Targeted Pol theta vinyl sulfonyl substituted compound and application thereof

Abstract

The invention provides a vinyl sulfonyl substituted compound targeting Pol [theta] and application of the vinyl sulfonyl substituted compound. Specifically, the invention provides a compound as shown in a formula I, and a stereoisomer, an isotope labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or eutectic thereof. The compounds are useful in the treatment or prevention of Pol [theta] mediated diseases or conditions.

Description

TECHNICAL FIELD The present application belongs to the field of medicine, and particularly relates to a vinylsulfonyl-substituted compound targeting Pol theta and application thereof. BACKGROUND

[0001] DNA polymerase theta (Pol theta) is one of the 16 DNA polymerases in the human genome, encoded by the POLQ gene, and is the core enzyme in the Polymerase theta-mediated end joining (TMEJ) repair pathway. Most double-strand breaks are repaired by non-homologous end joining (NHEJ) or homologous recombination repair (HDR). However, in some cases, NHEJ and HR are not sufficient, and TMEJ is the only solution to repair the break. TMEJ is usually described as an alternative NHEJ, but the difference is that it does not require Ku heterodimer, and it can only act on the sheared DNA end. After the short region of the DNA overhang (i.e. a few nucleotides) anneals, Pol theta bridges the break end by template-dependent DNA synthesis, stabilizing the mate structure (Mateos-Gomez PA, et al., Nature 2015, 518(7538): 254-7; Ceccaldi R., et al., Nature 2015, 518(7538): 258-62.). Pol theta is essentially not expressed in normal cells, but is up-regulated in breast cancer, lung cancer and ovarian cancer. In addition, the increase of Pol theta expression is associated with poor prognosis of breast cancer. Studies have shown that cancer cells lacking HR, NHEJ or ATM are highly dependent on Pol theta expression. Therefore, Pol theta has become a popular target in drug research.

[0002] Proteolysis-targeting chimera (PROTAC) technology is a new therapeutic model that uses the natural protein degradation mechanism of cells (ubiquitin-proteasome system) to selectively target and eliminate these proteins related to the pathogenesis of diseases. In recent years, due to its unique mechanism of action and broad application prospects, it has occupied an important position in the field of new drug research and development, and has provided a new direction for new drug discovery. Compared with traditional small molecule inhibitors, proteolysis-targeting chimera has many advantages. Proteolysis-targeting chimera can target proteins that are difficult for traditional small molecule inhibitors to bind, including 'undruggable' targets that have no active site or have a difficult-to-access active site. Proteolysis-targeting chimera works through a catalytic mechanism, and once the degradation of the target protein is induced, its effect can continue even if the drug concentration decreases. Its catalytic properties can theoretically achieve therapeutic effects at lower doses, which may help reduce drug side effects and improve safety. Proteolysis-targeting chimera can provide a wider therapeutic window because they do not need to continuously occupy the target protein, but achieve therapeutic effects by inducing its degradation. Because the effect of proteolysis-targeting chimera is to eliminate the entire protein, not just inhibit its activity, it can reduce the problem of drug resistance caused by mutations or overexpression of target proteins. For targets that act as structural proteins in the disease process, proteolysis-targeting chimera can disrupt their structure and function by degrading these proteins, while traditional small molecule inhibitors often have difficulty achieving this.

[0003] In summary, Polθ is essential for cells with homologous recombination deficiency, and the development of Polθ-targeting drugs can provide a new strategy for the treatment of homologous recombination deficiency cancer. Currently, there are a variety of Polθ inhibitors, such as WO2020243459, WO2022118210, WO2023050007, WO2023134739, WO2023060573, WO2023134708, WO2024099337 and WO2024088407; and Polθ protein degraders, such as WO2024149349. In recent years, some progress has been made in the study of Polθ inhibitors, and ART-6043, ART-4215 and GSK-101 are currently in clinical research. SUMMARY

[0004] The present application provides a Polθ-targeting compound having a structure as shown in Formula I and Formula II (including Formula IIa and IIb), stereoisomers, isotopically labeled, solvates, hydrates, and pharmaceutically acceptable salts or co-crystals thereof.

[0005] The present application also provides a pharmaceutical composition comprising an effective amount of a compound of Formula I and Formula II (including Formula IIa and IIb), stereoisomers, isotopically labeled, solvates, hydrates, and pharmaceutically acceptable salts or co-crystals thereof, for treating cancer.

[0006] In one specific embodiment, the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents for the treatment of cancer.

[0007] In one specific embodiment, the pharmaceutical composition may also contain at least one known anticancer drug or a pharmaceutically acceptable salt of said anticancer drug for the treatment of cancer.

[0008] This invention also relates to methods for preparing novel compounds of structural formulas I and II (including formulas IIa and IIb). Detailed Implementation

[0009] It should be understood that the features of the various embodiments described herein can be combined arbitrarily to form the technical solutions described herein; the definitions of each group herein apply to any embodiment described herein, for example, the definitions of alkyl substituents herein apply to any embodiment described herein, unless the alkyl substituents have been clearly defined in the embodiment.

[0010] The term "hydrogen (H)" as used in this article includes its isotopes deuterium (D) and tritium (T).

[0011] The heteroatoms mentioned in this article include oxygen (O), sulfur (S), and nitrogen (N).

[0012] As used herein, "alkyl" refers to a saturated, straight-chain or branched hydrocarbon group containing 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Useful alkyl groups include straight-chain or branched C4 groups. 1-10 Alkyl, preferably C 1-6 Alkyl group. In some embodiments, the alkyl group is C10. 1-4 Alkyl group. Typical C 1-10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl, and octyl, which can be optionally substituted.

[0013] As used herein, "alkylene" refers to a divalent group similar to an alkyl group. Specifically, alkylenes are those having 1, 2, 3, or 4 carbon atoms (C1-C4 alkylenes). Examples of alkylenes include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc.

[0014] The term "alkoxy" as used in this article refers to the alkoxy group that is oxidized by the aforementioned C. 1-10 Alkyl, preferably C 1-6 Alkyl or C 1-4 Alkyl-substituted oxygen groups, such as methoxy, ethoxy, etc. The alkyl group in the alkoxy group may optionally be substituted. Substituents in the alkoxy group include, but are not limited to, halogens, amino groups, and carboxyl groups (including their ester groups), wherein the amino group includes alkylamino and dialkylamino groups.

[0015] As used herein, "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 carbon atoms, either as a single group or as part of another group. An aryl group may be substituted by one or more of the substituents described herein.

[0016] Useful aryl groups include C 6-14 Aryl, preferably C 6-10 Aryl. Typical C 6-14 Aryl groups include phenyl, naphthyl, phenanthryl, anthraceneyl, indyl, azulel, biphenyl, biphenylene, and fumonisinyl.

[0017] Useful halogens or halogen groups include fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0018] As used herein, "heteroaryl" refers to a group containing 5–14, preferably 5–10, ring atoms, and having 6, 10, or 14 π electrons shared in the ring system. The ring atoms in a heteroaryl group are carbon atoms and 1–3 heteroatoms selected from oxygen, nitrogen, and sulfur. A heteroaryl group may be substituted with one or more of the substituents described herein.

[0019] Useful heteroaryl groups include thienyl (phenylthio), benzo[d]isothiazo-3-yl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthyl, furanyl, pyranyl, isobenzofuranyl, chromenyl, oxanthiinyl, phenoxanthiinyl, pyrroleyl, imidazolyl, pyrazolyl, pyridyl (including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indazinyl, isoindolyl, 3H-indolyl, indolyl, indazoleyl, purine, 4H-quinazinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthodinyl, quinazolinyl, terpineyl, pteridinyl, carbazolyl, β-carbazolyl, phenanthridine, acridineyl, and naphthalene-intercalated dicarboxylic acid. Azophenyl, phenanthroline, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazinyl, phenothiazinyl, tetrahydropyridinylpyrimidinyl, tetrahydropentamembered[c]pyrazol-3-yl, benzoisoxazolyl such as 1,2-benzisoxazol-3-yl, benzimidazolyl, 2-hydroxyindolyl, thiadiazoyl, 2-oxobenzimidazolyl, imidazopyridinyl, imidazopyridinyl, triazolpyridinyl, tetrahydropyridinylpyrimidinyl, pyrazolpyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, triazololopyridinyl, thienoquinolinyl, furanoquinolinyl, thiazonoquinolinyl, thiazonopyridinyl, thiazonopyridinyl, pyrazololoquinolinyl, pyrroloquinolinyl, imidazonoquinolinyl, oxazololoquinolinyl, etc. When a heteroaryl group contains a nitrogen atom in the ring, such nitrogen atom can be in the form of an N-oxide, such as pyridyl N-oxide, pyrazinyl N-oxide, and pyrimidinyl N-oxide.

[0020] As used herein, "heterocyclic group" refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic group composed of a carbon atom and 1-4 heteroatoms selected from O, N, and S. The total number of ring atoms in the heterocyclic group can be 3-14, for example, 3-7 membered monocyclic groups, 7-10 membered bicyclic groups, or 11-14 membered tricyclic groups. The heterocyclic group can be a helical ring group or a fused ring group, such as a 7-10 membered helical ring group or a fused ring group. In some embodiments, the heteroatoms nitrogen and sulfur in the heterocyclic group can be arbitrarily oxidized, and the nitrogen can be arbitrarily quaternized. The heterocyclic group also includes fused heterocycles formed by the fusion of any heterocycle defined above with a benzene ring in the aforementioned bicyclic system. If the resulting compound is stable, the carbon or nitrogen atom of the heterocycle can be substituted. The heterocyclic group can be substituted by one or more substituents as described herein.

[0021] The term "divalent heterocyclic group" as used in this article refers to a divalent group formed by the loss of an additional hydrogen atom from the ring of the heterocyclic group described in this article.

[0022] In this article, "fused cyclic group" refers to a group containing two or more rings that are interconnected by sharing two or more atoms. In this article, fused cyclic groups include "bridged cyclic groups" or "bridged ring groups." A "bridged cyclic group" or "bridged ring group" refers to a fused cyclic group formed by the connection of three or more atoms.

[0023] Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, aziridine, oxacyclobutyl, pyrrolyl, imidazoalkyl, imidazolinyl, dihydroindolyl, isodihydroindolyl, quininecycloyl, morpholinyl, isochromyl, chromanyl, pyrazolyl, pyrazolyl, tetrahydroisoquinolinyl, dihydropyrrolopyrazolyl, tetronoyl, and tetramoyl, which may be substituted by one or more of the substituents described herein.

[0024] The term "carbocyclic group" as used in this article includes cycloalkyl groups and partially saturated carbocyclic groups. Useful cycloalkyl groups are C16-C ... 3-8 cycloalkyl groups, such as C 3-6 cycloalkyl or C 3-4 Cycloalkyl groups. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C... 3-8 Cycloalkenyl, C 3-6 Cycloalkenyl or C 3-4 Cycloalkenyl groups, such as cyclopentenyl, cycloheptenyl, and cyclooctenyl. The carbocyclic group may be substituted by one or more substituents as described herein.

[0025] In this document, unless otherwise stated, when substituted, each of the alkyl, alkoxy, aryl, heterocyclic, or heteroaryl groups described in any embodiment herein may be substituted by one or more (e.g., 1, 2, 3, or 4) substituents selected from the following groups as defined herein: halogen, C 1-6 Alkoxy, C 1-6 Alkyl, C 6-10 Aryl, C 3-8 Cycloalkyl, heteroaryl, and heterocyclic groups, etc. The substituent itself may also be optionally substituted. More preferably, the substituents include, but are not limited to, halogens, C... 1-6 Alkoxy and C 1-6 alkyl.

[0026] It should be understood that in the various embodiments described herein, when the substituent is a heterocyclic group, aryl group, or heteroaryl group, the number of such heterocyclic group, aryl group, or heteroaryl group as a substituent is usually one.

[0027] Specifically, the present invention provides compounds of Formula I, their stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or cocrystals: in: A is either N or CR3; B1 and B2 are each independently CR4, N, or NR5; Cycle Q is a 5-10 member heteroaryl group with optional substitution; L is the bond, and C is optional. 1-4 Alkylene, optionally substituted -OC 1-4 Alkylene-, optionally substituted -C 1-4 alkylene carbonyl-, optionally substituted -C 1-4 Alkylene-NR5-, optionally substituted -C 1-4 Alkylene -O-, -C≡C-, or -NR5-; The ring W can be a substituted 4-12 heterocyclic group, a substituted aryl group, a substituted 5-10 heteroaryl group, or a substituted 4-12 carbocyclic group. Z is a 4-12 membered heterocyclic group that is bonded, -NR5-, or optionally substituted; R1 and R2 are each independently H, deuterium, halogen, hydroxyl, cyano, optionally substituted amino, or optionally substituted C. 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optional substituted C 3-6 cycloalkyl, optionally substituted C 2-4 alkenyl or optionally substituted C 2-4 alkynyl group; R3 is H, halogen, or optionally substituted C. 1-4 alkyl; R4 is C with H, =O, or optional substitution. 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-4 alkenyl or optionally substituted C 2-4 alkynyl group; R5 is H, with optional substitution of C. 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkyl-C 1-4 Alkylene, optionally substituted 6-14 aryl, optionally substituted 6-14 aryl-C 1-4 Alkylene, optionally substituted 5-10-membered heteroaryl, optionally substituted 5-10-membered heteroaryl-C 1-4 Alkylene, optionally substituted 4-10 membered heterocyclic group or optionally substituted 4-10 membered heterocyclic group -C 1-4 Alkylene; m can be 1, 2, 3, or 4; n is 1 or 2.

[0028] In one or more embodiments of the compound of formula I, A is N or CH.

[0029] In one or more embodiments of the compound of formula I, the heteroaryl group is preferably a 5-10 member nitrogen-containing heteroaryl group, including but not limited to pyridinyl, pyrazinyl, pyrroloyl, oxadiazolyl, thiazopyrazinyl, thiazopyridinyl, tetrahydrothiazopyridinyl, and thiadiazolyl. The heterocyclic group is preferably a 5-10 member nitrogen-containing heterocyclic group, including but not limited to pyrroloalkyl, piperazinyl, and piperidinyl.

[0030] In one or more embodiments of the compound of formula I, each R1 may independently be H, deuterium, halogen, hydroxyl, cyano, or optionally substituted C. 1-4 Alkyl, optionally substituted C 1-4 Alkoxy, optional substituted C 3-6 cycloalkyl or optionally substituted C 2-4 Alkyne group.

[0031] In one or more embodiments of the compound of formula I, the aryl or heteroaryl group containing A may optionally be substituted with 1, 2, 3, and 4 R1 groups, each R1 being independently a halogen, hydroxyl, cyano, C... 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl or C 2-4Alkyne group. In one or more embodiments, the aryl or heteroaryl group containing A is substituted by 1, 2, or 3 R1 groups; more preferably, the aryl or heteroaryl group containing A is substituted by 2 R1 groups, each R1 group being independently a halogen, cyano, or C group. 1-2 Alkyl, Halogenated C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy or ethynyl. In some embodiments, the aryl or heteroaryl group containing A is at least surrounded by one carbon atom. 1-4 Alkoxy, preferably C 1-2 The alkoxy group is substituted, and optionally further substituted with a halogen such as fluorine or chlorine. In some embodiments, the aryl or heteroaryl group containing A is substituted with a C. 1-4 Alkoxy, preferably C 1-2 The alkoxy group and one halogen, preferably fluorine or chlorine, are substituted.

[0032] In one or more embodiments of the compound of formula I, R4 is H, =O, or optionally substituted C. 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with one, two, three, or four substituents selected from halogens and hydroxyl groups. In some embodiments, R4 is H, =O, or C. 1-4 alkyl.

[0033] In one or more embodiments of the compound of formula I, R5 is H, optionally substituted C. 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl-C 1-4 Alkylene, optionally substituted 6-14 aryl-C 1-4 Alkylene, optionally substituted 5-10 aryl-C 1-4 Alkylene or optionally substituted 4-10 membered heterocyclic -C 1-4 Alkylene. The optionally substituted C 1-4 The alkyl group may optionally be substituted with 1, 2, 3, or 4 halogens. The optionally substituted C... 3-6 cycloalkyl-C 1-4 Alkylene, optionally substituted 6-14 aryl-C 1-4 Alkylene, optionally substituted 5-10 aryl-C 1-4 Alkylenes and optionally substituted 4-10 membered heterocyclic groups -C 1-4 Each alkylene group may optionally be surrounded by 1, 2, 3, or 4 atoms selected from halogens and C. 1-4 Alkyl substituent substitution. In some embodiments, R5 is an optionally substituted 5-10 membered heteroaryl-C. 1-4 Alkylene.

[0034] In one or more embodiments of the compound of formula I, B1 is CR4, B2 is N, and R4 is H or optionally substituted C.1-4 Alkyl group, preferably methyl. In one or more embodiments, B1 is N, B2 is CR4, wherein R4 is H or optionally substituted C. 1-4 Alkyl group, preferably H. In one or more embodiments, B1 is NR5 and B2 is C=O, wherein R5 is H or optionally substituted 5-10 heteroaryl-C. 1-2 Alkylene.

[0035] In one or more embodiments of the compound of formula I, R2 is H, halogen, or C. 1-4 Alkyl group. In some embodiments, R2 is H.

[0036] In one or more embodiments of the compound of formula I, ring Q is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 9- or 10-membered benzo[a]bicyclic heteroaryl, preferably a nitrogen-containing heteroaryl, preferably containing at least two cyclic nitrogen atoms. In one or more embodiments, ring Q is an optionally substituted 5-membered heteroaryl or an optionally substituted 5- or 6-membered heteroaryl. In one or more embodiments, when ring Q is substituted, it may be selected from 1, 2, or 3 atoms chosen from halogens, hydroxyl groups, or C. 1-4 Alkyl substituents. In one or more preferred embodiments, ring Q is a divalent thiazopyrazine group, thiazopyridine group, thiadiazole group, or tetrahydrothiazopyridine group. In some embodiments, ring Q is selected from the following groups: Where *1 and *2 represent the positions where ring Q is connected to -NH- and L in the compound structure, respectively.

[0037] In one or more embodiments of the compound of formula I, L is a bond, optionally substituted C. 1-2 Alkylene, optionally substituted -OC 1-2 Alkylene-, optionally substituted -C 1-2 alkylene carbonyl-, optionally substituted -C 1-2 Alkylene-NR5-, optionally substituted -C 1-2 Alkylene -O-, -C≡C-, or -NR5-, where R5 is H or C. 1-3 Alkyl group, preferably H. In one or more embodiments, L is C that is optionally halogenated. 1-2 Alkylene, optionally halogenated -OC 1-2 Alkylene-, optional halogen-substituted -C 1-2 alkylene carbonyl group -, optionally halogenated -C 1-2 Alkylene-O-, or optionally halogenated -C 1-2 The alkylene group is -NR5- or -C≡C-, and the number of halogen atoms can be 1, 2, 3, or 4. In one or more preferred embodiments, L is selected from the bond, -NH-, and the following groups: Where *3 and *4 represent the positions where L connects to ring Q and ring W in the compound structure, respectively.

[0038] In one or more embodiments of the compound of formula I, ring W is an optionally substituted 5-12 heterocyclic group, an optionally substituted aryl group, an optionally substituted 5-6 membered carbocyclic group, or an optionally substituted 5-6 membered N-containing heteroaryl group; preferably, ring W is a 6-membered N-containing heterocyclic group, an optionally substituted phenyl group, or an optionally substituted pyridyl group. Preferably, the 5-12 membered heterocyclic group is a nitrogen-containing heterocyclic group; preferably, the 5-12 membered heterocyclic group is a 5-6 membered heterocyclic group, more preferably a 5-6 membered nitrogen-containing heterocyclic group, including but not limited to pyrrolidinyl, piperidinyl, and piperazineyl groups. Preferably, the nitrogen-containing heteroaryl group is pyrrolidinyl, pyridinyl, or pyrazineyl. Preferably, the 5-6 membered carbocyclic group is a cycloalkenyl group. Preferably, when substituted, ring W may optionally be replaced by 1, 2, 3, or 4 groups selected from halogens and C. 1-4 Alkyl substituents. More preferably, the ring W is selected from the following groups: *4 and *5 represent the positions where ring W connects to L and Z in the compound structure, respectively.

[0039] In one or more embodiments of the compound of formula I, Z is a bond, -NH-, or an optionally substituted 4-12-membered heterocyclic group, preferably a nitrogen-containing heterocyclic group. Preferably, Z is a bond, -NH-, or a 5- or 6-membered N-containing heterocyclic group, such as pyrrolidinyl, piperazine, or piperidinyl. In one or more embodiments, Z is a bond, -NH-, or a group containing the following: *5 and *6 represent the positions where Z connects to the ring W and the vinyl sulfonyl group in the compound structure, respectively.

[0040] One group of preferred compounds of Formula I of the present invention are represented by compounds of Formula II (including Formulas IIa and IIb) or their stereoisomers, isotopically labeled compounds, solvates, hydrates or pharmaceutically acceptable salts or eutectics: Wherein, A, B1, B2, L, ring W, R1 and m are defined as in Equation I; Y is either CR6 or N; E1, E2 and E3 are each independently CR7 or N; R6 is H, halogen, hydroxyl, cyano, or an optionally substituted C. 1-4 Alkyl or optionally substituted C 1-4 Alkoxy; R7 is H, halogen, or optionally substituted C. 1-4 alkyl.

[0041] In one or more embodiments of the compounds of formula IIa and IIb, A is N or C.

[0042] In one or more embodiments of the compounds of formulas IIa and IIb, the aryl or heteroaryl group containing A may optionally be substituted with 1, 2, 3, and 4 R1 groups, each R1 being independently a halogen, hydroxyl, cyano, C... 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 3-6 cycloalkyl or C 2-4 Alkyne group. In one or more embodiments, the aryl or heteroaryl group containing A is substituted by 1, 2, or 3 R1 groups; more preferably, the aryl or heteroaryl group containing A is substituted by 2 R1 groups, each R1 group being independently a halogen, cyano, or C group. 1-2 Alkyl, Halogenated C 1-2 Alkyl, C 1-2 Alkoxy, halogenated C 1-2 Alkoxy or ethynyl. In some embodiments, the aryl or heteroaryl group containing A is at least surrounded by one carbon atom. 1-4 Alkoxy, preferably C 1-2 The alkoxy group is substituted, and optionally further substituted with a halogen such as fluorine or chlorine. In some embodiments, the aryl or heteroaryl group containing A is substituted with a C. 1-4 Alkoxy, preferably C 1-2 The alkoxy group and one halogen, preferably fluorine or chlorine, are substituted.

[0043] In one or more embodiments of the compounds of formulas IIa and IIb, R4 is H, =O, or optionally substituted C. 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with one, two, three, or four substituents selected from halogens and hydroxyl groups. In some embodiments, R4 is H, =O, or C. 1-4 alkyl.

[0044] In one or more embodiments of the compounds of formulas IIa and IIb, R5 is H, optionally substituted C. 1-4 Alkyl, optionally substituted C 3-6 cycloalkyl-C 1-4 Alkylene, optionally substituted 6-14 aryl-C 1-4 Alkylene, optionally substituted 5-10 aryl-C 1-4 Alkylene or optionally substituted 4-10 membered heterocyclic -C 1-4 Alkylene. The optionally substituted C 1-4 The alkyl group may optionally be substituted with 1, 2, 3, or 4 halogens. The optionally substituted C... 3-6 cycloalkyl-C 1-4Alkylene, optionally substituted 6-14 aryl-C 1-4 Alkylene, optionally substituted 5-10 aryl-C 1-4 Alkylenes and optionally substituted 4-10 membered heterocyclic groups -C 1-4 Each alkylene group may optionally be surrounded by 1, 2, 3, or 4 atoms selected from halogens and C. 1-4 Alkyl substituent substitution. In some embodiments, R5 is an optionally substituted 5-10 membered heteroaryl-C. 1-4 Alkylene.

[0045] In one or more embodiments of the compounds of formula IIa and IIb, B1 is CR4, B2 is N, wherein R4 is H or optionally substituted C. 1-4 Alkyl group, preferably methyl. In one or more embodiments, B1 is N, B2 is CR4, wherein R4 is H or optionally substituted C. 1-4 Alkyl group, preferably H. In one or more embodiments, B1 is NR5 and B2 is C=O, wherein R5 is H or optionally substituted 5-10 heteroaryl-C. 1-2 Alkylene.

[0046] In one or more embodiments of the compounds of formula IIa and IIb, L is a bond, optionally substituted C. 1-2 Alkylene, optionally substituted -OC 1-2 Alkylene-, optionally substituted -C 1-2 alkylene carbonyl-, optionally substituted -C 1-2 Alkylene-NR5-, optionally substituted -C 1-2 Alkylene -O-, -C≡C-, or -NR5-, where R5 is H or C. 1-3 Alkyl group, preferably H. In one or more embodiments, L is C that is optionally halogenated. 1-2 Alkylene, optionally halogenated -OC 1-2 Alkylene-, optional halogen-substituted -C 1-2 alkylene carbonyl group -, optionally halogenated -C 1-2 Alkylene-O-, or optionally halogenated -C 1-2 The alkylene group is -NR5- or -C≡C-, and the number of halogen atoms can be 1, 2, 3, or 4. In one or more preferred embodiments, L is selected from the bond, -NH-, and the following groups: Where *3 and *4 represent the positions where L connects to ring Q and ring W in the compound structure, respectively.

[0047] In one or more embodiments of the compound of formula IIb, E1 and E2 are both N, and E3 is CR7, wherein R7 is H or a halogen. In one or more embodiments, E1 is N, and E2 and E3 are both CR7, wherein R7 is H or a halogen.

[0048] In one or more embodiments of compounds of formula IIa and IIb, L is a bond, alkane, -O-alkane-; preferably from:

[0049] In one or more embodiments of the compounds of formulas IIa and IIb, ring W is an optionally substituted 5-12 heterocyclic group, an optionally substituted aryl group, an optionally substituted 5-6 membered carbocyclic group, or an optionally substituted 5-6 membered N-containing heteroaryl group; preferably, ring W is a 6-membered N-containing heterocyclic group, an optionally substituted phenyl group, or an optionally substituted pyridyl group. Preferably, the 5-12 membered heterocyclic group is a nitrogen-containing heterocyclic group; preferably, the 5-12 membered heterocyclic group is a 5-6 membered heterocyclic group, more preferably a 5-6 membered nitrogen-containing heterocyclic group, including but not limited to pyrrolidinyl, piperidinyl, and piperazine groups. Preferably, the nitrogen-containing heteroaryl group is pyrrolidinyl, pyridinyl, or pyrazine group. Preferably, the 5-6 membered carbocyclic group is a cycloalkenyl group. Preferably, when substituted, ring W may optionally be replaced by 1, 2, 3, or 4 groups selected from halogens and C. 1-4 Alkyl substituents. More preferably, the ring W is selected from the following groups: *4 and *5 represent the positions where ring W connects to L and Z in the compound structure, respectively.

[0050] In one or more embodiments of the compounds of formulas IIa and IIb, Y is CH2 or N.

[0051] It should be understood that the structural formulas and functional groups defined in this paper satisfy the bond valence theory.

[0052] In the formulas I and II (including formulas IIa and IIb) and various structural formulas of the present invention, when the alkyl, alkoxy, alkenyl, and alkynyl groups defined in each group are substituted, the substituents may be independently selected from amino, hydroxy, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and halogen, etc., and the number of substituents may be independently 1, 2, 3, 4, or 5. For example, the substituted alkyl group may be aralkyl, heteroarylalkyl, and haloalkyl, etc. It should be understood that when the substituent is aryl, heteroaryl, or heterocyclic, the number of substituents is usually 1; when the substituent is, for example, a halogen, the number of substituents may be up to 5 halogen groups depending on the carbon chain length of the alkyl, alkoxy, alkenyl, and alkynyl groups; exemplary such substituents include trifluoromethyl and pentafluoroethyl, etc. The aryl, heteroaryl, and heterocyclic groups and their substituents that are substituents of alkyl, alkoxy, alkenyl, or alkynyl groups may be as described in any embodiment herein. The optionally substituted amino group may optionally be replaced by one or two amino groups selected from C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl and Halogenated C 1-4 Substitution of alkoxy groups.

[0053] In the formulas I and II (including formulas IIa and IIb) and various structural formulas of this invention, when the cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in the group definition are substituted, the number of substituents can be independently 1, 2, 3, 4, or 5, and each substituent can be independently selected from halogens, hydroxyl groups, C... 1-6 Alkoxy, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, optionally substituted C 6-10 aryl, optionally substituted C 3-8 Cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclic groups, preferably selected from halogens, C 1-6 Alkoxy and C 1-6 Alkyl group. The C... 1-6 Alkoxy and C 1-6 Each alkyl group may also optionally be substituted with 1, 2, 3, 4, or 5 substituents selected from aryl, heteroaryl, and halogen groups. The C 6-10 Aryl, C 3-8 The cycloalkyl, heteroaryl, and heterocyclic groups may each optionally be represented by 1, 2, 3, 4, or 5 groups selected from halogens, C, and D. 1-6 Alkoxy and C 1-6 Alkyl substituents.

[0054] Preferred compound examples of Formula I include, but are not limited to: Or its stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or eutectics.

[0055] Examples of medicinal salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate, and oxalate; as well as inorganic and organic base salts formed with bases such as sodium hydroxyl, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucosamine.

[0056] The compounds of this invention can be prepared using methods known to those skilled in the art or novel methods of this invention. Specifically, the compounds of this invention having Formula I can be synthesized using a method similar to that shown in the reaction example of reaction scheme 1 below. 4-Bromo-6-methylnicotinic acid methyl ester and (5-chloro-2-methoxyphenyl)boronic acid react under alkaline conditions (e.g., K₂CO₃) and a palladium catalyst (e.g., Pd(dppf)Cl₂) to give 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid methyl ester. 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid methyl ester is hydrolyzed under alkaline conditions (e.g., NaOH) to give 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid. 4-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester and 5-bromo-1,3,4-thiadiazol-2-amine react under basic conditions (such as DIEA) to give 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester. 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid and 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester condense to give 4-(((5-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester. 4-(((5-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester was debocized under acidic conditions to give 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(piperidin-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide. 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(piperidin-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide and 2-chloroethane-1-sulfonyl chloride were reacted under alkaline conditions (such as TEA) to give the target compound 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide. Reaction Scheme 1

[0057] Other related compounds can be prepared using similar methods. For example, replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-methoxyphenyl)boronic acid yields the target compound 4-(2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazole-2-yl)nicotinamide. Replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-fluoro-6-methoxyphenyl)boronic acid yields the target compound 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazole-2-yl)nicotinamide. Replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-methoxy-5-methylphenyl)boronic acid yields the target compound 4-(2-methoxy-5-methylphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide. Replacing (5-chloro-2-methoxyphenyl)boronic acid with (5-fluoro-2-methoxyphenyl)boronic acid yields the target compound 4-(5-fluoro-2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide.

[0058] An important aspect of this invention is the discovery that compounds of formulas I and II (including formulas IIa and IIb) are compounds that target Polθ. Therefore, compounds of formulas I and II (including formulas IIa and IIb) or their tautomers, hydrates, solvates, isotopically labeled compounds, pharmaceutically acceptable salts, or mixtures thereof can be used to treat or prevent Polθ-mediated diseases or conditions, or to prepare medicaments for treating or preventing Polθ-mediated diseases or conditions. In this document, Polθ-mediated diseases or conditions refer to diseases or conditions in which Polθ is involved in their occurrence and / or development, including but not limited to tumors or cancers such as liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (such as small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, and chronic... Myeloid leukemia, primary brain cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumors, thyroid cancer, esophageal cancer, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer.

[0059] Therefore, the present invention provides a method for treating or preventing the Polθ-mediated diseases or conditions described herein, the method comprising administering to a desired subject an effective amount of a compound of formula I and II (including formula IIa and IIb) or its stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or cocrystals thereof, or a pharmaceutical composition containing an effective amount of a compound of formula I and II (including formula IIa and IIb) or its stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or cocrystals thereof, or mixtures thereof. In this invention, the subject includes mammals, such as humans.

[0060] In implementing the treatment methods of the present invention, an effective amount of a pharmaceutical preparation is administered to a patient with one or more of these symptoms. The pharmaceutical preparation contains an effective therapeutic concentration of compounds of formulas I and II (including formulas IIa and IIb), formulated for oral, intravenous, topical, or external administration to treat or prevent the Polθ-mediated diseases or conditions described herein. The dosage is the amount of medicine that effectively improves or eliminates one or more symptoms. For the treatment of a specific disease, an effective amount is sufficient to improve or alleviate, in some way, the symptoms associated with the disease. Such a dosage may be administered as a single dose or may be administered according to an effective treatment regimen. The dosage may cure the disease, but administration is generally intended to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired symptom improvement.

[0061] In another embodiment, this document provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula I and II (including formula IIa and IIb) as described in any embodiment herein, or a stereoisomer thereof, an isotopically labeled compound, a solvate, a hydrate, or a pharmaceutically acceptable salt or eutectic thereof.

[0062] Another embodiment of the present invention relates to a pharmaceutical composition capable of effectively treating or preventing Pol-mediated diseases or conditions described herein, comprising a compound of formula I and II (including formula IIa and IIb) as described in any embodiment herein, or a stereoisomer thereof, isotopically labeled compound, solvate, hydrate, or a pharmaceutically acceptable salt or eutectic thereof, with at least one known anticancer drug or a pharmaceutically acceptable salt of an anticancer drug. In this article, at least one known anticancer drug includes: (1) anticancer drugs related to DNA damage and repair mechanisms, including but not limited to HDAC inhibitors vorinostat, romidesin, pabistat, and belistat; (2) PARP inhibitors, including but not limited to olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, senaparib, and saraparib; (3) anticancer drugs related to cell division checkpoints, including but not limited to Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, WEE1 inhibitors, ATM inhibitors, and ATR inhibitors; (4) alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mitomycin C, bleomycin, and carboplatin; (5) topoisomerase I inhibitors, such as camptothecin, irinotecan, and topotecan; and topoisomerase II inhibitors, such as doxorubicin, epirubicin, and aclavatin. (6) RNA / DNA antimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil, and methotrexate; (7) DNA antimetabolites, such as 5-fluoro-2′-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; (8) antimitotics, such as colchicine, vincristine, vinorelbine, paclitaxel, ixaspirin, cabazitaxel, and docetaxel; 9) Antibodies, such as monoclonal antibodies, panitumumab, nezotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, oxantuzumab, ofamumab, rituximab, alemtuzumab, tiimumab, tosimoumab, bentoximab, daratumumab, erlotuzumab, ofatumumab, dinutuximab, blinatumomab, iprimumab, avastin, Herceptin, and rituximab;(10) Antibody-drug conjugates (ADCs), such as trastuzumab-metazine conjugate T-DM1, humanized anti-HER2 antibody-drug conjugates trastuzumab deruxtecan and trastuzumab emtansine, humanized anti-TROP2 monoclonal antibody-drug conjugates datopotamab deruxtecan and gemtuzumab ozogamicin, CD30-guided antibody-drug conjugates brrentuximab vedotin, innotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, and Belantamab. Mafodotin; (11) kinase inhibitors, such as imatinib, gefitinib, erlotinib, ostinib, afatinib, celitinib, alectinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralitinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, carbitinib, axitinib, tesimolimus, edalisib. Pazopanib, terazosin, and everolimus; and (12) other known anticancer drugs that may be used in combination therapy for cancer, including tamoxifen, letrozole, fulvestrant, mitoxantrone, octreotide, retinoid, arsenic, zoledronic acid, bortezomib, carfilzomib, vemodega, sinedega, denosumab, thalidomide, lenalidomide, venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipueucel-T (prostate cancer treatment vaccine).

[0063] In carrying out the method of the present invention, the compound of the present invention may be administered together with at least one known anticancer drug as a single pharmaceutical composition. Alternatively, the compound of the present invention may be administered separately from at least one known anticancer drug. In one embodiment, the compound of the present invention and at least one known anticancer drug are administered approximately simultaneously, i.e., all drugs are administered simultaneously or sequentially, as long as the compound simultaneously reaches therapeutic concentrations in the blood. In another embodiment, the compound of the present invention and at least one known anticancer drug are administered according to their respective dosage regimens, as long as the compound reaches therapeutic concentrations in the blood.

[0064] Another embodiment of the invention is a biocoupler, consisting of the said compound, that effectively inhibits tumors as a kinase inhibitor. This tumor-inhibiting biocoupler comprises the said compound with at least one known therapeutically active antibody, such as Herceptin or Rituxan, or a growth factor, such as EGF or FGF, or a cytokine, such as interleukin-2 or 4, or any molecule capable of binding to the cell surface. The antibody, along with other molecules, can deliver the compound to its target site, making it an effective anticancer drug. This biocoupler can also enhance the anticancer effects of therapeutically active antibodies, such as Herceptin or Rituxan.

[0065] Another embodiment of the invention relates to a pharmaceutical composition that can effectively treat or prevent Polθ-mediated diseases or conditions described herein, comprising compounds of formulas I and II (including formulas IIa and IIb) that target Polθ, their stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or cocrystals thereof, in combination with radiotherapy. In this embodiment, the compound of the invention and radiotherapy may be administered at the same time or at different times.

[0066] Another embodiment of the invention relates to a pharmaceutical composition effective for postoperative treatment of cancer, comprising compounds of formulas I and II (including formulas IIa and IIb) that target Polθ, their stereoisomers, isotopically labeled compounds, solvates, hydrates, or pharmaceutically acceptable salts or cocrystals thereof. The invention also relates to a treatment method involving surgical removal of a tumor followed by treatment of the cancer in that mammal with the pharmaceutical composition of the invention.

[0067] The pharmaceutical compositions of the present invention comprise pharmaceutical formulations in which the contents of all the compounds of the present invention effectively achieve their intended objectives. Although individual needs vary, those skilled in the art can determine the optimal dosage of each component of the pharmaceutical formulation. Generally, the compounds, or their available salicies, are administered orally to mammals daily at a dosage of about 0.0025 to 50 mg / kg body weight. However, it is preferable to administer orally at a dosage of about 0.01 to 10 mg / kg. If a known anticancer drug is also administered, its dosage should effectively achieve its intended purpose. The optimal dosages of these known anticancer drugs are well known to those skilled in the art.

[0068] A single oral dose may comprise about 0.01 to 50 mg, preferably about 0.1 to 10 mg, of the compound of the present invention. A single dose may be administered once or multiple times daily as one or more tablets, each tablet containing about 0.1 to 50 mg, preferably about 0.25 to 10 mg, of the compound of the present invention or a solvate thereof.

[0069] In topical formulations, the concentration of the compounds of the present invention can be from about 0.01 to 100 mg per gram of carrier.

[0070] The compounds of the present invention can be administered as unprocessed pharmaceutical products. They can also be administered as part of a suitable pharmaceutical formulation containing a pharmaceutically acceptable carrier (including excipients and adjuvants). These pharmaceutically acceptable carriers facilitate the processing of the compounds into pharmaceutically acceptable formulations. Preferred pharmaceutical formulations, particularly those for oral administration and preferred routes of administration such as tablets, lozenges, and capsules, as well as solutions suitable for injection or oral administration, contain about 0.01% to 99%, preferably from about 0.25% to 75%, of the active compound and excipients.

[0071] The scope of this invention also includes non-toxic, pharmaceutically acceptable salts of the compounds of this invention. Acid addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable acid with a solution of the compound of this invention. Examples of the acids include hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, etc. Base addition salts are formed by mixing a solution of a non-toxic, pharmaceutically acceptable base with a solution of the compound of this invention. Examples of the bases include sodium hydroxide, potassium hydroxide, hydrocholine, sodium carbonate, tris(hydroxymethyl)aminomethane, N-methylglucosamine, etc.

[0072] The pharmaceutical formulations of this invention can be administered to any mammal, provided they achieve the therapeutic effects of the compounds of this invention. Humans and veterinary animals are most important among these mammals, although this invention is not intended to be so limited.

[0073] The pharmaceutical formulation of this invention can be administered via any route to achieve its intended purpose. For example, it can be administered via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial, nasal, or topical routes. Alternatively or concurrently, it can be administered orally. The dosage of the drug will be determined based on the patient's age, health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.

[0074] The pharmaceutical formulations of the present invention can be manufactured using known methods. For example, they can be manufactured by conventional mixing, granulation, tableting, dissolving, or freeze-drying processes. When manufacturing oral formulations, solid excipients and active compounds can be combined, and the mixture can be selectively ground. If desired or necessary, appropriate excipients can be added, and the granular mixture can be processed to obtain tablets or tablet cores.

[0075] Suitable excipients, especially fillers, include sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes including corn starch, wheat starch, rice starch, potato starch, gelatin, astragalus gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone. If desired, disintegrants, such as the starches mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate, may be added. Adjuvants, especially flow conditioners and lubricants, include silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. If desired, a suitable coating that resists gastric juices can be provided to the tablet core. For this purpose, a concentrated sugar solution can be applied. This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. To prepare a gastric juice-resistant coating, a suitable cellulose solution, such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, can be used. Dyes or pigments may be added to the coating of the tablet or tablet core, for example, for identification or to characterize the dosage of the active ingredient.

[0076] Other orally edible pharmaceutical formulations include compressible capsules made of gelatin, and sealed soft capsules made of gelatin and plasticizers such as glycerin or sorbitol. The compressible capsule may contain an active compound in particulate form, mixed with fillers such as lactose; binders such as starch; and / or lubricants such as talc or magnesium stearate, and stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid such as oils or liquid paraffin, in which stabilizers may be added.

[0077] Suitable formulations for parenteral administration include aqueous solutions of the active compound, such as solutions of water-soluble salts and alkaline solutions. Additionally, oily injectable suspensions of the appropriate active compound can be administered. Suitable lipophilic solvents or carriers include oils such as sesame oils, synthetic fatty acid esters such as ethyl oleate or triglycerides or polyethylene glycol 400, or hydrogenated castor oil, or cyclodextrin. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran. Suspension stabilizers may also be included.

[0078] According to one aspect of the invention, the compounds of the invention are formulated for external and parenteral use and are used to treat skin cancer.

[0079] The topical formulations of this invention can be formulated into oils, creams, emulsions, ointments, etc., using a preferred suitable carrier. Suitable carriers include plant or mineral oils, white mineral oil (white paraffin), branched-chain fatty acids or oils, animal fats, and high molecular weight alcohols (greater than C10). 12Preferred carriers are those in which the active ingredient can dissolve. Emulsifiers, stabilizers, moisturizers, and antioxidants may also be included, as well as agents that impart color or fragrance if desired. Furthermore, these topical formulations may contain transdermal penetration enhancers. Examples of such enhancers can be found in U.S. Patent Nos. 3,989,816 and 4,444,762.

[0080] Creams are preferably formulated with a mixture of mineral oil, self-emulsifying beeswax, and water, mixed with an active ingredient dissolved in a small amount of oil, such as almond oil. A typical example of a cream includes approximately 40 parts water, 20 parts beeswax, 40 parts mineral oil, and 1 part almond oil.

[0081] Ointments can be formulated by mixing a plant oil containing active ingredients, such as almond oil, with warm paraffin wax, and then allowing the mixture to cool. A typical example of an ointment consists of approximately 30% by weight almond oil and 70% by weight white paraffin wax.

[0082] This invention also relates to the preparation of medicaments for treating Polθ-mediated clinical conditions using the compounds of this invention. These medicaments may include the pharmaceutical compositions described above.

[0083] The following examples are illustrative and not intended to limit the methods and formulations of the present invention. Other appropriate modifications and improvements to various conditions and parameters that will be apparent to those skilled in the art and that are commonly encountered in clinical treatment are all within the spirit and scope of the present invention. Example General instructions All reagents used were commercially available, and solvents were dried and purified according to standard methods. Mass spectrometry samples were analyzed using a single quadrupole mass spectrometer (Shimadzu 2020) with electrospray ionization. Recordings were performed using a Varian 400MHz NMR spectrometer. 1 1H NMR spectra, chemical shifts were recorded in ppm starting from the low field with TMS as the internal standard (0.00 ppm), and coupling constant J values ​​were in Hz. Example 1 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl) Niacinamide a) Preparation of methyl 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinate: methyl 4-bromo-6-methylnicotinate (200 mg, 0.87 mmol, 1.0 eq) and (5-chloro-2-methoxyphenyl)boronic acid (186 mg, 1.0 mmol, 1.15 eq) were placed in a mixture of dioxane / water (4 mL / 0.5 mL) under N2 conditions. K2CO3 (240 mg, 1.74 mmol, 2.0 eq) and Pd(dppf)Cl2 (32 mg, 0.044 mmol, 0.05 eq) were added. The reaction mixture was stirred overnight at 80 °C. Water (5 mL) was added to the mixture, and the mixture was extracted with EtOAc (5 mL × 5). The organic layers were combined, washed with saturated brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA = 1 / 0 to 1 / 1, to give the target product (213 mg, 84% yield, yellow solid). MS (ESI): m / z 291.95 [M+H] + . b) Preparation of 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid: Methyl 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid (210 mg, 0.72 mmol, 1.0 eq) was placed in a methanol / water mixture (2 mL / 2 mL), and NaOH (87 mg, 2.16 mmol, 3.0 eq) was added. The reaction mixture was stirred at 50 °C for 3 hours. MeOH was removed under reduced pressure. Water (5 mL) was added, and the pH was adjusted to 4–5 with 2 M hydrochloric acid solution. The precipitate was collected and filtered to obtain a white solid. The solid was dried under reduced pressure to give the target product (198 mg, 99% yield, white solid). MS (ESI): m / z 277.90 [M+H] + 275.90 [MH] - . c) Preparation of tert-butyl 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylate: 4-(hydroxymethyl)piperidin-1-carboxylate tert-butyl ester (2.0 g, 9.3 mmol, 1.0 eq) and 5-bromo-1,3,4-thiadiazol-2-amine (2.5 g, 13.9 mmol, 1.5 eq) were placed in anhydrous DMF (20 mL) under N2 protection at room temperature, and DIEA (3.6 g, 27.9 mmol, 3.0 eq) was added. The reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was analyzed by preparative HPLC (C60- ... 18 ACN was purified in H2O (0-40%, 0.1% FA) to obtain the target product (200 mg, 6.9% yield, yellow solid). d) Preparation of tert-butyl 4-(((5-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylic acid: 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid (362 mg, 1.3 mmol, 1.0 eq) and tert-butyl 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylic acid (410 mg, 1.3 mmol, 1.0 eq) were placed in anhydrous DMF (4 mL) under nitrogen protection at room temperature, and HATU (593 mg, 0.11 mmol, 1.2 eq) and DIEA (1.17 g, 9.1 mmol, 7.0 eq) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was analyzed by preparative HPLC (C600-C50). 18 ACN was directly purified in H₂O (5-60%, 0.1% FA) to obtain the target product (600 mg, 80%, yellow solid). MS (ESI): m / z 574.00 [M+H] + 571.85 [MH] - . e) Preparation of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(piperidin-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide: A solution of ethyl hydrogen chloride (1 M, 10 mL) was added to 4-(((5-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide)-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester (600 mg, 1.05 mmol, 1.0 eq) at room temperature and under N2 protection. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was analyzed by preparative HPLC (C10). 18 ACN was directly purified in H₂O (5-55%, 0.1% FA) to give the target product (221 mg, 45% yield, colorless solid). MS (ESI): m / z 474.10 [M+H] + 472.05 [MH] - . f) Preparation of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide: 221 mg, 0.47 mmol, 1.0 eq) of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(piperidin-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)nicotinamide and triethylamine (94 mg, 0.94 mmol, 2.0 eq) were placed in DCM (5 mL) and cooled to 0 °C. A solution of 2-chloroethane-1-sulfonyl chloride (77 mg, 0.47 mmol, 1.0 eq) in DCM (3 mL) was added dropwise under N2. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was analyzed by preparative HPLC (C60-C5 ... 18 ACN was directly purified in H₂O (5-60%, 0.1% FA) to give the target compound (9.1 mg, 3%, white solid). MS (ESI): m / z 563.85 [M+H] + . 1 H NMR (DMSO-d6): δ8.71(s,1H),7.41(dd,J=8.8,2.7Hz,1H),7.36(d,J=2.7Hz,1H),7.29(s, 1H),6.99(d,J=8.9Hz,1H),6.79(dd,J=16.5,10.0Hz,1H),6.14(d,J=10.1Hz,1H),6.10(d, J=16.5Hz,1H),4.27(d,J=6.5Hz,2H),3.55(d,J=11.6Hz,2H),3.50(s,3H),2.68–2.59(m, 2H), 2.55 (s, 3H), 1.99-1.86 (m, 1H), 1.81 (d, J = 13.6Hz, 2H), 1.32 (qd, J = 12.4, 4.2Hz, 2H). The compounds 2-13 in the following examples can be prepared using a synthetic method similar to that in Example 1. The compounds are as follows: Example 14 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(5-(5-(vinylsulfonyl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl) Niacinamide a) Preparation of 5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazole-2-amine: DIEA (8.2 g, 63.9 mmol) was added to a mixture of (5-bromopyridin-2-yl)methanol (4.0 g, 21.3 mmol) and 5-bromo-1,3,4-thiadiazole-2-amine (3.8 g, 21.3 mmol) in anhydrous DMF (50 mL) at room temperature and under N2 protection. The resulting reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give a yellow solid product (550 mg, yield 9%). MS (ESI): m / z 286.95 [M+H] + . b) Preparation of 2-((6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)thio)ethanol: Under N2 protection, xantphos (46 mg, 0.08 mg) was added to a mixture of 5-((5-bromopyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (470 mg, 1.6 mmol) and 2-mercaptoethanol (128 mg, 1.6 mmol) in dioxane (10 mL). 3.2 mmol), DIEA (413 mg, 3.2 mmol), and Pd2(dba)3 (73 mg, 0.08 mmol). The resulting reaction mixture was stirred overnight at 110 °C, and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 5). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid product (225 mg, yield 50%). MS (ESI): m / z 284.95 [M+H] + . c) Preparation of 4-(5-chloro-2-methoxyphenyl)-N-(5-((5-(((2-hydroxyethyl)thio)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide: HATU (456 mg, 1.2 mmol) and DIEA (722 mg, 5.6 mmol) were added to a dry DMF mixture of 2-((6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)thio)ethanol (225 mg, 0.8 mmol) and 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid (266 mg, 0.9 mmol) (5 mL) under N2 protection at room temperature. The resulting reaction mixture was stirred overnight at room temperature and purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a yellow solid product (250 mg, yield 57%). MS(ESI):m / z 544.00 [M+H] + 542.00 [MH] - . d) Preparation of 4-(5-chloro-2-methoxyphenyl)-N-(5-((5-(((2-hydroxyethyl)sulfonyl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide: 250 mg (0.5 mmol) of 4-(5-chloro-2-methoxyphenyl)-N-(5-((5-(((2-hydroxyethyl)thio)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide was dissolved in 5 mL of dry dichloromethane and cooled to 0 °C. Under nitrogen protection, a solution of 172 mg (1.0 mmol) of m-chloroperoxybenzoic acid in 3 mL of dichloromethane was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. The product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to give a white solid product (140 mg, yield 49%). MS (ESI): m / z 576.05 [M+H] + 574.00 [MH] - . e) Preparation of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-((5-(vinylsulfonyl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide: 100 mg (0.2 mmol) of 4-(5-chloro-2-methoxyphenyl)-N-(5-((5-(((2-hydroxyethyl)sulfonyl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide was dissolved in dry tetrahydrofuran (5 mL) and cooled to 0 °C. Under N2 protection, a mixture of methanesulfonyl chloride (62 mg, 0.3 mmol) and triethylamine (61 mg, 0.6 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at 0 °C for 2 hours. The product was purified by preparative high-performance liquid chromatography (formic acid, 0.1%, 0%–60%) to give a white solid product (5.2 mg, yield 5%). MS (ESI): m / z 558.00 [M+H] + 555.95 [MH] - . 1H NMR (400MHz, DMSO-d6): δ12.78(s,1H),9.00(d,J=2.3Hz,1H),8.67(s,1H),8.30 (dd,J=8.3,2.4Hz,1H),7.78(d,J=8.3Hz,1H),7.45–7.40(m,1H),7.39(d,J=2.6 Hz,1H),7.34(s,1H),7.21(dd,J=16.5,9.9Hz,1H),6.99(d,J=8.7Hz,1H),6.42( d,J=16.5Hz,1H),6.29(d,J=9.8Hz,1H),5.65(s,2H),3.47(s,3H),2.55(s,3H). Example 15 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(5-(5-(vinylsulfonamido)pyridin-2-yl)methoxy)-1,3,4-thiadiazole-2- Nicotinamide A synthetic method similar to that in Example 1 can be used, but 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(5-(5-(5-(vinylsulfonamido)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide can be prepared by replacing 4-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl sulfonamide with N-(6-(hydroxymethyl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide. MW 573.04. Example 16 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(5-(1-(vinylsulfonyl)piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide A synthetic method similar to that of Example 17 can be used, replacing 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid with 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid to prepare 4-(2-fluoro-6-methoxyphenyl)-6-methyl-N-(5-(5-(1-(vinylsulfonyl)piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide. MW 624.71. Example 17 2'-Chloro-5'-methoxy-6-methyl-N-(5-(5-(1-(vinylsulfonyl)piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide a) Preparation of 6-(hydroxymethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate: Under N2 protection, (5-bromopyridin-2-yl)methanol (2.0 g, 10.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate (3.95 g, 12 mmol) were reacted. In a 20 mL / 20 mL mixture of dried N,N-dimethylformamide (DMF) / dried tetrahydrofuran (THF), cesium carbonate (Cs₂CO₃, 6.91 g, 21.2 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (Pd(dppf)Cl₂·CH₂Cl₂, 850.1 mg, 1.06 mmol) were added. The resulting reaction mixture was stirred overnight at 80 °C, and water (5 mL) was added. The mixture was extracted with ethyl acetate (EtOAc, 20 mL × 5). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether (PE) / ethyl acetate (EA) as the eluent (gradient: 1 / 0→1 / 1→0 / 1) to give a green oily product (1.95 g, yield 63%). MS (ESI): m / z 291.10 [M+H] + . b) Preparation of tert-butyl 4-(6-(hydroxymethyl)pyridin-3-yl)piperidine-1-carboxylate: Under a nitrogen and hydrogen atmosphere, 10% palladium on carbon (Pd / C, 390 mg, 10% wt) was added to a methanol (MeOH, 20 mL) solution of 1.95 g, 6.7 mmol of 6-(hydroxymethyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate. The reaction mixture was refluxed overnight at 70 °C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient: (50 / 1→30 / 1→20 / 1) yielded a yellow oily product (1.49 g, 76% yield). MS (ESI): m / z 293.20 [M+H] + . c) Preparation of tert-butyl 4-(6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)piperidine-1-carboxylic acid: Under N2 and nitrogen protection, N,N-diisopropylethylamine (DIEA, 1.97 g, 15.3 mmol) was added to a dry DMF (20 mL) mixture of tert-butyl 4-(6-(hydroxymethyl)pyridin-3-yl)piperidine-1-carboxylic acid (1.49 g, 5.1 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (1.38 g, 7.65 mmol). The resulting reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) with water / acetonitrile (0%–60%) as the mobile phase to give a yellow solid product (346 mg, yield 17%). MS (ESI): m / z 392.15 [M+H] + 390.00 [MH] - . d) Preparation of tert-butyl 4-(6-(((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)piperidine-1-carboxylic acid: At room temperature and under N2 protection, 200.0 mg of tert-butyl 4-(6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester was prepared. To a dry DMF (4 mL) mixture of 0.51 mmol of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (213.4 mg, 0.765 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 232.6 mg, 0.612 mmol) and DIEA (460.5 mg, 3.57 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the solution was removed under reduced pressure. DMF. The residue was purified by preparative thin-layer chromatography with DCM / MeOH as the developing solvent of 10:1, yielding a white solid product (214 mg, yield 64%). MS (ESI): m / z 652.10 [M+H] + 650.05 [MH] - . e) Preparation of 2'-chloro-5'-methoxy-6-methyl-N-(5-((5-(piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: At room temperature and under nitrogen protection, 1 mol / L hydrochloric acid / ethyl acetate solution (HCl / EA, 12 mL) was added to 214.0 mg (0.33 mmol) of 4-(6-(((5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-yl)piperidin-1-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give a white solid product (179 mg, 99% yield). MS(ESI): m / z 552.10 [M+H] + 550.05 [MH] - . f) Preparation of 2'-chloro-5'-methoxy-6-methyl-N-(5-((5-(1-(vinylsulfonyl)piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide: Under N2 protection, 2'-chloro-5'-methoxy-6-methyl-N-(5-((5-(piperidin-4-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide (30 mg, 0.054 mmol) was dissolved in dichloromethane (DCM, 3 mL), cooled to 0 °C, and triethylamine (TEA, 11 mg, 0.108 mmol) was added. Under nitrogen protection and at 0°C, a solution of vinyl sulfonyl chloride (10.3 mg, 0.081 mmol) in DCM (3 mL) was slowly added dropwise, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was purified by Prep-HPLC with a mobile phase containing 0.1% formic acid (HCOOH) in a gradient of 0%–60%, yielding a white solid product (0.6 mg, yield 1.7%). MS (ESI): m / z 642.10 [M+H] + 640.00 [MH] - . 1H NMR (400MHz, DMSO-d6): δ8.93(s,1H),8.49(d,J=2.2Hz,1H),8.31(s,1H),8.11(s, 1H),7.74(dd,J=8.1,2.3Hz,1H),7.44(d,J=8.1Hz,1H),7.34(s,1H),7.19(s,1H), 6.85(dd,J=16.5,10.0Hz,1H),6.20–6.10(m,2H),5.40(s,2H),3.62(s,3H),2.77– 2.65(m,4H),2.52(s,3H),2.02-1.97(m,1H),1.90-1.83(m,2H),1.76-1.65(m,2H). Example 18 2'-Chloro-5'-methoxy-6-methyl-N-(5-(5-(4-(vinylsulfonyl)piperazin-1-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that of Example 17 can be used, by replacing 4-(6-(hydroxymethyl)pyridin-3-yl)piperazin-1-carboxylate with 4-(6-(hydroxymethyl)pyridin-3-yl)piperazin-1-carboxylate tert-butyl ester, to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(5-(4-(vinylsulfonyl)piperazin-1-yl)pyridin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 643.13. Example 19 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(vinylsulfonyl)piperazin-1-yl)ethyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-chloro-5-methoxypyridin-4-yl)boronic acid and replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)ethyl)piperazin-1-carboxylate with tert-butyl piperazine-1-carboxylate to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-(4-(vinylsulfonyl)piperazin-1-yl)ethyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 564.08. Example 20 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-oxo-2-(4-(vinylsulfonyl)piperazin-1-yl)ethyl)- 1,3,4-Thiadiazol-2-yl)-6-methylnicotinamide A synthetic method similar to that in Example 1 can be used, replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)-2,2-difluoroacetyl)piperazin-1-carboxylate tert-butyl ester with 4-(2-(5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl ester to prepare 4-(3-chloro-2-fluoro-6-methoxyphenyl)-N-(5-(1,1-difluoro-2-oxo-2-(4-(vinylsulfonyl)piperazin-1-yl)ethyl)-1,3,4-thiadiazol-2-yl)-6-methylnicotinamide. MW 631.04. Example 21 4-(2-methoxyphenyl)-N-(5-((4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)amino)methyl)-1,3,4-thiadiazol-2-yl) Niacinamide A synthetic method similar to that in Example 1 can be used, replacing (5-chloro-2-methoxyphenyl)boric acid with (2-methoxyphenyl)boric acid, replacing 4-bromo-6-methylnicotinic acid with methyl 4-bromonicotinic acid, and replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)methyl)amino)phenyl)piperazin-1-carboxylate with tert-butyl)piperidine-1-carboxylate to prepare 4-(2-methoxyphenyl)-N-(5-(((4-(4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)amino)methyl)-1,3,4-thiadiazol-2-yl)nicotinamide. MW 591.71. Example 22 2'-Chloro-5'-methoxy-6-methyl-N-(5-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenoxy)methyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-chloro-5-methoxypyridin-4-yl)boronic acid and replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)methoxy)phenyl)piperidine-1-carboxylate with tert-butyl piperidine-1-carboxylate to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(4-(1-(vinylsulfonyl)piperidine-4-yl)phenoxy)methyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 641.16. Example 23 2'-Chloro-5'-methoxy-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing (5-chloro-2-methoxyphenyl)boronic acid with (2-chloro-5-methoxypyridin-4-yl)boronic acid and replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)ethynyl)piperidine-1-carboxylate with tert-butyl piperidine-1-carboxylate to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(vinylsulfonyl)piperidine-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 559.06. Example 24 3-(2-methoxyphenyl)-N-(5-((4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)ethynyl)-1,3,4-thiadiazol-2-yl)iso Niacinamide A synthetic method similar to that in Example 1 can be used, replacing (5-chloro-2-methoxyphenyl)boric acid with (2-methoxyphenyl)boric acid, replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)ethynyl)phenyl)piperazin-1-carboxylate with 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylate with methyl 4-bromoisonitin instead of methyl 4-bromo-6-methylnicotinic acid, to prepare 3-(2-methoxyphenyl)-N-(5-(((4-(4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)ethynyl)-1,3,4-thiadiazol-2-yl)isonicotinamide. MW 586.69. Example 25 1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-(2-methyl-5-(trifluoromethyl)phenyl)-2-oxo-N-(5-((1-(vinylsulfonyl)piperidin-4-yl)ethynyl)-1,3,4-thiadiazol-2-alkyl)-1,2-dihydropyridine-4-carboxamide A synthesis method similar to that in Example 1 can be used, replacing 4-bromo-6-methylnicotinic acid methyl ester with methyl 5-bromo-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxylate, (2-methyl-5-(trifluoromethyl)phenyl)boronic acid with (5-chloro-2-methoxyphenyl)boronic acid, and 4-((5-amino-1,3,4-thiadiazol-2-yl)ethynyl)piperidine-1-carboxylate with tert-butyl ester. Replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylic acid tert-butyl ester yields 1-(((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-5-(2-methyl-5-(trifluoromethyl)phenyl)-2-oxo-N-(5-(((1-(vinylsulfonyl)piperidin-4-yl)ethynyl)-1,3,4-thiadiazol-2-alkyl)-1,2-dihydropyridine-4-carboxamide. MW 673.69. Example 26 2'-Chloro-5'-methoxy-6-methyl-N-(6-(4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)thiazo[4,5-b]pyrazin-2-yl)- [4,4'-Bipyridine]-3-carboxamide a) Preparation of N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide: Under N2 protection at room temperature, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 196.1 mg, 0.516 mmol) and N,N-diisopropylethylamine (DIEA, 388.3 mg, 3.01 mmol) were added to anhydrous N,N-dimethylformamide (DMF, 4 mL) of anhydrous 6-bromothiazo[4,5-b]pyrazin-2-amine (100.0 mg, 0.43 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (213.4 mg, 0.65 mmol) at anhydrous N,N-dimethylformamide (DMF, 4 mL ... The reaction mixture was stirred overnight at room temperature, and DMF was removed under reduced pressure. The residue was purified by preparative thin-layer chromatography with dichloromethane / methanol as eluent (15:1) to give a yellow solid product (80 mg, 38% yield). MS (ESI): m / z 490.90 [M+H] + 492.85 [M+H] + 488.85 [MH] - 490.85 [MH] - . b) Preparation of 4-(4-(2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazo[4,5-b]pyrazin-6-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester: Under N2 protection, N-(6-bromothiazo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (65 mg, 0.132 mg) was prepared. To a mixture of dioxane / water (12 mL / 3 mL) containing 4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)phenyl)boronic acid (49 mg, 0.159 mmol), sodium carbonate (86 mg, 0.264 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (Pd(dppf)Cl2·CH2Cl2, 11 mg, 0.013 mmol) were added. The reaction mixture was stirred overnight at 100 °C in a sealed tube, and water (5 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3), dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-TLC with DCM / MeOH = 20:1 as eluent to give a yellow solid product (73 mg, 82% yield). MS(ESI):m / z 673.10[M+H] +671.00 [MH] - . c) Preparation of 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide: Under N2 protection at room temperature, a trifluoroacetic acid / dichloromethane mixture (2 mL / 10 mL) was added to 73 mg of 4-(4-(2-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)thiazo[4,5-b]pyrazin-6-yl)phenyl)piperazin-1-carboxylic acid tert-butyl ester (100 mg). The reaction mixture was stirred at room temperature for 1.5 h and concentrated under reduced pressure to give a yellow solid crude product (100 mg). MS (ESI): m / z 573.15 [M+H] + 571.05 [MH] - . d) Preparation of 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(4-(methylene(vinyl)sulfinyl)piperazin-1-yl)phenyl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide: Under N2 protection, 2'-chloro-5'-methoxy-6-methyl-N-(6-(4-(piperazin-1-yl)phenyl)thiazo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.035 mmol) was dissolved in DCM (3 mL), cooled to 0 °C, and triethylamine (TEA, 14.2 mg, 0.14 mmol) was added. Under nitrogen protection and at 0°C, a DCM solution of vinylsulfonyl chloride (13.3 mg, 0.105 mmol) was slowly added dropwise, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was purified by preparative high-performance liquid chromatography (HPLC) with a mobile phase containing 0.1% formic acid (HCOOH) in a gradient of 0%–60%, yielding a yellow solid product (0.8 mg, two-step yield = 6%). MS (ESI): m / z 663.10 [M+H] + 661.05 [MH] - . 1H NMR (400MHz, DMSO-d6): δ9.11(s,1H),8.74(s,1H),8.35(s,2H),8.11(s,1H),7.94(d,J=8.6Hz,2H),7.34(s,1H),7.15(s,1H),7 .05(d,J=8.7Hz,2H),6.86(dd,J=16.5,10.0Hz,1H),6.25–6.13(m,2H),3.63(s,3H),3.22-3.15(m,4H),2.53(s,3H),2.48-243(m 4H). The compounds 27-30 in the following examples can be prepared using a synthetic method similar to that in Example 26. The compounds are as follows: Example 31 2'-Chloro-5'-methoxy-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidin-1-carboxylate tert-butyl ester with 4-(2-amino-6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)piperidin-1-carboxylate to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 589.13. Example 32 2'-Chloro-5'-methoxy-6-methyl-N-(5-((3-(vinylsulfonyl)-3-azaspiro[5.5]undecane-9-yl)methyl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylate with 9-(((2-amino-6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-((3-(vinylsulfonyl)-3-azaspiro[5.5]undecane-9-yl)methyl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW 671.27. Example 33 2'-Chloro-5'-methoxy-6-methyl-N-(5-(4-(4-(vinylsulfonyl)piperazin-1-yl)phenyl)-4,5,6,7-tetrahydrothiazo[5,4-c] pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide A synthetic method similar to that in Example 1 can be used, replacing 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl ester with 4-(4-(2-amino-6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)phenyl)piperidine-1-carboxylate tert-butyl ester to prepare 2'-chloro-5'-methoxy-6-methyl-N-(5-(4-(4-(vinylsulfonyl)piperidine-1-yl)phenyl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide. MW666.21. Example 34 4-(5-fluoro-2-methoxyphenyl)-6-methyl-N-(5-(1-(vinylsulfonyl)piperidin-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)nicotinamide The target compound can be prepared by using a synthetic method similar to that in Example 1, but by replacing (5-chloro-2-methoxyphenyl)boronic acid with (5-fluoro-2-methoxyphenyl)boronic acid. MS: 547.62 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ 8.73(s,1H),7.23(d,J=3.8Hz,2H),7.21–7.11(m,2H),6.96(dd,J=8.9,4.5Hz,1H),6.78(dd,J=16.5,10.0Hz,1H),6.18–6.05(m,2H),4.2 8–4.20(m,2H),3.57–3.55(m,2H),3.49(s,3H),2.69–2.58(m,2H),2.53(s,3H),1.98-1.86(m,1H),1.85–1.76(m,2H),1.37-1.22(m,2H). Example 35 The inhibitory effect of the compounds of this invention on Polθ enzyme activity The helicase activity of Polθ was measured using a commercial ADP-Glo ​​assay kit. First, the Polθ protein was expressed in an insect cell system. DMSO was serially diluted to 10 dose points. 40 nL of each concentration of compound or DMSO was transferred to appropriate wells using I.DOT (DISPENDIX GmbH). The protein was diluted to the appropriate concentration using modified Tris-HCl (pH 7.5) buffer, and the compound and protein were pre-incubated together for 15 min at 25°C. Substrate DNA was then added, and the mixture was incubated at 25°C for 20 min. ATP was then added to initiate the reaction, and the mixture was incubated at 25°C for 120 min. Finally, ADP Glo reagent (Promega, V9101) was added to stop the reaction, and the mixture was incubated at 25°C for 120 min. To detect the generated ADP, ADP-Glo™ assay solution was added, and the mixture was incubated at 25°C for 1 h. Data were acquired by EnVision (PerkinElmer) using ultrasensitive luminescence mode. Wells containing 1% DMSO, enzyme, and ATP served as the high-signal-value control group, while wells containing 1% DMSO and ATP served as the low-signal-value control group. The percentage of inhibition in the compound-treated wells was normalized between the high-signal-value and low-signal-value control groups (%inhibition rate = (average value of high-signal-value control group wells - value of compound-treated wells) / (average value of high-signal-value control group wells - average value of low-signal-value control group wells) * 100). The IC50 was calculated by fitting the logarithm of the %inhibition value and the compound concentration to a nonlinear regression equation using GraphPad software. 50 The nonlinear regression equation is: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)). Y represents the compound inhibition rate, and X represents the logarithm of the compound concentration. IC 50 This is the compound concentration corresponding to an inhibition rate of 50%. The inhibitory effect of the compound in this application on Polθ enzyme activity was determined by the above experimental methods, and the measured IC50 value was... 50 The values ​​are shown in Table 1 below. Where ++++ indicates IC 50 ≤10nM. Table 1. IC50 values ​​of the compounds in the examples for inhibiting Polθ enzyme activity 50 Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 ++++ 11 ++++ 12 ++++ Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 14 ++++ 17 ++++ 26 ++++ Example IC 50 (nM) 34 ++++ The compound of this invention has a good inhibitory effect on Polθ enzyme activity. Example 36 The inhibitory effect of the compounds of this invention on the growth of DLD-1BRCA2-deficient cells The cytotoxicity of Polθ inhibitors in the human colorectal cancer DLD-1BRCA2-deficient cell line was assessed using a chemiluminescent cell viability assay. The DLD-1BRCA2-deficient cell line was obtained from Kelp Biotech. 40 μL of cell suspension was added to each well of a 384-well plate according to the planned layout, and the plate was incubated overnight in a CO2 incubator. Following the plate layout, 40 nL of different doses of the compound (DMSO was serially diluted to 9 dose points) were added to the plate using I.DOT HT. The final DMSO concentration was normalized to 0.1%. The cell plates were centrifuged at 1000 rpm for 1 min and incubated in a CO2 incubator for 5 days. The culture medium was removed using a vacuum pump and discarded. Then, 40 μL of culture medium was added to the plate, and 40 nL of different doses of the compound were added using I.DOT HT according to the plate layout. The plate was incubated in a CO2 incubator for another 5 days, for a total incubation period of 10 days. After 10 days of incubation, 30 μL of CellTiter-Glo Reagent was added to the detection plate according to the test method in the CTG manual, and CTG was run. The experimental plate was loaded, and the luminescence signal was recorded using Envision. Wells containing only culture medium served as the low signal control group, and wells containing 0.1% DMSO and cells served as the high signal control group. The percentage of cell death in the compound-treated wells was standardized between the high and low signal control groups (% kill rate = (average value of high signal control wells - value of compound-treated wells) / (average value of high signal control wells - average value of low signal control wells) * 100). The IC50 was calculated by fitting the logarithm of the % kill value and the compound concentration to a nonlinear regression equation using GraphPad software. 50 The nonlinear regression equation is: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)). Y represents the cell killing rate, and X represents the logarithm of the compound concentration. IC 50 This is the compound concentration corresponding to a kill rate of 50%. The compound described in this application exhibits an inhibitory effect on the growth of DLD-1BRCA2-deficient cells. The IC50 was determined using the above experimental methods. 50 The values ​​are shown in Table 2 below. Where ++++ indicates IC 50 ≤10nM; +++ indicates 10nM <IC 50 ≤100nM; ++ indicates 100nM <IC 50 ≤500nM; + indicates IC 50 >1μM. Table 2. IC50 of the compounds in the examples inhibiting the proliferation activity of DLD-1BRCA2-deficient cells. 50 Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 ++++ 11 +++ 12 +++ Example IC 50 (nM) Example IC 50 (nM) Example Example IC 50 (nM) 14 + 17 ++ 34 +++ The results showed that the compound of the present invention had a good inhibitory effect on the proliferation activity of DLD-1BRCA2-deficient cells.

[0084] While the invention has been fully described, those skilled in the art will understand that the same practices can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the invention or any embodiments thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound of Formula I, a stereoisomer, an isotopically-labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or co-crystal thereof: Formula I wherein: A is N or CR3; B1and B2are each independently CR4, N or NR5; ring Q is an optionally substituted 5-10 membered heteroaryl; ring W is an optionally substituted 4-12 membered heterocyclyl, an optionally substituted aryl, an optionally substituted 5-10 membered heteroaryl or an optionally substituted 4-12 membered carbocyclyl; Z is a bond, -NR5- or an optionally substituted 4-12 membered heterocyclyl; m is 1, 2, 3 or 4; n is 1 or 2.

2. The compound of claim 1, a stereoisomer, an isotopically-labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or co-crystal thereof, wherein: A is N or CH; and / or B1and B2are each independently CR4, N or NR5.

3. The compound of claim 1, a stereoisomer, an isotopically-labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or co-crystal thereof, wherein: A is N or CH; and / or B1and B2are each independently CR4, N or NR5.

4. The compound of claim 1, a stereoisomer, an isotopically-labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or co-crystal thereof, wherein: A is N or CH; and / or B1and B2are each independently CR4, N or NR5. Preferably, ring Q is a bivalent thiazolopyrazine, thiazolopyridine, thiadiazole or tetrahydrothiazolopyridine group; more preferably, ring Q is selected from the group consisting of: wherein *1and *2indicate the positions where ring Q is attached to -NH- and L in the structure of the compound, respectively; and / or L is selected from the group consisting of a bond, -NH- and: L is a bond, optionally substituted C 1-4 alkylene, optionally substituted -O-C 1-4 alkylene-, optionally substituted -C 1-4 alkylene carbonyl-, optionally substituted -C 1-4 alkylene-NR5-, optionally substituted -C 1-4 alkylene-O-, -CºC- or -NR5-; Preferably, ring W is an optionally substituted 5-12 membered heterocyclyl, an optionally substituted aryl, an optionally substituted 5-6 membered carbocyclyl or an optionally substituted 5-6 membered N-containing heteroaryl; more preferably, ring W is selected from the group consisting of: wherein *4and *5indicate the positions where ring W is attached to L and Z in the structure of the compound, respectively. Z is a bond, -NH- or an optionally substituted 4-12 membered heterocyclyl; preferably, the 4-12 membered heterocyclyl is preferably a nitrogen-containing heterocyclyl; more preferably, Z is a bond, -NH- or a 5- or 6-membered N-containing heterocyclyl, such as pyrrolidinyl, piperazinyl or piperidinyl; more preferably, Z is a bond, -NH- or: R1and R2are each independently H, deuterium, halogen, hydroxyl, cyano, optionally substituted amino, optionally substituted C 1-4 alkyl, optionally substituted C 1-4 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-4 alkenyl, or optionally substituted C 2-4 alkynyl; R3is H, halogen or optionally substituted C 1-4 alkyl; R4is H, =0, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-4 alkenyl or optionally substituted C 2-4 alkynyl; R5is H, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkyl-C 1-4 alkylene, optionally substituted 6-14 membered aryl, optionally substituted 6-14 membered aryl-C 1-4 alkylene, optionally substituted 5-10 membered heteroaryl, optionally substituted 5-10 membered heteroaryl-C 1-4 alkylene, optionally substituted 4-10 membered heterocyclyl, or optionally substituted 4-10 membered heterocyclyl-C 1-4 alkylene; The compound has a structure of Formula IIa or IIb: Formula IIa Formula IIb wherein A, B1, B2, L, ring W, R1and m are as defined in any one of claims 1-6; Y is CR6or N; E1, E2and E3are each independently CR7or N; the compound is selected from the group consisting of:

9. A pharmaceutical composition comprising: (I) a compound of any one of claims 1-8, a stereoisomer, an isotopically-labeled compound, a solvate, a hydrate or a pharmaceutically acceptable salt or co-crystal thereof; (II) a pharmaceutically acceptable carrier or diluent; and optionally (III) at least one known anti-cancer drug or anti-cancer agent, including: ​ ​ The aryl or heteroaryl group containing A is optionally substituted with 1, 2, 3, and 4 R1, each R1 is independently halo, hydroxy, cyano, C 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, haloC 1-4 alkoxy, C 3-6 cycloalkyl, or C 2-4 alkynyl; preferably, the aryl or heteroaryl group containing A is substituted with 2 R1, each R1 is independently halo, cyano, C 1-2 alkyl, haloC 1-2 alkyl, C 1-2 alkoxy, haloC 1-2 alkoxy, or ethynyl; preferably, the aryl or heteroaryl group containing A is substituted with at least 1 C 1-4 alkoxy, preferably C 1-2 alkoxy, optionally further substituted with 1 halo, such as fluoro or chloro; preferably, the aryl or heteroaryl group containing A is substituted with 1 C 1-4 alkoxy, preferably C 1-2 alkoxy and 1 halo, preferably fluoro or chloro. ​ R4is H, =0, or optionally substituted C 1-4 alkyl, which C 1-4 alkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halo and hydroxy; preferably, R4is H, =0, or C 1-4 alkyl; and / or R5is H, optionally substituted C 1-4 alkyl, optionally substituted C 3-6 cycloalkyl-C 1-4 alkylene, optionally substituted 6-14 membered aryl-C 1-4 alkylene, optionally substituted 5-10 membered heteroaryl-C 1-4 alkylene or optionally substituted 4-10 membered heterocyclyl-C 1-4 alkylene; preferably, R5is optionally substituted 5-10 membered heteroaryl-C 1-4 alkylene; and / or B1 is CR4, B2 is N, wherein R4 is H or optionally substituted C 1-4 alkyl, preferably H; or B1 is NR5, B2 is C=0, wherein R5 is H or optionally substituted 5-10 membered heteroaryl-C 1-4 alkyl, preferably H; or B1 is NR5, B2 is C=0, wherein R5 is H or optionally substituted 5-10 membered heteroaryl-C 1-2 alkylene. ​ Ring Q is an optionally substituted 5- or 6-membered heteroaryl or an optionally substituted 9- or 10-membered fused heteroaryl, preferably the heteroaryl is a nitrogen containing heteroaryl, preferably containing at least 2 ring nitrogen atoms; preferably, when ring Q is substituted, it is substituted with 1, 2, or 3 substituents selected from halogen, hydroxyl, or C1-C3alkyl, preferably halogen or C1-C3alkyl, more preferably halogen, most preferably fluoro. 1-4 substituted with 1, 2, or 3 substituents selected from halogen, hydroxyl, or C1-C3alkyl, preferably halogen or C1-C3alkyl, more preferably halogen, most preferably fluoro. ​ ​ ​ L is a bond, optionally substituted C 1-2 alkylene, optionally substituted -O-C 1-2 alkylene-, optionally substituted -C 1-2 alkylene carbonyl-, optionally substituted -C 1-2 alkylene-NR5-, optionally substituted -C 1-2 alkylene-O-, -C≡C- or -NR5-, wherein R5 is H or C 1-3 alkyl, preferably H; preferably, L is C optionally substituted by halogen 1-2 alkylene, -O-C optionally substituted by halogen 1-2 alkylene-, -C optionally substituted by halogen 1-2 alkylene carbonyl-, -C optionally substituted by halogen 1-2 alkylene-O-, -C optionally substituted by halogen 1-2 alkylene-NR5- or -C≡C-, the number of halogen atoms being 1, 2, 3 or 4; ​ ​ 5. The compound, stereoisomer, isotopically labeled compound, solvate, hydrate or pharmaceutically acceptable salt or co-crystal thereof according to claim 1, wherein ​ Preferably, when substituted, ring W is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen and C 1-4 substituted by substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, and C3-C6cycloalkyl; ​ ​ 6. The compound, stereoisomer, isotopically labeled compound, solvate, hydrate or pharmaceutically acceptable salt or co-crystal thereof according to claim 1, wherein ​ ​ ​ ​ 7. The compound, stereoisomer, isotopically labeled compound, solvate, hydrate or pharmaceutically acceptable salt or co-crystal thereof according to claim 1, wherein ​ ​ ​ ​ R6is H, halogen, hydroxyl, cyano, optionally substituted C 1-4 alkyl or optionally substituted C 1-4 alkoxy; R7is H, halogen or optionally substituted C 1-4 alkyl.

8. The compound, stereoisomer, isotopically labeled compound, solvate, hydrate or pharmaceutically acceptable salt or co-crystal thereof according to claim 1, wherein ​ ​ ​ ​ ​ (1) anticancer drugs related to DNA damage and repair mechanisms, including but not limited to HDAC inhibitors vorinostat, romidepsin, panobinostat and belinostat; (2) PARP inhibitors, including but not limited to olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, senaparib and saruparib; (3) anticancer drugs related to cell division checkpoints, including but not limited to Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, WEE1 inhibitors, ATM inhibitors, ATR inhibitors; (4) alkylating agents, such as busulfan, mafosfamide, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mytomycin C, bleomycin and carboplatin; (5) topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclarubicin, mitoxantrone, elliptinium and etoposide; (6) RNA / DNA antimetabolites, such as 5-azacytosine, gemcitabine, 5-fluorouracil and methotrexate; (7) DNA antimetabolites, such as 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea and thioguanine; (8) antimitotic agents, such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel and docetaxel; (9) antibodies, such as mAb, panitumumab, inotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumab, brentuximab, daratumumab, eribulin, ofatumumab, dinutuximab, blinatumomab, ipilimumab, avastin, herceptin and mabthera; (10) antibody conjugate drugs (ADC), such as trastuzumab-maytansinoid conjugate T-DM1, humanized anti-HER2 antibody-drug conjugate trastuzumab deruxtecan, trastuzumab emtansine, humanized anti-TROP2 monoclonal antibody-drug conjugate datopotamab deruxtecan, gemtuzumab ozogamicin, CD30-directed antibody-drug conjugate brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin and belantamab mafodotin; (11) kinase inhibitors, such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, icotinib, airolinib, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralatinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabimetinib, axitinib, temsirolimus, idelalisib, pazopanib, temsirolimus and everolimus; and (12) other known anticancer drugs that can be used for anticancer combination therapy, including tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, white arsenic, zoledronic acid, bortezomib, carfilzomib, ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, venetoclax, aldesleukin (recombinant human interleukin-2) and sipueucel-T (prostate cancer treatment vaccine).

10. Use of a compound, stereoisomer, isotopically labeled compound, solvate, hydrate or pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-8 for the manufacture of a medicament for the treatment or prevention of a PolQ-mediated disease or disorder; Preferably, the PolQ-mediated disease is a tumor or cancer, preferably selected from the group consisting of hepatocarcinoma, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer (such as small cell lung cancer), Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myelocytic leukemia, primary brain cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myelocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, urogenital tumor disease, thyroid cancer, esophageal cancer, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, idiopathic thrombocytopenia, adrenal cortex cancer, skin cancer and prostate cancer; Preferably, the medicament further comprises at least one known anticancer drug or anticancer drug, including: (1) anticancer drugs related to DNA damage and repair mechanisms, including but not limited to HDAC inhibitors vorinostat, romidepsin, panobinostat and belinostat; (2) PARP inhibitors, including but not limited to olaparib, niraparib, rucaparib, talazoparib, pamiparib, fluzoparib, senaparib and saruparib; (3) anticancer drugs related to cell division checkpoints, including but not limited to Chk1 / 2 inhibitors, CDK4 / 6 inhibitors such as palbociclib, WEE1 inhibitors, ATM inhibitors, ATR inhibitors; (4) alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cisplatin, mytomycin C, bleomycin, and carboplatin; (5) topoisomerase I inhibitors, such as camptothecin, irinotecan, and topotecan; topoisomerase II inhibitors such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium, and etoposide; (6) RNA / DNA antimetabolites, such as 5-azacytosine, gemcitabine, 5-fluorouracil, and methotrexate; (7) DNA antimetabolites, such as 5-fluoro-2'-deoxyuridine, fludarabine, nelarabine, cytarabine, pralatrexate, pemetrexed, hydroxyurea, and thioguanine; (8) antimitotics, such as colchicine, vinblastine, vincristine, vinorelbine, paclitaxel, ixabepilone, cabazitaxel, and docetaxel; (9) antibodies, such as panitumumab, inotuzumab, nivolumab, pembrolizumab, ramucirumab, bevacizumab, pertuzumab, trastuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, alemtuzumab, ibritumomab, tositumomab, brentuximab, daratumumab, eribulin, ofatumumab, dinutuximab, blinatumomab, ipilimumab, avastin, herceptin, and mabthera; (10) antibody drug conjugates (ADC), such as trastuzumab-mertansine conjugate T-DM1, humanized anti-HER2 antibody-drug conjugate trastuzumab deruxtecan, trastuzumab emtansine, humanized anti-TROP2 monoclonal antibody-drug conjugate datopotamab deruxtecan, gemtuzumab ozogamicin, brentuximab vedotin, inotuzumab ozogamicin, sacituzumab govitecan, enfortumab vedotin, and belantamab mafodotin; (11) kinase inhibitors, such as imatinib, gefitinib, erlotinib, osimertinib, afatinib, icotinib, elacridar, crizotinib, erlotinib, lapatinib, sorafenib, regorafenib, vemurafenib, dabrafenib, aflibercept, sunitinib, nilotinib, dasatinib, bosutinib, pralsetinib, ibrutinib, cabozantinib, lenvatinib, vandetanib, trametinib, cabozantinib, axitinib, temsirolimus, idelalisib, pazopanib, trastuzumab, and everolimus; and (12) other drugs, such as thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, thal (12) other known anticancer drugs that can be used in anticancer combination therapy, including tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, white arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2), and Sipueucel-T (prostate cancer treatment vaccine).

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