Fused ring compound, pharmaceutical composition comprising same, and use thereof

Abstract

The present invention relates to a compound of formula (I), a pharmaceutical composition comprising same, and a use of the compound in the prevention or treatment of diseases.

Description

Condensed ring compound, pharmaceutical composition containing the same and use thereof Field of the Invention

[0001] The present invention relates to a fused ring compound, a pharmaceutical composition containing the same, and use thereof for preventing or treating diseases.

[0002] Background of the Invention

[0003] Microsatellite instability (MSI) is a genomic damage caused by mismatch repair deficiency (dMMR). Although progress has been made in treating microsatellite high instability (MSI-H) cancers, tumor evolution and drug resistance remain the main causes of treatment failure and death in cancer patients. For example, about half of patients with dMMR colorectal cancer who receive PD-1 and PD-L1 checkpoint inhibitors experience primary drug resistance. See, for example, Overman MJ et al., J Clin Oncol. 2018 Mar 10; 36(8): 773-779. For patients who are difficult to treat with currently available treatments, there is still a clinical need for new treatment options that have not yet been met.

[0004] Werner helicase (WRN) is considered to be a synthetic lethal target for MSI-H cancer (see, for example, Chan EM et al., Nature.2019 Apr; 568(7753): 551-556). WRN is one of the members of the DNA helicase RecQ family and plays an important role in maintaining genomic stability, DNA repair, replication, transcription and telomere maintenance. In the study of the WRN dependency mechanism, it was found that dinucleotide TA repeats were amplified on a large scale in MSI cells. These amplified TA repeats formed secondary DNA structures, requiring WRN helicase to unwind (see, for example, van Wietmarschen N et al., Nature.2020 Oct; 586(7828): 292-298). In the absence of WRN (or when WRN helicase is inhibited), the TA repeats amplified in MSI cells are cut by nucleases and eventually lead to chromosome breakage. Therefore, inhibition of WRN helicase is an effective strategy for treating cancers characterized by microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR), including colorectal, gastric, or endometrial cancer.

[0005] SUMMARY OF THE INVENTION

[0006] The present application provides compounds used as WRN inhibitors, which can be used to prevent or treat cancers characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR). In addition, the compounds of the present invention also have excellent properties such as good physicochemical properties (such as solubility, physical and / or chemical stability), good pharmacokinetic properties (such as improved bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (lower toxicity (such as reduced cardiotoxicity) and / or fewer side effects), and are less likely to develop drug resistance.

[0007] One aspect of the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of Formula (I):

[0008] in:

[0009] Selected from

[0010] W is CR 1 or N;

[0011] R 1 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b 、-C 1-6 Alkylene-R a 、-C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b 、(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 alkyl halide;

[0012] Alternatively, two R 1 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0013] R 2 for

[0014] R 3 、R 21 、R 22 、R 23 and R 24 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a、-S(=O)2R a 、-S(=O)2NR a R b 、-S(=O)(=NR a )R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b 、-C 1-6 Alkylene-R a 、-C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b 、(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 alkyl halide;

[0015] Or, R 3 With R 21 or R 22 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0016] R 4 for

[0017] R 41 Selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings;

[0018] Ring X and ring Z are each independently selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings;

[0019] Ring Y is absent or selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings; when ring Y is absent, R 24 It does not exist either;

[0020] L 2 Selected from -O-, -C(=O)-, -NRC(=O)-, -S-, -S(=O)-, -S(=O)2-, C 1-6 Alkylene and -O-(C 1-6 alkylene)-;

[0021] R, R a and R b Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0022] The above alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocycle, aryl, aromatic ring, heteroaryl, heteroaryl ring and aralkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of deuterium atoms, halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R c 、-OC(=O)R c 、-C(=O)OR c 、-OR c 、-SR c 、-S(=O)R c 、-S(=O)2R c 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)NR c R d 、-NR c -C(=O)R d 、-NR c -C(=O)OR d 、-NRc -S(=O)2-R d 、-NR c -C(=O)-NR c R d 、-C 1-6 Alkylene-OR c 、-C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d When the same ring atom or adjacent ring atoms of a cycloalkylene group, a cycloalkyl group, a hydrocarbon ring, a heterocyclyl group, a heterocycle, an aryl group, an aromatic ring, a heteroaryl group, or a heteroaromatic ring are substituted by two substituents, the two substituents together with the group to which they are attached optionally constitute a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; each of the alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl is further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl;

[0023] R c and R d Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10Aryl, 5-14 membered heteroaryl, C 6- 12 Aralkyl and -C 1-6 Alkylene-OC 1-6 alkyl; and

[0024] p, q and t are each independently an integer selected from 1, 2 or 3.

[0025] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0026] Another aspect of the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for use as a WRN inhibitor.

[0027] Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a WRN inhibitor.

[0028] Another aspect of the present invention provides a method for preventing or treating cancer (preferably a cancer characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR)), which comprises administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0029] Detailed Description of the Invention

[0030] definition

[0031] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0032] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0033] As used herein, the term "alkylene" refers to a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0034] As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4 "Alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

[0035] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 6 carbon atoms ("C 2-6 The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compound of the present invention contains an alkenyl group, the compound may be in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 Alkenylene", "C 2-4 Specific examples include, but are not limited to, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenylene, pentenylene, hexenylene, etc.

[0036] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "alkynylene" is a corresponding divalent radical, including, for example, "C 2-8 Alkynylidene", "C 2-6 Alkynylidene", "C 2-4 Examples include, but are not limited to, The alkynylene group is optionally substituted with one or more (such as 1 to 3) identical or different substituents.

[0037] As used herein, the term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures that share two adjacent atoms.

[0038] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0039] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.

[0040] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including spiro, fused or bridged ring systems) having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl and the like.

[0041] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6"Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0042] As used herein, the term "heterocyclyl" (or "heterocycle") refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and one or more (e.g., one, two, three or four) heteroatoms selected from O, S, N and P in the ring, and the "heterocyclyl" (or "heterocycle") may contain -C(=O)- as a ring member. The heterocyclyl group may be attached to the rest of the molecule via the carbon atoms and / or heteroatoms, if present. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxiranyl, an aziridinyl, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a dioxolinyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl or a trithianyl group.

[0043] As used herein, the term "heterocyclyl" (or "heterocycle") encompasses a parallel ring structure, and the connection point of the parallel ring structure to the other groups can be on any ring in the parallel ring structure. Therefore, the heterocyclyl of the present invention also includes but is not limited to heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, aryl and heterocyclyl, heteroaryl and heterocyclyl, such as 3-7 membered (mono) heterocyclyl and 3-7 membered (mono) heterocyclyl, 3-7 membered (mono) heterocyclyl and (mono) cycloalkyl, 3-7 membered (mono) heterocyclyl and C 4-6 (mono)cycloalkyl, C 6-10 Aryl and 3-7 membered heterocyclic group, 5-6 membered heteroaryl and 3-7 membered heterocyclic group, examples of which include but are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0044] As used herein, the term "heterocyclyl" (or "heterocycle") encompasses bridged heterocyclyls (bridged heterocycle) and spiro heterocyclyls (spiro heterocycle).

[0045] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle" and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.

[0046] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more rings sharing a ring atom, including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing 6-10 ring atoms, at least one of which is a nitrogen atom.

[0047] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0048] The term "aralkyl" refers to an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0049] As used herein, the terms "heteroaryl(ene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaryl ring” is selected from thienyl (ring), furanyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), etc., and benzo derivatives thereof; or pyridinyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and benzo derivatives thereof.

[0050] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0051] The term "alkylthio" as used herein, means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. 1-6 Representative examples of alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.

[0052] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or partially unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, S, S=O and S(=O); the nitrogen-containing heterocycle is connected to the rest of the molecule via any ring member. The nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring. In particular, the 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as aziridine), a four-membered nitrogen-containing heterocycle (such as azetidinyl), a five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), a six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl), a seven-membered nitrogen-containing heterocycle, etc.

[0053] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0054] If a substituent is described as being "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0055] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0056] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0057] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0058] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0059] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0060] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0061] In this article, solid lines can be used Solid wedge or virtual wedge The carbon-carbon bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0062] Atropisomers are compounds that can be separated into rotationally restricted isomers.

[0063] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0064] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0065] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0066] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0067] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0068] Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0069] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0070] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0071] As used herein, the term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0072] Compound

[0073] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of Formula (I):

[0074] in:

[0075] Selected from

[0076] W is CR 1 or N;

[0077] R 1 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b 、-C 1-6 Alkylene-R a 、-C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b 、(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 alkyl halide;

[0078] Alternatively, two R 1 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0079] R 2 for

[0080] R 3 、R 21 、R 22 、R 23 and R 24 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-S(=O)(=NR a )R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b 、-C 1-6 Alkylene-R a 、-C 1-6 Alkylene-OR a 、-C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b 、(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 alkyl halide;

[0081] Or, R 3 With R 21 or R 22 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0082] R 4 for

[0083] R 41 Selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings;

[0084] Ring X and ring Z are each independently selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings;

[0085] Ring Y is absent or selected from C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic rings and 5-14 membered heteroaromatic rings; when ring Y is absent, R 24 It does not exist either;

[0086] L 2 Selected from -O-, -C(=O)-, -NRC(=O)-, -S-, -S(=O)-, -S(=O)2-, C 1-6 Alkylene and -O-(C 1-6 alkylene)-;

[0087] R, R a and R b Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0088] The above alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocycle, aryl, aromatic ring, heteroaryl, heteroaryl ring and aralkyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of deuterium atoms, halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R c 、-OC(=O)R c 、-C(=O)OR c 、-OR c 、-SR c 、-S(=O)R c、-S(=O)2R c 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)NR c R d 、-NR c -C(=O)R d 、-NR c -C(=O)OR d 、-NR c -S(=O)2-R d 、-NR c -C(=O)-NR c R d 、-C 1-6 Alkylene-OR c 、-C 1-6 Alkylene-NR c R d and -OC 1-6 Alkylene-NR c R d When the same ring atom or adjacent ring atoms of a cycloalkylene group, a cycloalkyl group, a hydrocarbon ring, a heterocyclyl group, a heterocycle, an aryl group, an aromatic ring, a heteroaryl group, or a heteroaromatic ring are substituted by two substituents, the two substituents together with the group to which they are attached optionally constitute a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; each of the alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl is further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl;

[0089] R c and R d Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6- 12 Aralkyl and -C 1-6 Alkylene-OC 1-6 alkyl; and

[0090] p, q and t are each independently an integer selected from 1, 2 or 3.

[0091] In some embodiments, R 1 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR a and -NR a R b , preferably, R 1 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OR a wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, =CH2, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl; said alkyl, alkenyl, =CH2, cycloalkyl, heterocyclyl, aryl and heteroaryl are each further optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group and -C 1-6 Alkylene-C 3-6 Cyclic hydrocarbon group.

[0092] In a preferred embodiment, R 1 is H, methyl, halogen, methoxy,

[0093] In some embodiments, the two R 1 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring, wherein the hydrocarbon ring, heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0094] In a preferred embodiment, the two R 1 Together with the groups to which they are attached, they optionally constitute a phenyl ring or a pyridine ring, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0095] In some embodiments, ring X is a benzene ring, a 5-6 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring (preferably a thiophene ring, a thiazole ring, or a pyridine ring), and ring Y is absent.

[0096] In some embodiments, ring X is a benzene ring or a 5-6 membered heteroaromatic ring, and ring Y is C 3-6 a hydrocarbon ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring.

[0097] In a preferred embodiment, for More preferably

[0098] In some embodiments, R 21 、R 22 、R 23 and R 24 Each occurrence is independently selected from H, halogen, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, -O-(C 1-6 alkyl), -S(=O)2-(C 1-6 alkyl), -S(=O)2-(C 3-6 Cycloalkyl), -P(=O)(C 1-6 Alkyl)2, (-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 Alkyl, said alkyl, cycloalkylene, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 Alkyl and halogenated C 1-6 alkyl.

[0099] In a preferred embodiment, R 21 、R 22 、R 23 and R 24 Each occurrence is independently selected from H, halogen, -SF5, C 1- 6 alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group and -O-(C 1-6 alkyl), said alkyl, cycloalkyl and heterocyclyl being each optionally substituted by one or more substituents independently selected from the group consisting of halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0100] In some embodiments, Selected from:

[0101] In some embodiments, Selected from:

[0102] In some embodiments, R 3 H, C 1-6 Alkyl, -OR a or -SR a Preferably, R 3 It is H, ethyl, -O-CH3 or -S-CH3.

[0103] In some embodiments, R 3 With R 21 or R 22 Together with the group to which it is attached, it optionally forms C 3-6 hydrocarbon ring or 3-10 membered heterocyclic ring, wherein the hydrocarbon ring and heterocyclic ring are optionally substituted by one or more selected from deuterium atoms, halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 When the same ring atom or adjacent ring atoms of the hydrocarbon ring and heterocyclic ring are substituted by two substituents, the two substituents together with the group to which they are connected optionally constitute a C 3-6 a hydrocarbon ring or a 3-10 membered heterocyclic ring.

[0104] In a preferred embodiment, R 3 With R 21 or R 22Together with the groups to which they are connected, they optionally constitute a cyclopentene ring, a cyclohexene ring, a pyrrolidine ring, a piperidine ring or a morpholine ring, wherein the cyclopentene ring, the cyclohexene ring, the pyrrolidine ring, the piperidine ring and the morpholine ring are optionally substituted by one or more deuterium atoms, halogens, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 When the same ring atom of the cyclopentene ring, cyclohexene ring, pyrrolidine ring, piperidine ring and morpholine ring is substituted by two substituents, the two substituents together with the group to which they are connected optionally constitute a C 3-6 Hydrocarbon ring.

[0105] In some embodiments, ring Z is a 3-10 membered heterocycle or a benzene ring; preferably a 5-10 membered heterocycle; more preferably a 5-6 membered heterocycle; and

[0106] The heterocyclic ring and the phenyl ring are each optionally substituted at each occurrence by one or more substituents independently selected from the group consisting of halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0107] In a preferred embodiment, ring Z is

[0108] In some embodiments, L 2 -C(=O)- or -NRC(=O)-, wherein R is H or C 1-6 alkyl;

[0109] In a preferred embodiment, L 2 It is -C(=O)-.

[0110] In some embodiments, R 41 Selected from 3-10 membered heterocyclic ring, C 6-10 aromatic ring and 5-14 membered heteroaromatic ring, wherein the heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 Alkyl, preferably, the heterocyclic ring, aromatic ring and heteroaromatic ring are at least -OH or -OC 1-6 Alkyl substitution.

[0111] In some embodiments, -L 2 -R 41 for

[0112] In some embodiments, R 41 It is a 5-6 membered heteroaromatic ring, preferably a 6 membered heteroaromatic ring, more preferably a pyridine ring or a pyrimidine ring, which is substituted by at least one -OH group.

[0113] In a preferred embodiment, -L 2 -R 41 for

[0114] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein the compound has the structure of the following formula:

[0115] in:

[0116] Ring C and Ring D are each independently C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring, wherein the hydrocarbon ring, heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 Alkyl, when the same ring atom or adjacent ring atoms of the hydrocarbon ring, heterocycle, aromatic ring and heteroaromatic ring are substituted by two substituents, the two substituents together with the group to which they are connected optionally constitute a C 3-6 hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring;

[0117] Preferably, ring C is a phenyl ring or a pyridine ring, each of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; and / or

[0118] Ring D is a cyclopentene ring, a cyclohexene ring, a pyrrolidine ring, a piperidine ring or a morpholine ring, each of which is optionally substituted by one or more substituents independently selected from the following: a deuterium atom, a halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 Alkyl; when the same ring atom or adjacent ring atoms of ring D are substituted by two substituents, the two substituents together with the group to which they are attached optionally constitute C 3-6 a hydrocarbon ring or a 3-10 membered heterocyclic ring;

[0119] The remaining groups are as defined above.

[0120] The present disclosure encompasses technical solutions / compounds obtained by any combination of the various embodiments.

[0121] In a preferred embodiment, the present disclosure provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from:

[0122] Pharmaceutical compositions and methods of treatment

[0123] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. In some embodiments, the pharmaceutical composition may further comprise one or more other therapeutic agents.

[0124] In some embodiments, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for use as a WRN inhibitor.

[0125] In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention, for use as a WRN inhibitor.

[0126] In some embodiments, the present invention provides a method for preventing or treating cancer (preferably cancer characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR)), which comprises administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, or a pharmaceutical composition of the present invention.

[0127] In some embodiments, the cancer includes colorectal cancer, gastric cancer, endometrial cancer, uterine cancer, adrenocortical cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer, and ovarian cancer.

[0128] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0129] As used herein, unless otherwise indicated, the terms "treat," ...

[0130] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0131] In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents. Example

[0132] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0133] The abbreviations used in this invention have the following meanings:

[0134] General synthetic route:

[0135] Route 1

[0136] Route 2

[0137] Wherein, in Scheme 1 and Scheme 2, PG is a protecting group, and the remaining groups are as defined herein.

[0138] Example 1: Synthesis of Compound B1

[0139] 1) Synthesis of intermediate B1-3:

[0140] Compound B1-1 (9.0 g, 38.03 mmol), compound B1-2 (21.72 g, 68.45 mmol), and TEA (11.52 g, 114.09 mmol) were added to 1,4-dioxane (100 mL). The atmosphere was replaced with nitrogen three times, then the temperature was raised to 120°C and the reaction was stirred overnight under a nitrogen atmosphere. TLC monitoring showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 3 / 1) to obtain a yellow solid compound B1-3 (15.0 g, yield 76%). LCMS (ESI) m / z = 518.2 [M+H] + .

[0141] 2) Synthesis of intermediate B1-4:

[0142] Compound B1-3 (12 g, 23.2 mmol) was added to a mixed solution of ethanol and tetrahydrofuran (2:1) (450 mL), cooled to 0°C, and NaOH (1.85 g, 46.4 mmol) was dissolved in 10 mL of water and slowly added dropwise to the reaction solution. The solution was stirred at room temperature overnight. TLC monitoring showed that the reaction of the starting material was complete. HCl (1 M) was added dropwise to the reaction solution to adjust the pH to 5. The solution was washed with water and extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was added with diethyl ether and then filtered to obtain compound B1-4 (9.0 g, yield 79%) as a yellow solid. LCMS (ESI) m / z = 490.3 [M+H] + .

[0143] 3) Synthesis of intermediate B1-6:

[0144] Compound B1-4 (9.6 g, 19.6 mmol), compound B1-5 (3.78 g, 39.26 mmol), TEA (7.92 g, 78.4 mmol), and HATU (8.94 g, 23.52 mmol) were added to DMF (100 mL), replaced with nitrogen three times, and stirred at room temperature under a nitrogen atmosphere overnight. TLC monitoring showed that the raw materials had reacted completely. The mixture was washed with water and extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 4 / 1) to obtain compound B1-6 (4.5 g, yield 60%) as a yellow solid. LCMS (ESI) m / z = 383.2 [M+H] + .

[0145] 4) Synthesis of intermediate B1-7:

[0146] Compound B1-6 (5.0 g, 13.09 mmol) was added to a tetrahydrofuran solution (100 mL), the atmosphere was replaced with nitrogen three times, and the mixture was cooled to 0°C. Methyl Grignard reagent (1 M, 52.4 mL, 52.4 mmol) was slowly added dropwise, and the reaction was stirred at 0°C for 1 hour. LC-MS showed that the reaction was complete. Aqueous ammonium chloride solution was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 6 / 1) to obtain compound B1-7 (3.6 g, 81% yield) as a yellow solid. LCMS (ESI) m / z = 338.1 [M+H] + .

[0147] 5) Synthesis of intermediate B1-8:

[0148] Compound B1-7 (3.6 g, 10.7 mmol) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (10 mL). The mixture was heated to 40° C. and stirred for 2 hours. LC-MS indicated that the reaction was complete. A saturated aqueous solution of sodium bicarbonate was slowly added dropwise to the reaction solution until the pH reached 7. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=4 / 1) to obtain compound B1-8 (1.7 g, 85% yield) as a yellow solid. LCMS (ESI) m / z=188.3 [M+H] + .

[0149] 6) Synthesis of intermediate B1-9:

[0150] Compound B1-8 (1.0 g, 5.3 mmol) was added to dichloromethane (20 mL), cooled to 0°C, and propionyl chloride (0.99 g, 10.6 mmol) and pyridine (2.09 g, 26.5 mmol) were slowly added dropwise. The reaction solution was stirred at 0°C for 3 hours. LC-MS showed that the reaction of the starting material was complete. The mixture was quenched with water 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. The residue was purified by column chromatography (PE / EA = 3 / 1) to obtain compound B1-9 (0.98 g, yield 75%) as a yellow solid. LCMS (ESI) m / z = 244.1 [M+H] + .

[0151] 7) Synthesis of intermediate B1-10:

[0152] Compound B1-9 (950 mg, 3.9 mmol) was added to tert-butanol (50 mL), and potassium tert-butoxide (2190 mg, 19.54 mmol) was slowly added. The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 95° C. and stirred under a nitrogen atmosphere for 2 hours. LC-MS showed that the reaction of the starting materials was complete. The reaction solution was cooled to room temperature, and HCl (1 M) was added dropwise to the reaction solution to adjust the pH to 7. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH=50 / 1) to obtain compound B1-10 (450 mg, yield 51%) as a yellow solid. LCMS (ESI) m / z=226.3 [M+H] + .

[0153] 8) Synthesis of intermediate B1-12:

[0154] Compound B1-11 (3.0 g, 15.34 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (3.10 g, 15.34 mmol) and bromoacetyl bromide (3.0 g, 15.34 mmol) were added at 0°C. The mixture was stirred at room temperature for 5 hours. LC-MS showed that the starting material was completely reacted. Aqueous solution was slowly added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=50 / 1) to obtain compound B1-12 (4.0 g, yield 83%) as an off-white solid. LCMS (ESI) m / z=315.9 [M+H] + .

[0155] 9) Synthesis of intermediate B1-13:

[0156] Compound B1-12 (950 mg, 3.02 mmol) and compound B1-10 (678.6 mg, 3.02 mmol) were added to acetonitrile (10 mL), and DIEA (1168.7 mg, 9.06 mmol) was slowly added dropwise. The atmosphere was purged with nitrogen three times, and the reaction solution was heated to 80°C and stirred overnight. LC-MS showed that the reaction of the starting materials was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA=6 / 4) to obtain compound B1-13 (850 mg, yield 61.27%) as a white solid. LCMS (ESI) m / z=461.0 [M+H] + .

[0157] 10) Synthesis of intermediate B1-14:

[0158] Compound B1-13 (600 mg, 1.30 mmol) was added to dichloromethane (20 mL), and NBS (232.17 mg, 1.3 mmol) was added at 0°C. The reaction was stirred at room temperature for 1 hour. LC-MS showed that the starting material reaction was complete. Aqueous solution was slowly added dropwise to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 2 / 1) to obtain compound B1-14 (550 mg, yield 78%) as an off-white solid. LCMS (ESI) m / z = 538.9 [M+H] + .

[0159] 11) Synthesis of intermediate B1-15:

[0160] Compound B1-14 (180 mg, 0.33 mmol), piperazine (567.6 mg, 6.6 mmol), and silver tetrafluoroborate (130 mg, 0.66 mmol) were added to dimethyl sulfoxide (4 mL), and the reaction solution was heated to 120°C for reaction. LC-MS showed that the starting material reaction was complete. Aqueous solution was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound B1-15 (25 mg, yield 14%) as an off-white solid. LCMS (ESI) m / z = 545.1 [M+H] + .

[0161] 12) Synthesis of Product B1:

[0162] Compound B1-16 (8.87 mg, 0.059 mmol), HOBT (5.94 mg, 0.044 mmol), and EDCI (11.52 mg, 0.06 mmol) were added to DMF (4 mL), the atmosphere was replaced with nitrogen three times, and the reaction was stirred under a nitrogen atmosphere for 2 hours. Compound B1-15 (23 mg, 0.04 mmol) and DIEA (15.48 mg, 0.12 mmol) were added to the reaction solution, and stirring was continued at room temperature for another 2 hours. LC-MS showed that the starting materials reacted completely. Aqueous solution was added dropwise to quench the reaction, and the mixture was extracted with dichloromethane. 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 preparative high-performance liquid chromatography to obtain compound B1 (5.4 mg, yield 19%). LCMS (ESI) m / z = 680.9 [M+H] +.1 H NMR (400MHz, CD3OD): δ8.53 (s, 1H), 8.32 (d, J = 7.6Hz, 1H), 8.11-8.07 (m, 2H), 7.9 9-7.95(m,1H),7.90-7.86(m,1H),7.81(s,1H),7.58(dd,J1=1.2Hz,J2=8.8Hz,1H) ,5.70(s,2H),4.74-4.70(m,1H),4.07-3.91(m,3H),3.52-3.40(m,3H),3.22-3.13 (m,1H),2.99-2.96(m,1H),2.84-2.81(m,1H),2.53(s,3H),1.43(t,J=7.6Hz,3H).

[0163] Example 2: Synthesis of Compound B6

[0164] 1) Synthesis of intermediate B6-2:

[0165] Compound B6-1 (9 g, 38.31 mmol) was dissolved in methanol (100 mL), cooled to -30°C, and stirred for ten minutes. A solution of 2,3-butanedione (3.3 g, 38.31 mmol) and sodium acetate (10.18 g, 122.59 mmol) in water (100 mL) was then added. After the addition was complete, 40 mL (3.6 mol / L) of sodium hydroxide solution was added. The reaction was then incubated at 0°C for 30 minutes, then transferred to room temperature and allowed to react overnight. LCMS indicated the reaction was complete. The mixture was extracted with water (200 mL) and ethyl acetate (200 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield crude product B6-2 (3.85 g, yield: 81.6%). LCMS (ESI) m / z = 124.1 [M+H]+ .

[0166] 2) Synthesis of intermediate B6-3:

[0167] Compound B6-2 (3.8 g, 24.99 mmol) was dissolved in acetonitrile (40 mL), cooled to 0°C, and NBS (4.45 g, 24.99 mmol) was added. The reaction solution was stirred at 25°C for 0.5 hours. LCMS showed that the reaction was complete. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL*3). The organic phases were combined and then washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain B6-3 (3.9 g, yield: 77.23%). LCMS (ESI) m / z = 202.0 [M+H] + .

[0168] 3) Synthesis of intermediate B6-4:

[0169] Compound B6-3 (3.9 g, 19.3 mmol) and cuprous cyanide (4.13 g, 46.13 mmol) were dissolved in DMF (40 mL) and then reacted under microwave at 120°C for 2 h. LCMS indicated the reaction was complete. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL*3). The organic phases were combined and washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain B6-4 (0.74 g, yield: 25.85%). LCMS (ESI) m / z = 149.2 [M+H] + .

[0170] 4) Synthesis of intermediate B6-5:

[0171] Compound B6-4 (0.57 g, 3.85 mmol) was dissolved in tetrahydrofuran (6 mL), cooled to 0°C, and then methylmagnesium bromide (3 M, 13 mL, 38.5 mmol) was added. The mixture was then allowed to react overnight at 50°C. The reaction was monitored for completion by LCMS. The mixture was extracted with water (100 mL) and ethyl acetate (100 mL*3). The organic phases were combined and then washed with saturated brine (20 mL*3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain B6-5 (0.5 g, yield: 78.68%). LCMS (ESI) m / z = 166.5 [M+H] + .

[0172] 5) Synthesis of intermediate B6-6:

[0173] Compound B6-5 (0.7 g, 4.24 mmol) was added to dichloromethane (20 mL), cooled to 0°C, and propionyl chloride (0.78 g, 8.48 mmol) and pyridine (1.68 g, 21.20 mmol) were slowly added dropwise. The reaction solution was stirred at 0°C for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction was quenched with water 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. The residue was purified by column chromatography to obtain compound B6-6 (0.6 g, yield 63.99%) as a yellow solid. LCMS (ESI) m / z = 222.2 [M+H] + .

[0174] 6) Synthesis of intermediate B6-7:

[0175] Compound B6-6 (0.35 g, 1.58 mmol) was added to 1,4-dioxane (5 mL), and potassium tert-butoxide (0.27 g, 2.37 mmol) was slowly added. The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 110°C and stirred under a nitrogen atmosphere for 1 hour. LC-MS showed that the reaction of the raw materials was complete. The reaction solution was cooled to room temperature 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. The residue was purified by column chromatography to obtain a yellow solid compound B6-7 (0.3 g, yield 93.31%). LCMS (ESI) m / z = 204.2 [M+H] + .

[0176] 7) Synthesis of intermediate B6-8:

[0177] Compound B6-7 (0.28 g, 1.38 mmol) and compound B1-12 (0.48 g, 1.52 mmol) were added to acetonitrile (3 mL), and DIPEA (0.89 g, 6.9 mmol) was slowly added dropwise. The atmosphere was replaced with nitrogen three times, and the reaction solution was heated to 45°C and stirred for 4 h. LC-MS showed that the reaction of the starting materials was complete. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain a white solid compound B6-8 (0.5 g, yield 82.7%). LCMS (ESI) m / z = 439.2 [M+H] + .

[0178] 8) Synthesis of intermediate B6-9:

[0179] Compound B6-8 (0.45 g, 1.03 mmol) was added to dichloromethane (10 mL), and NBS (0.32 g, 1.77 mmol) was added at 0°C. The reaction was stirred at room temperature for 1 hour. LC-MS showed that the starting material was completely reacted. Aqueous solution was slowly added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound B6-9 (0.2 g, yield 37.67%) as an off-white solid. LCMS (ESI) m / z = 517.2 [M+H] + .

[0180] 9) Synthesis of intermediate B6-11:

[0181] Compound B6-9 (0.15 g, 0.29 mmol), compound B6-10 (0.45 g, 2.12 mmol), silver tetrafluoroborate (0.3 g, 1.54 mmol), and DIPEA (0.39 g, 2.9 mmol) were added to dimethyl sulfoxide (4 mL), and the reaction solution was heated to 140°C. LC-MS showed that the starting materials were completely reacted. Aqueous solution was added dropwise to quench the reaction, and the mixture was 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. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain compound B6-11 (20 mg, yield 10.63%) as an off-white solid. LCMS (ESI) m / z = 649.2 [M+H] + .

[0182] 10) Synthesis of intermediate B6-12:

[0183] Compound B6-11 (20 mg, 0.031 mmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction mixture was stirred at 25°C for 1.5 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated to obtain the trifluoroacetate salt of B6-12 (60 mg, crude) as a yellow oil. LCMS (ESI) m / z = 549.2 [M+H] + .

[0184] 11) Synthesis of Product B6:

[0185] Compound B1-16 (7.2 mg, 0.059 mmol), HOAT (6.7 mg, 0.046 mmol), and EDCI (11.52 mg, 0.056 mmol) were added to DMF (0.5 mL), the atmosphere was replaced with nitrogen three times, and the reaction was stirred under a nitrogen atmosphere for 1 hour. The trifluoroacetate salt of compound B6-12 (60 mg, crude product) and DIPEA (12 mg, 0.093 mmol) were added to the reaction solution, and stirring was continued at room temperature for another 0.5 hour. LC-MS showed that the starting materials reacted completely. The product was purified by preparative chromatography on a reverse phase C18 column (0.5% aqueous formic acid:acetonitrile = 9:1 to 1:9) to give compound B6 (3.5 mg, two-step yield 16.5%). LCMS (ESI) m / z = 685.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.50(s,1H),8.01–7.94(m,2H),7.69( dd,J=8.8,2.1Hz,1H),5.44(s,2H),4.48(d,J=13.0Hz,1H),3.88(d,J=8.9Hz, 1H),3.60–3.11(m,6H),2.60(s,3H),2.59(s,3H),2.41(s,3H),1.99(dt,J=1 3.4,7.0Hz,1H),1.65-1.45(m,2H),1.34–1.27(m,3H),1.06(t,J=8.2Hz,1H).

[0186] Example 3: Synthesis of Compound B18

[0187] 1) Synthesis of intermediate B18-2:

[0188] To a 1000 mL three-necked flask, B18-1 (9.0 g, 44.53 mmol) and anhydrous tetrahydrofuran (225 mL) were added sequentially. Under nitrogen, the mixture was stirred at -70 to -75°C. A solution of n-butyllithium in n-hexane (2.5 mol / L, 48 mL, 120 mmol) was slowly added. The mixture was stirred at -70 to -75°C for 20 minutes. The temperature was slowly raised to -5-0°C, stirred at -5-0°C for 70 minutes, cooled to -70 to -75°C, and hexachloroethane (31.6 g, 133.6 mmol) was added at -70 to -75°C. The mixture was stirred at -70 to -75°C for 40 minutes, then slowly returned to room temperature and stirred for another 40 minutes. The reaction was quenched with 10% w / w aqueous citric acid solution and extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford B18-2 (3.5 g, 33%).

[0189] 2) Synthesis of intermediate B18-3:

[0190] To a solution of B18-2 (3 g, 12.68 mmol) in anhydrous tert-butanol (30 mL) was added diphenylphosphoryl azide (4.08 g, 14.84 mmol). After the addition was complete, N,N-diisopropylethylamine (1.92 g, 19.02 mmol) was added to the reaction mixture. The reaction mixture was heated to 80°C and stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was added to a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound B18-3 (2.8 g, 71%) as a white solid.

[0191] 3) Synthesis of intermediate B18-4:

[0192] B18-3 (450 mg, 1.46 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated to give a brown oil B18-4 (300 mg, mixture, yield: 98.8%). ESI m / z [M+H] + =208.1.

[0193] 4) Synthesis of intermediate B18-5:

[0194] Compound B18-4 (0.3 g, 1.45 mmol) and potassium carbonate (0.6 g, 4.35 mmol) were dissolved in dichloromethane (2 mL). Bromoacetyl bromide (0.44 g, 2.17 mmol) was added dropwise with stirring at 0°C. The mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. The reaction solution was poured into water, extracted with dichloromethane (50 mL*2), and concentrated to obtain B18-5 (0.3 g, 63%) as a yellow solid.

[0195] 5) Synthesis of product B18:

[0196] Referring to the synthesis method of compound B6 in Example 2, compound B18-5 was used instead of B1-12 to synthesize compound B18. LCMS (ESI) m / z = 697.2 [M+H] +.1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.57(s,1H),7.41(m,2H),5.39(s,2H),4.57–4.41(m,1H),3.91(d,J=8.6Hz,1H),3.75–3 .06(m,6H),2.64(s,3H),2.63(s,3H),2.46(s,3H),1.62-1.50(m,1H),1.40-1.28(m,2H),1.28–1.22(m,3H),1.20-1.14(m,1H).

[0197] Example 4: Synthesis of Compound B113

[0198] 1) Synthesis of intermediate B113-9:

[0199] Will (0.6 g, 2.38 mmol, prepared according to the synthesis method disclosed in patent application WO2008082484) and methylboronic acid (1.42 g, 23.8 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). Potassium carbonate (0.99 g, 7.14 mmol) was added with stirring. After three gas replacements, 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.17 g, 0.24 mmol) was added and stirred at 80°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether) to obtain B113-9 as a white solid (0.4 g, yield: 89.8%). m / z [M+H] + =188.1.

[0200] 2) Synthesis of intermediate B113-2:

[0201] 4-Nitro-2H-1,2,3-triazole (1.0 g, 8.76 mmol, 1.0 eq), phenylboronic acid (2.14 g, 17.50 mmol, 2.0 eq.), and copper acetate monohydrate (524 mg, 2.63 mmol, 0.3 eq.) were dissolved in DMSO (15 mL). The reaction mixture was purged with oxygen three times and stirred at 110°C overnight. After completion of the reaction, the reaction mixture was diluted with water (150 mL), filtered, and the filtrate was extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was isolated and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether = 1:10) to afford B113-2 (210 mg, 12%). LCMS: m / z = 191.1 [M+H] + ; 1H NMR (400MHz, CDCl3) δ8.37(s,1H),8.17–8.12(m,2H),7.57–7.48(m,3H).

[0202] 3) Synthesis of intermediate B113-3:

[0203] B113-2 (9.0 g, 47.33 mmol, 1.0 eq), ammonium chloride (7.6 g, 141.98 mmol, 3.0 eq), and iron powder (7.9 g, 141.98 mmol, 3.0 eq) were mixed in ethanol (90 mL) and water (90 mL). The reaction mixture was stirred at 70°C under nitrogen for 2 h. After completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain B113-3 (8.5 g, 95%) as a yellow solid. LCMS m / z = 161.1 [M+H] +.1 H NMR (400MHz, DMSO-d6) δ7.82–7.78(m,2H),7.48–7.44(m,2H),7.26(s,1H),6.76–6.73(m,1H),5.50(s,2H).

[0204] 4) Synthesis of intermediate B113-4:

[0205] B113-3 (2.0 g, 9.79 mmol, 1.0 eq), methyl 3-oxopentanoate (10.2 g, 78.34 mmol, 8.0 eq), and anhydrous magnesium sulfate (2 g) were dissolved in toluene (10 mL). The reaction solution was stirred at 110°C overnight. After completion of the reaction, the reaction solution was diluted with dichloromethane (50 ml) and filtered through celite. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:2) to obtain B113-4 (2.9 g, 93% yield). LCMS m / z = 273.2 [M+H] +

[0206] 5) Synthesis of intermediate B113-5:

[0207] The solid B113-4 (310 mg, 1.1 mmol, 1.0 eq) was directly poured into diphenyl ether (10 mL) at 235°C. The reaction solution was stirred at 235°C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with petroleum ether (20 mL), and stirred for 20 minutes. The reaction mixture was filtered and washed with petroleum ether. The filter cake was dried under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 40:1) to obtain B113-5 (80 mg, 30% yield). LCMS m / z = 241.1 [M+H] +.1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.14(d,J=8.0Hz,2H),7.64(t,J=8.0Hz,2 H),7.58–7.49(m,1H),5.93(s,1H),2.63(q,J=7.6Hz,2H),1.25(t,J=7.6Hz,3H).

[0208] 6) Synthesis of intermediate B113-6:

[0209] Under nitrogen protection, diisopropylamine (303 mg, 3 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (1.3 mL) and cooled to -78°C. n-Butyl lithium (2.5 M in hexane, 1.2 mL, 3 mmol, 1.0 eq) was slowly added dropwise to the reaction system, and the reaction solution was reacted at -78°C for 30 min.

[0210] Under nitrogen, B113-5 (29 mg, 0.12 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (2 mL) and anhydrous DMSO (0.2 mL). The reaction mixture was cooled to 0°C. The prepared LDA solution (0.6 mL, 0.6 mmol, 5.0 eq) was slowly added to the reaction mixture, and the reaction mixture was allowed to react at 0°C for 30 minutes. (S)-Chloropropylene oxide (22 mg, 0.24 mmol, 2.0 eq) was dissolved in anhydrous tetrahydrofuran (0.4 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by thin-layer preparative chromatography (eluent: dichloromethane:methanol=10:1) to give B113-6 (10 mg, 28%) as a light yellow solid. LCMS m / z=297.1 [M+H] +

[0211] 7) Synthesis of intermediate B113-7:

[0212] Under nitrogen, B113-6 (298 mg, 1.0 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (12 mL). The reaction mixture was cooled to 0°C, and N-bromosuccinimide (268 mg, 1.5 mmol, 1.5 eq) was slowly added to the reaction mixture. The reaction mixture was slowly warmed to room temperature and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give B113-7 (375 mg, 100% crude product) as a red solid. LCMS m / z = 375.1 [M+H] +

[0213] 8) Synthesis of intermediate B113-8:

[0214] B113-7 (375 mg, 1.0 mmol, 1.0 eq), sodium bicarbonate (840 mg, 10 mmol, 10.0 eq), potassium bromide (12 mg, 0.1 mmol, 0.1 eq), TOMAC (21 mg, 0.05 mmol, 0.05 eq), and TEMPO (8 mg, 0.05 mmol, 0.05 eq) were dissolved in dichloromethane (12 mL) and water (9 mL). The reaction solution was cooled to 0°C, and 5% aqueous sodium hypochlorite (7.5 g, 5.0 mmol, 5.0 eq) was slowly added dropwise. The reaction solution was slowly warmed to room temperature and stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction solution was quenched by adding sodium bicarbonate solution and extracted with dichloromethane (3 × 20 mL). The resulting aqueous phase was adjusted to pH 3 with 3 M hydrochloric acid solution and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give B113-8 (120 mg, 31%) as a light yellow solid. LCMS m / z = 389.1 [M+H] +

[0215] 9) Synthesis of intermediate B113-10:

[0216] Under nitrogen, compound B113-8 (120 mg, 0.31 mmol, 1.0 eq), B113-9 (70 mg, 0.37 mmol, 1.2 eq), and N,N-diisopropylethylamine (160 mg, 1.23 mmol, 4.0 eq) were dissolved in anhydrous dichloromethane (2.5 mL). CMPI (119 mg, 0.46 mmol, 1.5 eq) was then added, and the reaction mixture was stirred at room temperature for 1.5 hours. After completion, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (eluent: dichloromethane:methanol = 150:1) to obtain B113-10 (85 mg, 46% yield) as a light yellow solid. LCMS m / z=558.1[M+H] +.1 H NMR (400MHz, CDCl3) δ10.09(s,1H),8.12–8.03(m,1H),7.86–7.77(m,1H),7.52–7.41(m,1H),7.38–7.28(m,3H),6.88(d,J=8.5 Hz,1H),5.43–5.32(m,1H),3.31–3.09(m,1H),2.79–2.63(m,1H),2.41–2.36(m,3H),2.10–1.90(m,1H),1.41(d,J=7.1Hz,3H).

[0217] 10) Synthesis of intermediate B113-12:

[0218] Under nitrogen, B113-10 (53 mg, 0.09 mmol, 1.0 eq), B113-11 (160 mg, 1.42 mmol, 15.0 eq), N,N-diisopropylethylamine (48 mg, 0.47 mmol, 5.0 eq), and silver tetrafluoroborate (28 mg, 0.14 mmol, 1.5 eq) were dissolved in dry DMSO (0.8 mL), and the reaction mixture was stirred at 125°C for 3.5 hours. After completion of the reaction, the reaction mixture was diluted with methanol (2 mL), filtered, and the filtrate was directly separated and purified by C18 column chromatography (10-60% ACN in H2O (0.1% formic acid)) to obtain B113-12 (30 mg, crude, 50% purity) as a yellow solid. LCMS m / z = 590.30 [M+H] + .

[0219] 11) Synthesis of product B113:

[0220] Under nitrogen, B1-16 (9.8 mg, 0.063 mmol) and HOAt (8.8 mg, 0.065 mmol) were dissolved in acetonitrile (2 mL). EDCI (16.1 mg, 0.084 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. B113-12 (25 mg, crude, 50% purity) and N,N-diisopropylethylamine (18.9 mg, 0.14 mmol, 3.5 eq) were then added to the reaction solution, and the reaction solution was stirred at room temperature for another 0.5 hour. After completion of the reaction, the reaction solution was quenched by addition of water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by thin-layer preparative chromatography (eluent: dichloromethane:methanol = 10:1) to afford B113 (1 mg). LCMS m / z = 726.2 [M+H] +.1 H NMR (400MHz, CD3OD) δ8.56–8.52(m,1H),8.28–8.15(m,2H),7.63–7.57(m,2H),7.55–7. 49(m,1H),7.13–6.96(m,2H),5.50–5.42(m,1H),4.79–4.66(m,1H),4.00–3.88(m,3H), 3.78–3.69(m,2H),3.57–3.48(m,1H),3.18–3.13(m,1H),2.65–2.54(m,1H),2.52–2.50 (m,3H),2.31–2.22(m,4H),1.82–1.67(m,1H),1.61(d,J=7.3Hz,3H),1.55–1.44(m,2H).

[0221] Biological testing section

[0222] Experimental Example 1 Biological Activity Test

[0223] ATPase activity assay of WRN helicase

[0224] The commercial ADP-Glo ​​assay kit (Promega, #V9102) was used to detect the ADP content produced by the hydrolysis of ATP by WRN helicase, which can reflect the ATPase activity of WRN helicase.

[0225] 45nt oligoDNA single-stranded FLAP26 (TTTTTTTTTTTTTTTTTTTTTTCCAAGTAAAACGACGGCCAGTGC) was synthesized by Anshengda. See, for example, Brosh RM Jr et al., J Biol Chem, 2002 Jun; 277(26): 23236-45. Reaction buffer (30mM Tris pH 7.5, 2mM MgCl2, 0.02% BSA, 50mM NaCl, 0.1% pluronic F127) was prepared, and 5μL of 3× test compound (diluted to 0.5% DMSO in reaction buffer, final starting concentration of 10μM, 1:3 dilution, a total of 9 steps) was added to a 384-well transparent plate, 5μL of 3× WRN recombinant protein and 3× ATP substrate solution (diluted in reaction buffer, final concentrations of WRN and ATP were 10nM and 300μM, respectively) in sequence, shaken to mix, and incubated at 37°C for 3 hours. Next, a 3×FLAP26 solution was prepared with reaction buffer, and 5 μL of the solution (final concentration of FLAP26 was 0.4 nM) was added to a 384-well transparent plate, shaken to mix, and the enzymatic reaction was initiated, followed by incubation at room temperature for 30 minutes.

[0226] Transfer 5 μL of the above mixture to a 384-well white plate, add 5 μL of ADP-Glo ​​reagent, shake and mix, and incubate at room temperature in the dark for 40 minutes. Add 10 μL of kinase detection reagent to the above solution, shake and mix, incubate at room temperature in the dark for 30 minutes, and record the chemiluminescence reading. Calculate the inhibition rate of the compound on enzyme activity, and use nonlinear regression (dose response-variable slope) to fit the inhibition rate value and the logarithm of the compound concentration to obtain the IC value of the test compound. 50 value.

[0227] Table 1 WRN ATPase activity data of the compounds in the examples of this application

[0228] As can be seen from Table 1, the compounds of the present application have good inhibitory activity on the ATPase activity of the WRN protein.

[0229] Tumor cell proliferation inhibitory activity assay

[0230] The WRN gene was stably knocked out in DLD1 cells using CRISPR / Cas9 technology to construct the DLD1-WRN-KO cell line, which was used to evaluate the potential off-target effects of the compounds.

[0231] After the test compound was treated with the microsatellite unstable SW48 cell line and the control cell DLD1-WRN-KO cell line for 4 days, the ATP level was detected using the CellCounting-Lite kit of Novozymes to evaluate the inhibitory effect of the test compound on the growth of tumor cell lines.

[0232] In the present application, SW48 cell lines and DLD1-WRN-KO cell lines were seeded in 96-well cell culture plates at an appropriate cell density. After 24 hours, the test compound was used to treat the cells with a maximum concentration of 10 μM and 9 gradient dilutions of 1:3. A DMSO treatment group was also set up. Cultured in a 37°C / 5% CO2 incubator for 4 days. To test the inhibition of tumor cell proliferation by the test compound, the cells were equilibrated at room temperature for 30 minutes, and then 100 μL of cell proliferation detection reagent CellCounting-Lite (CCL) was added to each well. After shaking for 5 minutes, the cells were incubated in the dark for 10 minutes. The chemiluminescence value was read using a Thermo Varioskan LUX-3020 multifunctional microplate reader to convert it into a proliferation index to calculate the inhibition rate of the compound on tumor cell proliferation. The inhibition rate value and the logarithm of the compound concentration were fitted using nonlinear regression (dose response-variable slope) to obtain the IC value of the compound. 50 value.

[0233] Table 2 Tumor cell proliferation inhibitory activity data of the compounds in the examples of this application

[0234] As can be seen from Table 2, the compound of the present application has good proliferation inhibitory activity against microsatellite unstable SW48 cells, but has no significant proliferation inhibitory activity against WRN knockout DLD1 cells, and has good selectivity.

[0235] Experimental Example 2 Liver microsome stability test

[0236] The test compounds were assessed for their first-phase metabolic stability in liver microsomes of CD-1 mice, Sprague-Dawley rats, beagle dogs, cynomolgus monkeys, and humans.

[0237] Experimental system:

[0238] The animal and human liver microsomes used in this test system were purchased from Xenotech, Corning or other qualified suppliers and stored in a freezer below -60°C before use.

[0239] Experiment Introduction:

[0240] Test and control compounds were incubated with animal and human liver microsomes at 37 ± 1°C for a specified period of time, with a maximum incubation time of 60 minutes. Samples were removed at designated time points and the reaction was terminated with acetonitrile or other organic solvent containing an internal standard. After centrifugation, the resulting supernatant was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0241] Experimental methods:

[0242] 1. Preparation of buffer

[0243] Dissolve 73.21 g of potassium phosphate dibasic trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH of the solution to 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide, for a final concentration of 100 mM.

[0244] 2. Preparation of working solution

[0245] The test sample powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.

[0246] The control compounds testosterone, diclofenac, and propafenone were prepared as 10 mM stock solutions in DMSO and then further diluted in appropriate organic solvents.

[0247] 3. Preparation of Liver Microsome Solution

[0248] Dilute each microsome to a 2x working solution using 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system is 0.5 mg / mL.

[0249] 4. Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system

[0250] Weigh an appropriate amount of nicotinamide adenine dinucleotide phosphate (NADP) and isocitrate (ISO) powder, dissolve in magnesium chloride solution, and vortex to mix thoroughly. Add an appropriate amount of isocitrate dehydrogenase (IDH) and gently invert the solution to mix thoroughly. The final concentrations in the reaction system are: 1 mM NADP, 1 mM magnesium chloride, 6 mM ISO, and 1 unit / mL IDH.

[0251] 5. Preparation of Stop Solution

[0252] The stop solution is prepared with acetonitrile or other organic solvent containing an internal standard (tolbutamide or other suitable compound). The prepared stop solution is stored in a refrigerator at 2-8°C.

[0253] 6. Incubation Process

[0254] Incubations will be performed in 96-well plates. Prepare eight incubation plates, designated T0, T5, T15, T30, T45, T60, Blank60, and NCF60. The first six plates correspond to reaction time points of 0, 5, 15, 30, 45, and 60 minutes, respectively. In the Blank60 plate, no test or control compound is added, and a sample is taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer is used instead of the NADPH regeneration system solution and incubated for 60 minutes. All conditions are replicated in triplicate.

[0255] Mix the microsomes with the test article or control compound, then preincubate the Blank60, T5, T15, T30, T45, and T60 plates (excluding T0 and NCF60) in a 37°C waterbath for approximately 10 minutes. Add the stop solution to the T0 plate, followed by the NADPH regeneration system working solution. In the NCF60 plate, 98 μL of potassium phosphate buffer was added to each well to initiate the reaction. After the preincubation period, 98 μL of the NADPH regeneration system working solution was added to each well of the Blank60, T5, T15, T30, T45, and T60 plates to initiate the reaction. The reaction temperature was 37 ± 1°C, and the final reaction volume was 200 μL. The reaction system contained 0.5 mg / mL microsomes, 1.0 μM substrate, 1 mM NADP, 6 mM ISO, and 1 unit / mL IDH.

[0256] The reaction was terminated by adding cold stop solution containing internal standard to the reaction plate at 5, 15, 30, 45 and 60 minutes, respectively.

[0257] All reaction plates were shaken and centrifuged at 3220 × g for 20 minutes at 4°C. The supernatant was diluted to a certain ratio and then analyzed by LC-MS / MS.

[0258] Sample analysis

[0259] Sample analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS / MS) without a standard curve or quality control samples. Semiquantitative determination was performed using the ratio of the analyte peak area to the internal standard peak area. Analyst software (Sciex, Framingham, Massachusetts, USA) was used for analyte and internal standard retention times, chromatogram acquisition, and chromatogram integration.

[0260] The CV of the internal standard peak area in each matrix should be within 20% for each analytical run.

[0261] Data Analysis

[0262] The in vitro elimination rate constant ke of the compound was obtained by converting the ratio of the compound to the internal standard peak area into a residual rate using the following formula:

[0263] CL int(mic) =0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation mg / mL)

[0264] CL int(liver) =CL int(mic) × amount of microsomal protein in the liver (mg / g) × liver weight to body weight ratio

[0265] According to the well stir model, the hepatic intrinsic clearance and hepatic clearance can be converted using the following formula.

[0266] CL (liver) =(CL int(liver) *Q h ) / (CL int(liver) +Q h )

[0267] The parameters in the formula are shown in the table below.

[0268] Parameters in data analysis formulas

[0269] Experimental Example 3 Hepatocyte Metabolic Stability Test

[0270] This experiment was used to test the metabolic stability of compounds in hepatocytes.

[0271] Prepare 0.5 x 10 6 / mL of hepatocyte suspension, then 198μL of preheated cell suspension was added to a 96-well plate. 2μL of the test compound was added to each well of the 96-well plate to a final concentration of 1μM, and 2 replicates were set. For samples at T=0 minutes, the compound and cells were thoroughly mixed for 1 minute, and then 25μL of sample was immediately added to 125μL of stop solution (containing 200ng / mL tolbutamide and 200ng / mL labetalol in acetonitrile) in an ice bath and mixed. At the same time, all plates were placed in an incubator at 37°C and 5% CO2, with the shaker set to 600rpm. The samples were mixed at 15, 30, 60, and 90 minutes of incubation, and 25μL of sample was added to 125μL of stop solution (containing 200ng / mL tolbutamide and 200ng / mL labetalol in acetonitrile) in an ice bath, and shaken at 500rpm for 10 minutes after mixing. The plates were then centrifuged at 3220 × g for 20 minutes at 4°C. After centrifugation, 80 μL of supernatant was transferred from each well to another 96-well plate containing 240 μL of ultrapure water. The intrinsic clearance (CLint) and half-life (T1 / 2) were then calculated using LC-MS / MS.

[0272] Experimental Example 4 Pharmacokinetic Test in Rats

[0273] In this experiment, the pharmacokinetic behavior of the test compound was investigated in SD rats after intravenous (IV) and oral (PO) administration.

[0274] On the day of administration, the actual body weight of the rats was weighed and the administration volume was calculated. There were 3 rats in each group, and two groups of tests were performed for each compound, one group was administered with a single intravenous injection, and the other group was administered with a single oral gavage. Whole blood samples were collected at the specified time (0.25, 0.5, 1, 2, 4, 8, 24h after administration) by blood sampling from the jugular vein. After blood sample collection, it was immediately transferred to a labeled commercial sample tube containing K2-EDTA (0.85-1.15mg), followed by centrifugation (3200x g, 4°C, 10 minutes) and plasma was collected. The plasma was transferred to a pre-cooled centrifuge tube, quick-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or lower until LC-MS / MS analysis.

[0275] Plasma concentrations were determined using LC-MS / MS. Plasma concentration data were analyzed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software using a non-compartmental model. Pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0276] Experimental Example 5 Pharmacokinetic Test in Mice

[0277] In this experiment, the pharmacokinetic behavior of the test compound was investigated in BALB / c mice after intravenous (IV) and oral (PO) administration.

[0278] On the day of administration, the actual body weight of the mice was weighed and the administration volume was calculated. There were 9 mice in each group, and two groups of tests were performed for each compound, one group was administered with a single intravenous injection, and the other group of mice was administered with a single oral gavage. Whole blood samples were collected at the specified time (0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration) by orbital bleeding. After blood sample collection, it was immediately transferred to a labeled commercial sample tube containing K2-EDTA (0.85-1.15 mg), followed by centrifugation (3200x g, 4°C, 10 minutes) and plasma was collected. The plasma was transferred to a pre-cooled centrifuge tube, quickly frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or lower until LC-MS / MS analysis.

[0279] Plasma concentrations were determined using LC-MS / MS. Plasma concentration data were analyzed using WinNonlin Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software using a non-compartmental model. Pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0280] Experimental Example 6 hERG inhibition test

[0281] HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and 5% CO2. TM After express digestion, centrifugation was performed and the cell density was adjusted to 2 × 10 6 cells / mL, then gently mix the cells on a room temperature balanced shaker for 15-20 minutes, and perform patch clamp detection on the machine. The culture medium of the prepared cells was replaced with extracellular fluid. The intracellular and extracellular fluids were aspirated from the liquid pool and added to the intracellular fluid pool, cell and test substance pool of the QPlate chip respectively. The whole-cell patch clamp records the voltage stimulation of the whole-cell hERG potassium current, and the experimental data is collected and stored by Qpatch. The compound started at 30μM, diluted 3 times, and 6 concentration points were set. Each drug concentration was set to be administered twice for at least 5 minutes. The current detected in the external fluid without the compound for each cell was used as its own control group, and at least two cells were used for each concentration to repeat the test twice independently. All electrophysiological experiments were performed at room temperature.

[0282] Data analysis: First, the current after each drug concentration is normalized with the blank control current. Then calculate the inhibition rate corresponding to each drug concentration Calculate the mean and standard error for each concentration and calculate the half-inhibitory concentration for each compound: The above equation was used to perform nonlinear fitting of the dose-dependent effect, where Y represents the inhibition rate, C represents the concentration of the test substance, and IC 50 is the half-inhibitory concentration, and HillSlope represents the Hill coefficient. Curve fitting and IC 50 The calculations were completed using Graphpad software.

[0283] Experimental Example 7 Cytochrome oxidase P450 inhibition test

[0284] 1) Preparation of buffer solution:

[0285] 100mM K-Buffer: Mix 9.5mL of stock solution A with 40.5mL of stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer to pH 7.4 with KOH or H3PO4.

[0286] Raw material A (1M potassium dihydrogen phosphate): 136.5 g potassium dihydrogen phosphate in 1 L water;

[0287] Stock B (1M KH2PO4): 174.2 g KH2PO4 in 1 L water.

[0288] 2) Preparation of test substance

[0289] The test substance powder is prepared into a stock solution of a certain concentration using DMSO or other organic solvents, and then further diluted with a suitable organic solvent.

[0290] 3) In vitro incubation

[0291] The in vitro incubation system of liver microsomes for CYP450 enzyme metabolic phenotype studies is a biochemical reaction carried out under conditions simulating physiological temperature and physiological environment, with the prepared liver microsomes supplemented with redox coenzymes and enzyme-specific selective inhibitors.

[0292] 4) Detection of parent drug or metabolites

[0293] The concentration of parent drug or its metabolites in the incubation solution was determined by LC-MS / MS.

[0294] Experimental Example 8 Mouse Tumor Pharmacodynamic Model

[0295] In this experimental example, the in vivo efficacy of the test compound was evaluated in a mouse xenograft tumor model after oral administration (PO).

[0296] Human colon adenocarcinoma cell line SW48 was cultured in a monolayer in vitro using DMEM medium containing 10% fetal bovine serum, 1% penicillin, and streptomycin at 37°C and 5% CO2. The cells were passaged twice a week using trypsin. When the cell saturation reached 80%-90%, the cells were harvested, counted, and inoculated. 0.1 mL (10 7 SW48 cells were subcutaneously inoculated on the right back of each mouse. On the 14th day after cell inoculation, the average tumor volume reached 200 mm 3 Around 20 days, mice were randomly divided into groups and given drugs by gavage once daily. Changes in body weight and tumor volume were recorded. After a certain number of days of drug administration, the experiment was terminated. Changes in tumor volume and mouse body weight were statistically analyzed.

[0297] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein the compound has the structure of formula (I): in: Selected from W is CR 1 or N; R 1 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b , -C 1-6 Alkylene-R a , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b ,(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 Haloalkyl; Alternatively, two R 1 Together with the group to which it is attached, it optionally forms C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring; R 2 for R 3 , R 21 , R 22 , R 23 and R 24 Each occurrence is independently selected from H, halogen, -OH, -NH2, -CN, -NO2, -SF5, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R a 、-OC(=O)R a 、-C(=O)OR a 、-OR a 、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR a R b 、-S(=O)(=NR a )R b 、-NR a R b 、-C(=O)NR a R b 、-NR a -C(=O)R b 、-NR a -C(=O)OR b 、-NR a -S(=O)2-R b 、-NR a -C(=O)-NR a R b 、-P(=O)R a R b , -C 1-6 Alkylene-R a , -C 1-6 Alkylene-OR a , -C 1-6 Alkylene-NR a R b 、-OC 1-6 Alkylene-NR a R b ,(-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 Haloalkyl; Or, R 3 With R 21 or R 22 Together with the group to which it is attached, it optionally forms C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring; R 4 for R 41 Selected from C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings; Ring X and ring Z are each independently selected from C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings; Ring Y is absent or selected from C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring and 5-14 membered heteroaromatic ring; when ring Y is absent, R 24 Nor does it exist; L 2 Selected from -O-, -C(=O)-, -NRC(=O)-, -S-, -S(=O)-, -S(=O)2-, C 1-6 Alkylene and -O-(C 1-6 Alkylene)-; R, R a and R b Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl; The above alkylene, alkyl, alkenyl, alkynyl, cycloalkylene, cycloalkyl, hydrocarbon ring, heterocyclic group, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl are each optionally substituted with one or more substituents independently selected from the following: deuterium atoms, halogen, -OH, =O, -NH2, -CN, -NO2, =CH2, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R c 、-OC(=O)R c 、-C(=O)OR c 、-OR c 、-SR c 、-S(=O)R c 、-S(=O)2R c 、-S(=O)2NR c R d 、-NR c R d 、-C(=O)NR c R d 、-NR c -C(=O)R d 、-NR c -C(=O)OR d 、-NR c -S(=O)2-R d 、-NR c -C(=O)-NR c R d , -C 1-6 Alkylene-OR c , -C 1-6 Alkylene-NR c R d and-OC 1-6 Alkylene-NR c R d When the same ring atom or adjacent ring atoms of a cycloalkylene group, a cycloalkyl group, a hydrocarbon ring, a heterocyclyl group, a heterocycle, an aryl group, an aromatic ring, a heteroaryl group, and a heteroaromatic ring are substituted by two substituents, the two substituents together with the group to which they are attached optionally constitute a C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 aromatic ring or 5-14 membered heteroaromatic ring; the alkylene, alkyl, alkenyl, =CH2, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclic radical, heterocyclic ring, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl are each further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, -OC 1-6 Alkyl and -C 1-6 Alkylene-OC 1-6 alkyl; R c and R d Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH2, -CN, -NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6- 12 Aralkyl and -C 1-6 Alkylene-OC 1-6 Alkyl; and p, q and t are each independently an integer selected from 1, 2 or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the structure of the following formula: in: Ring C and Ring D are each independently C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 The hydrocarbon ring, heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: deuterium atom, halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 Alkyl, when the same ring atom or adjacent ring atoms of the hydrocarbon ring, heterocyclic ring, aromatic ring and heteroaromatic ring are substituted by two substituents, the two substituents together with the groups to which they are attached optionally constitute a C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 Aromatic ring or 5-14 membered heteroaromatic ring; Preferably, ring C is A benzene ring or a pyridine ring, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 Alkyl; and / or Ring D is a cyclopentene ring, a cyclohexene ring, a pyrrolidine ring, a piperidine ring or a morpholine ring, each of which is optionally substituted by one or more substituents independently selected from the following: a deuterium atom, a halogen, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 When the same ring atom or adjacent ring atoms of ring D are substituted by two substituents, the two substituents together with the groups to which they are attached optionally constitute C 3-6 A hydrocarbon ring or a 3-10 membered heterocyclic ring; The remaining groups are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein: R 1 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, -OR a and-NR a R b , preferably, R 1 is independently selected at each occurrence from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OR a wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 2-6 Alkenyl, =CH2, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-14 membered heteroaryl; each of the alkyl, alkenyl, =CH2, cycloalkyl, heterocyclyl, aryl and heteroaryl is further optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic group and -C 1-6 Alkylene-C 3-6 Cycloalkyl; Preferably, R 1 is H, methyl, halogen, methoxy, Alternatively, two R 1 Together with the group to which it is attached, it optionally forms C 3-6 Hydrocarbon ring, 3-10 membered heterocyclic ring, C 6-10 The hydrocarbon ring, heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl; Preferably, the two R 1 Together with the groups to which they are attached, they optionally constitute A benzene ring or a pyridine ring, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

4. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Ring X is a benzene ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring (preferably a thiophene ring, a thiazole ring or a pyridine ring), and Ring Y does not exist; or Ring X is a benzene ring or a 5-6 membered heteroaromatic ring, and Ring Y is C 3-6 A hydrocarbon ring, a 5-6 membered heterocyclic ring or a 5-6 membered heteroaromatic ring; Preferably, for More preferably 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein R 21 , R 22 , R 23 and R 24 Each occurrence is independently selected from H, halogen, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic, -O-(C 1-6 alkyl), -S(=O)2-(C 1-6 alkyl), -S(=O)2-(C 3-6 Cycloalkyl), -P(=O)(C 1-6 Alkyl)2, (-C 3-6 Cycloalkylene)-CN and (-C 3-6 Cycloalkylene)-C 1-6 alkyl, wherein the alkyl, cycloalkylene, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl; Preferably, R 21 , R 22 , R 23 and R 24 Each occurrence is independently selected from H, halogen, -SF5, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclic and -O-(C 1-6 alkyl), wherein the alkyl, cycloalkyl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein Selected from:

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 3 H, C 1-6 Alkyl, -OR a or -SR a Preferably, R 3 is H, ethyl, -O-CH3 or -S-CH3; Or, R 3 With R 21 or R 22 Together with the group to which it is attached, it optionally forms C 3-6 A hydrocarbon ring or a 3-10 membered heterocyclic ring, wherein the hydrocarbon ring and the heterocyclic ring are optionally substituted by one or more selected from deuterium atoms, halogens, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 When the same ring atom or adjacent ring atoms of the hydrocarbon ring and the heterocyclic ring are substituted by two substituents, the two substituents together with the groups to which they are connected optionally constitute a C 3-6 A hydrocarbon ring or a 3-10 membered heterocyclic ring; Preferably, R 3 With R 21 or R 22 Together with the groups to which they are connected, they optionally constitute a cyclopentene ring, a cyclohexene ring, a pyrrolidine ring, a piperidine ring or a morpholine ring, wherein the cyclopentene ring, the cyclohexene ring, the pyrrolidine ring, the piperidine ring and the morpholine ring are optionally substituted by one or more deuterium atoms, halogens, -OH, C 1-6 Alkyl, halogenated C 1-6 Alkyl and -OC 1-6 When the same ring atom of the cyclopentene ring, cyclohexene ring, pyrrolidine ring, piperidine ring and morpholine ring is substituted by two substituents, the two substituents together with the group to which they are attached optionally constitute a C 3-6 Hydrocarbon ring.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein ring Z is a 3-10 membered heterocycle or a benzene ring; preferably a 5-10 membered heterocycle; more preferably a 5-6 membered heterocycle; and The heterocyclic ring and the benzene ring are each optionally substituted at each occurrence by one or more substituents independently selected from the following: halogen, C 1-6 Alkyl and halogenated C 1-6 alkyl; Preferably, ring Z is 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein L 2 is -C(=O)- or -NRC(=O)-, wherein R is H or C 1-6 alkyl; Preferably, L 2 It is -C(=O)-.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 41 Selected from 3-10 membered heterocyclic ring, C 6-10 aromatic ring and 5-14 membered heteroaromatic ring, wherein the heterocyclic ring, aromatic ring and heteroaromatic ring are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, C 1-6 Alkyl, -OC 1-6 Alkyl and -SC 1-6 Alkyl, preferably, the heterocyclic ring, aromatic ring and heteroaromatic ring are at least -OH or -OC 1-6 Alkyl substitution; Preferably, -L 2 -R 41 for 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound, or prodrug thereof, wherein R 41 is a 5-6 membered heteroaromatic ring, preferably a 6 membered heteroaromatic ring, more preferably a pyridine ring or a pyrimidine ring, which is substituted by at least one -OH; Preferably, -L 2 -R 41 for 12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester, stereoisomer, atropisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound is selected from:

13. A pharmaceutical composition comprising a preventively or therapeutically effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, or a pharmaceutical composition according to claim 13 in the preparation of a medicament for use as a WRN inhibitor, preferably, the medicament is used to prevent or treat cancer (preferably, the cancer is characterized by microsatellite high instability (MSI-H) or mismatch repair deficiency (dMMR)); preferably, the cancer is selected from colorectal cancer, gastric cancer, endometrial cancer, uterine cancer, adrenocortical carcinoma, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer and ovarian cancer.

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