 -、-L 4 -L 5 -L 6 -、-L 5 -L 6 -、-L 2 -L 4 -L 5 -L 6 - or -L 1 -L 2 -L 3 -L 5 -L 6 -; (in each L, L 6 is connected to ring E, and the other end of L is connected to ring A); Each - L 1 - independently is Each - L 2 - independently unsubstituted or substituted by one or more R P2 alkylene, unsubstituted or substituted by one or more R 1-8 alkylene, unsubstituted or substituted by one or more R P2 alkynylene, unsubstituted or substituted by one or more R 2-6 alkynylene, unsubstituted or substituted by one or more R P2 cycloalkylene, unsubstituted or substituted by one or more R 3-10 cycloalkylene, unsubstituted or substituted by one or more R P2 substituted 3 - 6 - membered monocyclic heterocycloalkylene, unsubstituted or substituted by one or more R P2 substituted 5 - 6 - membered heteroarylene or wherein, Z 1 independently is O, Z 2 independently is a single bond or O; m1 independently is 0, 1 or 2; m2 independently is 0, 1 or 2; m3 independently is 0, 1 or 2; the heteroatoms of the 3 - 6 - membered monocyclic heterocycloalkylene are selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatoms of the 5 - 6 - membered heteroarylene are N, and the number of heteroatoms is 1, 2 or 3; Each - L 3 - independently for Each - L 4 - Independently unsubstituted or substituted by one or more R P2 - Substituted phenylene or unsubstituted or substituted by one or more R P2 - Substituted 5-6 membered heteroarylene; the heteroatoms of the 5-6 membered heteroarylene are N, and the number of heteroatoms is 1, 2 or 3; Each -L 5 - independently is an unsubstituted 3- to 6-membered monocyclic heteroalkyl or an unsubstituted 5- to 6-membered heteroalkenyl, the heteroatom of the 3- to 6-membered monocyclic heteroalkyl is selected from one or two of N and O, and the number of heteroatoms is 1 or 2; the heteroatom of the 5- to 6-membered heteroalkenyl is N, the number of heteroatoms is 1 or 2, and the number of double bonds of the 5- to 6-membered heteroalkenyl is 1 or 2; Each - L 6 - independently unsubstituted or substituted by one or more R P2 substituted C 1-8 alkylene; Each R P2 is independently a halogen.

6. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that, The compound represented by formula I is any of the following compounds:

7. A pharmaceutical composition, which comprises: (1) A compound of formula I as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, and (2) a pharmaceutical excipient.

8. Use of a substance A in the preparation of an inhibitor of Polθ enzyme and / or PARP1 enzyme, wherein the substance A is a compound of formula I as described in any one of claims 1-6, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 7.

9. Use of a substance A in the preparation of a medicament for treating and / or preventing diseases related to Polθ enzyme and / or PARP1 enzyme, wherein the diseases related to Polθ enzyme and / or PARP1 enzyme may be breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, and the substance A is a compound of formula I as described in any one of claims 1-6, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 7.

10. Use of a substance A in the preparation of a medicament for treating and / or preventing breast cancer, colorectal cancer, prostate cancer or pancreatic cancer, wherein the substance A is a compound of formula I as described in any one of claims 1-6, a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 7.

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