Compound targeting POL theta helicase structural domain and application thereof

Abstract

The invention discloses a compound targeting a POL theta helicase structural domain and application thereof. The compound has a structure shown in a general formula (I) or (II),

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a compound that targets the POLθ helicase domain and its applications, including its stereoisomers, deuterated derivatives, solvates, pharmaceutically acceptable salts or cocrystal forms, and the use of these compounds in the prevention and treatment of POLθ-mediated diseases. Background Technology

[0002] DNA polymerase theta (POLθ) is a key DNA repair enzyme that participates in the repair of DNA double-strand breaks (DSBs) through the microhomological end joining (MMEJ) pathway. Studies have shown that POLθ is abnormally activated or overexpressed in various tumors and is closely related to tumor development, progression, and drug resistance, thus identifying it as a highly promising target for anti-tumor therapy.

[0003] In recent years, significant progress has been made in the research of small molecule inhibitors targeting POLθ function. Multiple studies have confirmed that clinically-developed POLθ inhibitors (such as GSK4524101, MOMA-313, RP-3467, SYN818, and SIM0508) can effectively enhance the sensitivity of tumor cells to DNA damage factors (such as PARP inhibitors), demonstrating promising potential for combination therapy. However, traditional small molecule inhibitors typically rely on potent binding to the active site of the target protein to block its function. This mechanism of action has certain limitations, such as difficulty in targeting certain "undruggable" targets lacking a clear active pocket, the potential for drug resistance due to target mutations or compensatory mechanisms, and the need to maintain high in vivo drug concentrations to sustainably inhibit target protein activity.

[0004] Against this backdrop, targeted protein degradation (TPD) technology has rapidly developed as a revolutionary new drug development strategy. Unlike traditional occupation-driven small molecule inhibitors, protein degraders (such as PROTACs) utilize the cell's natural ubiquitin-proteasome system to catalytically induce the complete degradation of target proteins in an event-driven manner. This mechanism endows degraders with unique potential advantages: firstly, their action is not strictly dependent on the active site of the target protein, providing a new pathway for targeting traditionally "undruggable" targets (potentially including specific domains of POLθ); secondly, the catalytic degradation characteristic may lead to more durable effects, reduce dependence on sustained high drug concentrations, and potentially overcome certain forms of drug resistance. Currently, although small molecule inhibitors targeting POLθ have entered clinical trials, the variety of such compounds remains limited, and patients have very limited treatment options. Summary of the Invention

[0005] To address the aforementioned shortcomings of existing technologies, the present invention aims to provide a compound that targets the POLθ helicase domain and its application, thereby solving the problems of limited types of compounds that can be used to prepare small molecule inhibitors of POLθ and limited drug options for patients in existing technologies.

[0006] To address the aforementioned technical problems, in a first aspect, the present invention provides a compound targeting the POLθ helicase domain and its application, wherein the compound has a structure of general formula (I) or (II):

[0007]

[0008] in:

[0009] W, X, Y, and Z are each independently selected from N or CR. X ;R X Selected from H, D, halogens, OH, NH2, CN, C 1-4 Alkyl or C 1-4 Alkoxy;

[0010] R A1 R A2 R A3 R A4 Each is independently selected from H, D, halogens, OH, CN, NH2, SF5, and C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The heterocyclic alkyl group or 5-10 heteroaryl group contains 1-3 heteroatoms selected from N, S, and O; the heterocyclic alkyl group, aryl group, and heteroaryl group are optionally surrounded by 1-5 R atoms. 1a replace;

[0011] R 1a Each is independently selected from D, halogens, CN, =O, OH, NH2, C 1-4 Alkyl or C 1-4 Alkoxy;

[0012] B is selected from C. 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-12The heterocyclic alkyl group or 5-12 heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are optionally surrounded by 1-5 R atoms. 1b replace;

[0013] R 1b Each is independently selected from D, halogen, CN, =O, OH, NH2, COOH, C 1-4 Alkyl or C 1-4 Alkoxy;

[0014] L is a linking group, selected from one or more of the following groups: straight-chain or branched alkyl, alkoxy, alkylamine, haloheterocyclic, alkenyl, alkynyl, alkynoxy, alkynamine, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, phencycloalkyl, heterophenocycloalkyl, aryl, haloaryl, heteroaryl.

[0015] -CO(CH2) n -、-CO(CH2) n O-, -(CH2) n NH2-, -(CH2) n NR L -、-CO(CH2) n NH-, -CO(CH2) n NR L -、

[0016] -(CH2) n CONH(CH2) n -、-(CH2) n CONH(CH2) n NH-, -(CH2) n CONH(CH2) n NR L -、

[0017] -CO(CH2) n NHCO(CH2) n -、-CO(CH2) n NHCO(CH2) n NH-, -CO(CH2) n NHCO(CH2)nNR L -、

[0018] -CO(CH2OCH2) n CH2NHCO(CH2) n -、-CO(CH2OCH2) n CH2NHCO(CH2) n NH-,

[0019] -CO(CH2OCH2) n CH2NHCO(CH2) n NR L -, -CH2(CH2OCH2) n CH2-、

[0020] -CH2(CH2OCH2) n CH2NH-、-CH2(CH2OCH2) n CH2NR L -, -CH2(CH2OCH2) n CH2O-、

[0021] -CH2CONHCH2(CH2OCH2) n CH2NH-、-CH2CONHCH2(CH2OCH2) n CH2NR L -、

[0022] -CH2CONHCH2(CH2OCH2) n CH2NHCO(CH2) n NH-,

[0023] -CH2CONHCH2(CH2OCH2) n CH2NHCO(CH2) n NR L -, -CH2CONHCH2(CH2OCH2) n CO-、

[0024] -CH2(CH2OCH2) n CH2CO- or any combination thereof;

[0025] n represents a natural number from 1 to 20;

[0026] R L For H or C 1-10 alkyl;

[0027] E3 ligand is the E3 ligase ligand for CRBN or VHL.

[0028] Preferably, It can be any of the following structural formulas:

[0029]

[0030] Preferably, It can be any of the following structural formulas:

[0031]

[0032] Preferably, It can be any of the following structural formulas:

[0033]

[0034] Preferably, B is from R. 1b The following heterocyclic alkyl, aryl, or heteroaryl groups are substituted:

[0035]

[0036] Preferably, R 1b It is selected from any one of hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyano, and ethynyl.

[0037] Preferably, L is selected from any one of the following structures: acetylene, propyne, -O-, -CONH-, -CH2CH2-,

[0038]

[0039] Preferably, in the general formula, E3 Ligand is selected from any one of the following structures:

[0040]

[0041] Preferably, the compound has any one of the following structures:

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Secondly, the present invention provides an application of a compound, wherein the above-mentioned compound and its isomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof are used to prepare a drug targeting the POLθ helicase domain.

[0048] Thirdly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II), or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0049] Fourthly, the compounds of the present invention, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, can be administered, either in pure form or as suitable pharmaceutical compositions, by any acceptable route of administration for providing a medicament of similar use. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention can be formulated into solid, semi-solid, liquid, or gaseous formulations.

[0050] Fifthly, the present invention provides the use of compounds of formula (I) or (II), or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating POLθ-mediated diseases.

[0051] Preferably, the POLθ-mediated disease is a disease of POLθ overexpression.

[0052] Preferably, the POLθ-mediated disease is cancer.

[0053] Preferably, the cancer is a cancer with a missing or reduced function of the BRCA gene.

[0054] Preferably, the cancer is colorectal cancer, breast cancer, or ovarian cancer.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] This invention discovers a novel compound. Traditional inhibitors rely on occupying the active site of POLθ to achieve functional inhibition. However, the compound of this invention induces POLθ ubiquitination and degradation in a catalytic manner through E3 ubiquitin ligase. This mechanism does not strictly depend on active site binding, which provides the possibility of targeting the domains in POLθ that lack the classic drug-binding pocket. It is expected to overcome the "undruggable" challenge that may be faced in the design of traditional inhibitors. Detailed Implementation

[0057] This invention will describe the technical solutions of the embodiments of the invention clearly and completely. Obviously, the described embodiments are only some embodiments of the invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on this invention are within the scope of protection of this invention.

[0058] Unless otherwise specified in the specific circumstances, the numerical ranges listed herein include upper and lower limits, as well as all integers and fractions within that range, but are not limited to the specific values ​​listed when the range is defined.

[0059] I. Preparation of intermediates

[0060] 1. Preparation of intermediate warhead 1

[0061]

[0062] Step 1: Preparation of intermediate 1B

[0063] 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1A, 0.28 g, 1.00 mmol) (prepared according to the method described in WO2022118210) and 6-bromothiazo[4,5-b]pyrazin-2-amine (0.27 g, 1.00 mmol) were dissolved in 5.0 mL of DCM. EDCI (0.38 g, 2.0 mmol) and 4-PPY (0.097 g, 0.8 mmol) were added sequentially, and the mixture was refluxed for 4 h. The mixture was diluted with water, extracted with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a white solid 1B (0.25 g) in 25% yield. ESI-MS: 491.1 [M+H] + .

[0064] Step 2: Preparation of intermediate 1C

[0065] 1B (0.25 g, 0.24 mmol) and 4-piperidinemethanol (0.055 g, 0.48 mmol) were dissolved in 5.0 mL of 1,4-Dioxane. Sodium tert-butoxide (0.45 g, 0.48 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (0.029 g, 0.048 mmol), and tris(dibenzylacetone dipalladium) (0.022 g, 0.024 mmol) were added sequentially. The mixture was purged with nitrogen three times and reacted at 100 °C for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give a white solid 1C (0.093 g), with a yield of 74%. ESI-MS: 526.1 [M+H] + .

[0066] Step 3: Preparation of warhead 1

[0067] 1C (0.090 g, 0.17 mmol) was dissolved in 5.0 mL of DCM, and Dess-Martin oxidant (0.11 g, 0.34 mmol) was added. The reaction was carried out at room temperature for 2 h, diluted with water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a white solid, warhead 1 (0.075 g), in 85% yield. ESI-MS: 524.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),9.72(s,1H),8.85(s,1H),8.53(s,1H),8.36(s,1H),7.94(m,1H),7.45(s,1H),3.75-3.72( m,2H),3.61(s,3H),3.31-3.23(m,2H),2.78-2.67(m,2H),2.60(s,3H),1.82-1.72(m,2H),1.60-1.47(m,1H),1.36-1.22(m,2H).

[0068] 2. Preparation of intermediate warhead 2

[0069]

[0070] Step 1: Preparation of intermediate 2B

[0071] Intermediate 2B was prepared following the synthesis of intermediate 1C, except that 4-piperidinemethanol was replaced with tert-butylpiperidine-4-ylcarbamate, yielding a white solid 2B (0.45 g) in 73% yield. ESI-MS: m / z = 611.1 [M+H] + .

[0072] Step 2: Preparation of warhead 2

[0073] 2B (0.45 g, 0.75 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (3 mL) and methyl tert-butyl ether (3 mL) were added to the residue, mixed thoroughly, and then concentrated under reduced pressure to give a yellow solid, warhead 2 (0.40 g), in 80% yield. ESI-MS: 511.1 [M+H] + .

[0074] 3. Preparation of intermediates warhead 3-warhead 5

[0075] The intermediates warhead 3-warhead 5 were prepared by referring to the synthesis of warhead 2, respectively by replacing tert-butylpiperidin-4-ylcarbamate with tert-butyl(piperidin-4-ylmethyl)carbamate, tert-butyl(2-(piperidin-4-yl)ethyl)carbamate, and 1-carboxylic acid tert-butylpiperazine ester. The rest of the process was the same. Their structural formulas are shown in Table 1 below.

[0076] Table 1

[0077]

[0078] 4. Preparation of intermediate warhead 6

[0079]

[0080] Step 1: Preparation of intermediate 3B

[0081] 1B (1.0 g, 0.96 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid ester (0.30 g, 1.0 mmol) were dissolved in 27 mL of dioxane and 9 mL of water. Pd(dppf)Cl2 (0.080 g, 0.10 mmol) and potassium carbonate (0.30 g, 2.21 mmol) were added sequentially. The mixture was purged three times with nitrogen and reacted at 100 °C for 10 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give a white solid 3B (0.398 g), yield 70%. ESI-MS: 594.1 [M+H] + .

[0082] Step 2: Preparation of intermediate 3C

[0083] 3B (0.12 g, 0.20 mmol) was dissolved in methanol (5 mL), and platinum dioxide (40 mg, 0.17 mmol) was added. The mixture was purged with hydrogen three times and reacted for 4 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give a white solid 3C (0.04 g), with a yield of 30%. ESI-MS: 596.1 [M+H] + .

[0084] Step 3: Preparation of intermediate warhead 6

[0085] 3C (0.04 g, 0.067 mmol) was dissolved in 1.0 mL of DCM, stirred until homogeneous, and then trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (1 mL) and methyl tert-butyl ether (1 mL) were added to the residue, mixed thoroughly, and then concentrated under reduced pressure to give a yellow solid, warhead 6 (0.033 g), in 100% yield. ESI-MS: 496.1 [M+H] + . 1HNMR(400MHz,DMSO-d6)δ12.75(s,1H),8.90(s,1H),8.80(s,1H),8.53(s,1H),8.33(s,1H),7.92(m,1H),3.70(s,3H),3.68 -3.64(m,1H),2.80-2.74(m,1H),2.71(s,3H),2.14-2.08(m,2H),2.04-1.97(m,2H),1.73-1.61(m,2H),1.43-1.45(m,2H).

[0086] 5. Preparation of intermediate warhead 7

[0087]

[0088] Step 1: Preparation of intermediate 4B

[0089] 6-Iodopyridin-3-ol (1.0 g, 4.54 mmol) was dissolved in 10 mL of dioxane, and Pd(PPh3)4 (0.050 g, 0.045 mmol) and hexabutyltin (0.87 g, 15.00 mmol) were added. The mixture was purged with nitrogen three times and refluxed for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was directly used for the next step without purification.

[0090] Step 2: Preparation of intermediate warhead 7

[0091] 1B (1.0 g, 0.96 mmol) and 4B (0.9 g) were dissolved in 10 mL of dioxane, and Pd(PPh3)4 (0.10 g, 0.09 mmol) and triethylamine (0.27 g, 0.27 mmol) were added. The mixture was purged with nitrogen three times and refluxed for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give a yellow solid, warhead 7 (0.50 g), in 53% yield. ESI-MS: m / z = 506.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.63(s,1H),10.18(s,1H),9.05(s,1H),8.80(s,1H),8.71(m,1H), 8.58(s,1H),8.42(s,1H),8.22(s,1H),8.02(s,1H),7.53(m,1H),3.70(s,3H),2.89(s,3H).

[0092] 6. Preparation of intermediate warhead 8

[0093]

[0094] 1B (1.0 g, 0.96 mmol) and (4-hydroxyphenyl)boronic acid (7A, 0.56 g, 1.01 mmol) were dissolved in a mixed solvent of 10 mL dioxane and 2 mL water. Pd(PPh3)4 (0.10 g, 0.09 mmol) and triethylamine (0.27 g, 0.27 mmol) were added. The mixture was purged three times with nitrogen and reacted at 90 °C for 1.5 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography to give a white solid, warhead 8 (0.48 g), in 69% yield. ESI-MS: m / z = 505.1 [M+H] + .

[0095] 7. Preparation of intermediate warhead-9-warhead 13

[0096] The preparation of intermediate warhead-9-warhead 13 was performed in accordance with the synthesis of warhead 1, with the starting material 6-bromothiazo[4,5-b]pyrazin-2-amine replaced by 5-bromothiazo[5,4-d]pyrimidine-2-amine, 6-bromothiazo[4,5-b]pyrimidine-2-amine, 5-bromothiazo[5,4-b]pyrimidine-2-amine, 6-bromobenzo[d]thiazole-2-amine, and 6-bromo-5-fluorobenzo[d]thiazole-2-amine, respectively, while maintaining the same other parameters. The structural formula of intermediate warhead-9-warhead 13 is shown in Table 2 below.

[0097] Table 2

[0098]

[0099] 8. Preparation of intermediate warhead-14-warhead 20

[0100] The preparation of intermediates warhead-14 and warhead 20 was based on the synthesis of warhead 1, with the starting material 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1A) replaced by 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid, 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid, 2'-chloro-5'-methoxy-6-(pentafluorosulfonyl)-[4,4'-bipyridine]-3-carboxylic acid, and 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid, respectively. The following fragments were prepared according to the method described in WO2024088407A1: 4'-bipyridine]-3-carboxylic acid, 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid, and 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid. All other components were prepared in the same manner. The intermediate warhead-14-warhead 20 has the structural formula shown in Table 3 below.

[0101] Table 3

[0102]

[0103]

[0104] 9. Preparation of intermediate warhead 21

[0105]

[0106] Step 1: Preparation of intermediate 5B

[0107] NaH (60%, 0.36 g, 3.0 mmol) was added to a two-necked flask, and after N2 replacement, a DMF solution of tert-butyl-4-(hydroxymethyl)piperidine-1-carboxylic acid ester (5A, 0.45 g, 1.0 mmol) was added. The mixture was stirred at 0 °C for 10–15 min, and then a DMF solution of 5-bromo-1,3,4-thiadiazol-2-amine (0.39 g, 1.2 mmol) was added. The reaction was carried out at room temperature for 1 hour. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and purified by column chromatography to give a white solid 5B (0.65 g, yield 59%). ESI-MS: 315.1 [M+H] + .

[0108] Step 2: Preparation of intermediate 5C

[0109] 5B (0.31 g, 1.0 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1A, 0.28 g, 1.00 mmol) were dissolved in 5.0 mL of DCM. EDCI (0.38 g, 2.0 mmol) and 4-PPY (0.097 g, 0.8 mmol) were added sequentially, and the mixture was refluxed for 3.5 h. The mixture was diluted with water, extracted with dichloromethane, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a white solid 5C (0.29 g), in 29% yield. ESI-MS: 575.1 [M+H] + .

[0110] Step 3: Preparation of intermediate warhead 21

[0111] 5C (0.57 g, 1.0 mmol) was dissolved in 5.0 mL of DCM, stirred thoroughly, and then trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (3 mL) and methyl tert-butyl ether (3 mL) were added to the residue, mixed thoroughly, and then concentrated under reduced pressure to give a pale yellow solid, warhead 21 (0.50 g), with a yield of 98%. ESI-MS: 475.1 [M+H] + .

[0112] 10. Preparation of intermediates warhead 22-warhead 23

[0113] The preparation of intermediates warhead 22-warhead 23 is the same as that of warhead 21, except that the starting material tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate is replaced with tert-butyl 3-(hydroxymethyl)azacyclobutane-1-carboxylate and tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate, respectively. The structural formulas of intermediates warhead 22-warhead 23 are shown in Table 4 below.

[0114] Table 4

[0115]

[0116] 11. Preparation of intermediate warhead 24

[0117]

[0118] 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)phenol (6A, 0.29 g, 1.0 mmol) (prepared according to the method described in WO2022118210) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1A, 0.28 g, 1.00 mmol) were dissolved in DCM (5.0 mL), followed by the addition of EDCI (0.38 g, 2.0 mmol) and 4-PPY (0.097 g, 0.8 mmol). The mixture was refluxed for 2 h, diluted with water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na2SO4, and purified by column chromatography to give a white solid, Warhead 24 (0.24 g), in 30% yield. ESI-MS: 484.1 [M+H] + .

[0119] 12. Preparation of intermediate warhead 25

[0120]

[0121] The preparation of intermediate Warhead 25 was the same as that of Warhead 24, except that the starting material 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)phenol (6A) was replaced with 6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)pyridin-3-ol, otherwise the preparation was the same, yielding a white solid Warhead 25 (0.34 g), in 38% yield. ESI-MS: 484.1 [M+H] + .

[0122] 13. Preparation of intermediates warhead 26-warhead 31

[0123] The preparation of intermediates Warhead 26-Warhead 31 is the same as that of Warhead 21, except that the starting material 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (1A) is replaced with 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid, 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid, 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid, 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid, 2'-chloro-5'-(methoxy-d3)-6-methyl-[4,4'-bipyridine]-3-carboxylic acid, and 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid, while the rest is the same. The structural formulas of intermediate warhead 26-warhead31 are shown in Table 5 below.

[0124] Table 5

[0125]

[0126] 14. Preparation of intermediate L-1

[0127]

[0128] Step 1: Preparation of intermediate 1b

[0129] 2-(2,6-dioxadiazin-3-yl)-5-fluoroisoindole-1,3-dione (1a, 0.55 g, 2.0 mmol) and tert-butylpiperazine-1-carboxylic acid ester (0.37 g, 2.0 mmol) were dissolved in 10.0 mL of DMSO, and DIPEA (0.52 g, 4.0 mmol) was added. The reaction was carried out at 70 °C for 3 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a yellow solid 1b (0.44 g), in 50% yield. ESI-MS: 443.1 [M+H] + .

[0130] Step 2: Preparation of intermediate L-1

[0131] 1b (0.44 g, 1.0 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (3 mL) and methyl tert-butyl ether (3 mL) were added to the residue, mixed thoroughly, and then concentrated under reduced pressure to give a yellow solid L-1 (0.17 g), with a yield of 50%. ESI-MS: 343.1 [M+H] + .

[0132] 15. Preparation of intermediate L-2-L-6

[0133] The preparation of intermediate L-2-L-4 is the same as that of L-1, except that the starting material tert-butylpiperazine-1-carboxylate is replaced with tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, and tert-butyl4-(2-aminoethyl)piperidine-1-carboxylate, respectively, and the rest is the same;

[0134] The preparation of intermediates L-5 and L-6 is the same as that of L-1, except that the starting material 1a is replaced with 2-(2,6-dioxypiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione and 3-(5-fluoro-1-oxoisoindoline-2-yl)piperidin-2,6-dione, respectively.

[0135] The structural formula of intermediate L-2-L-6 is shown in Table 6 below.

[0136] Table 6

[0137]

[0138] 16. Preparation of intermediate L-7

[0139]

[0140] Step 1: Preparation of intermediate 2b

[0141] 4-Bromo-N-(2,6-dioxopiperidin-3-yl)benzamide (2a, 0.62 g, 2.0 mmol) and tert-butylpiperazine-1-carboxylic acid ester (0.37 g, 2.0 mmol) were dissolved in 10.0 mL of THF. Pd₂(dba)₃ (0.12 g, 0.2 mmol), BINAP (0.21 g, 0.4 mmol), and CsCO₃ (1.01 g, 3.5 mmol) were added, and the reaction was carried out at 50 °C for 2.5 h. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a yellow oily liquid 2b (0.44 g), in 50% yield. ESI-MS: 417.2 [M+H] + .

[0142] Step 2: Preparation of intermediate L-7

[0143] 2b (0.44 g, 1.0 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. Methanol (3 mL) and methyl tert-butyl ether (3 mL) were added to the residue, mixed thoroughly, and then concentrated under reduced pressure to give a white solid L-7 (0.64 g), with a yield of 98%. ESI-MS: 317.1 [M+H] + .

[0144] 17. Preparation of intermediate L-8-L-10

[0145] The preparation of intermediate L-8-L-10 was based on the synthesis of L-7, with the starting material 2a replaced by 3-((6-bromopyridin-3-yl)amino)piperidin-2,6-dione, 3-((4-bromophenyl)amino)piperidin-2,6-dione, or 1-(5-bromo-4-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrido[2,1-d]pyrimidine-2,4(1H,3H)-dione, while all other steps remained the same. The structural formula of intermediate L-8-L-10 is shown in Table 7 below.

[0146] Table 7

[0147]

[0148] 18. Preparation of intermediate L-11

[0149]

[0150] Step 1: Preparation of intermediate 3b

[0151] Dissolve 1a (0.55 g, 2.0 mmol) and 4-piperidinylmethanol (0.23 g, 2.0 mmol) in 10.0 mL DMSO, add DIPEA (0.52 g, 4.0 mmol), and react at 70 °C for 3 hours. Dilute with water, extract with ethyl acetate, combine organic phases, wash with saturated NaCl solution, dry over anhydrous Na₂SO₄, and purify by column chromatography to give yellow solid 3b (0.29 g), yield 52%. ESI-MS: m / z = 372.1 [M+H] + .

[0152] Step 2: Preparation of intermediate L-11

[0153] 3b (0.29 g, 0.783 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then Dess-Martin oxidant (0.64 g, 1.56 mmol) was added. The mixture was reacted at room temperature for 2 h, diluted with water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a yellow solid L-11 (0.18 g), with a yield of 65%. ESI-MS: m / z = 370.1 [M+H] + .

[0154] 19. Preparation of intermediate L-12-L-22

[0155] The preparation of intermediates L-12-L-15 and L-17 is the same as that of L-11, except that the starting material 4-piperidinylmethanol is replaced with 3-azacyclobutylmethanol, pyrrolidine-3-ylmethanol, azacyclobutane-3-ol, 2-(azacyclobutane-3-yl)ethanol, and 1-(azacyclobutane-3-yl)piperidin-4-yl)methanol, respectively.

[0156] The preparation of intermediate L-16 is the same as that of L-11, except that starting material 1a is replaced with 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione.

[0157] The preparation of intermediates L-18-L-22 is the same as that of L-11, except that the starting material 1a is replaced with 2-(2,6-dioxypiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione, 3-(5-fluoro-1-oxoisoindoline-2-yl)piperidin-2,6-dione, 4-bromo-N-(2,6-dioxopiperidin-3-yl)benzamide, 3-((4-bromophenyl)amino)piperidin-2,6-dione, 1-(5-bromo-4-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrido[2,1-d]pyrimidin-2,4(1H,3H)-dione, and the starting material 4-piperidinylmethanol is replaced with aziridine-3-ylmethanol, and the rest is the same.

[0158] The structural formula of intermediate L-12-L-22 is shown in Table 8 below.

[0159] Table 8

[0160]

[0161] 20. Preparation of intermediate L-23

[0162]

[0163] Step 1: Preparation of intermediate 4b

[0164] 4a (0.14 g, 2.0 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then MS2O (0.74 g, 5.0 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography to give a white solid 4b (0.12 g), with a yield of 91%.

[0165] Step 2: Preparation of intermediate L-23

[0166] 4b (0.33 g, 2.0 mmol) and 4a (0.96 g, 2.0 mmol) were dissolved in 5.0 mL of LMF, and DIPEA (0.49 g, 3.5 mmol) was added. The mixture was reacted at 78 °C for 2 hours. The solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a white solid L-23 (0.29 g), in 30% yield. ESI-MS: 422.1 [M+H] + .

[0167] 21. Preparation of intermediate L-24-L-27

[0168] The preparation of intermediate L-24 was the same as that of L-23, except that starting material 4a was replaced with piperidin-4-ylmethanol. The preparation of intermediates L-25-L-27 was the same as that of L-23, except that starting material 4a was replaced with 2-(2-(2-aminoethoxy)ethoxy)ethanol, 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethanol, and 6-aminohexanol, respectively, and starting material 1a was replaced with 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione. The structural formulas of intermediates L-24-L-27 are shown in Table 9 below.

[0169] Table 9

[0170]

[0171] 22. Preparation of intermediate L-28

[0172]

[0173] Step 1: Preparation of intermediate 5c

[0174] Dissolve 5a (0.84 g, 1.5 mmol) and 5b (0.96 g, 1.5 mmol) in 10.0 mL LMF, add HATU (0.76 g, 1.0 mmol) and DIPEA (0.52 g, 4.0 mmol), and react at room temperature for 1 hour. Dilute with water, extract with ethyl acetate, combine organic phases, wash with saturated NaCl solution, dry to anhydrous Na₂SO₄, and purify by column chromatography to give white solid 5c (0.58 g), yield 60%. ESI-MS: 605.2 [M+H] + .

[0175] Step 2: Preparation of intermediate L-28

[0176] 5c (0.60 g, 1.0 mmol) was dissolved in 5.0 mL of DCM, stirred until homogeneous, and then MS₂O (0.52 g, 3.0 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by column chromatography to give a white solid, L-28 (0.54 g), with a yield of 91%. ESI-MS: 683.2 [M+H] + .

[0177] 23. Preparation of intermediates L-29 and L-30

[0178] The preparation of intermediate L-29 is the same as that of L-28, except that the starting material 5a is replaced with 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propionic acid.

[0179] The preparation of intermediate L-30 is the same as that of L-28, except that starting material 5a is replaced with 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propionic acid, and starting material 5b is replaced with (2S,4R)-1-((R)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide, and the rest is the same.

[0180] The structural formulas of intermediate L-29-L-30 are shown in Table 9 below.

[0181] Table 9

[0182]

[0183] 24. Example

[0184] Example 1: Preparation of compound A1

[0185]

[0186] Warhead-1 (0.52 g, 1.0 mmol) and L-1 (0.34 g, 1.00 mmol) were dissolved in 3.0 mL of LDM, and DIPEA (0.11 g, 1.0 mmol) was added. After reacting at room temperature for 15 min, acetic acid (0.05 g, 1.0 mmol) was added first, followed by NaBH3CN (0.18 g, 3.0 mmol), and the reaction was continued at room temperature for 6 h. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, and purified by column chromatography to give a yellow solid Al (0.19 g), in 21% yield. ESI-MS: 849.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ12.63(s,1H),11.06(s,1H),9.05(s,1H),8.58(s,1H),8.38(s,1H),8.19(s,1H),8.08(s,1H),7.99-7 .25(m,3H),5.31(m,1H),3.65(s,3H),3.54-3.34(m,8H),3.33-3.04(m,4H),2.69(s,3H),2.22-2.09(m,6H),1.56-1.31(m,5H).

[0187] Example 2: Preparation of compound A2

[0188]

[0189] The preparation of compound A2 followed the synthesis of compound A1, except that starting material L-1 was replaced with L-2, all other steps were the same, yielding a yellow solid A2 (XX g), in XX% yield. ESI-MS: 890.2 [M+H] + .

[0190] Example 3: Preparation of compound A3

[0191]

[0192] Warhead-2 (0.69 g, 2.0 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1a, 0.55 g, 2.0 mmol) were dissolved in 4.0 mL of DMSO. DIPEA (0.52 g, 4.0 mmol) was added, and the mixture was reacted at 90 °C for 5 hours. The solution was diluted with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a white solid A₃ (0.20 g), in 29% yield. ESI-MS: 766.1 [M+H] + .

[0193] Example 4: Preparation of compounds A4-A5

[0194] The preparation of compounds A4-A5 follows the same procedure as compound A2, except that the starting material warhead-2 is replaced with warhead-3 and warhead-4, respectively. The structural formulas of compounds A4 and A5 are shown in Table 10 below.

[0195] Table 10

[0196]

[0197] Example 5: Preparation of compounds A6-A7

[0198] The preparation of compounds A6-A7 is the same as that of compound A1, except that starting material L-1 is replaced with L-3 and L-4 respectively. The structural formulas of compounds A6 and A7 are shown in Table 11 below.

[0199] Table 11

[0200]

[0201] Example 6: Preparation of compounds A8-A13

[0202] The preparation of compounds A8-A11 was performed following the synthesis of compound A1, using warhead 5 as a common starting material. L-1 was replaced with L-11, L-12, L-14, and L-15, respectively, while maintaining the same procedure. The preparation of compounds A12-A13 was similar to the synthesis of compound A1, using warhead 6 as a common starting material. L-1 was replaced with L-12 and L-11, respectively, while maintaining the same procedure. The structural formulas of compounds A8-A13 are shown in Table 12 below.

[0203] Table 12

[0204]

[0205] Example 7: Preparation of compound A14

[0206]

[0207] Warhead-7 (0.45 g, 2.0 mmol) and L-23 (0.70 g, 2.0 mmol) were dissolved in 3.5 mL of LDMF, and DIPEA (0.52 g, 4.0 mmol) was added. The mixture was reacted at 50 °C for 3 hours. The solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and purified by column chromatography to give a yellow solid A14 (0.27 g), in 25% yield. ESI-MS: 830.1 [M+H] + .

[0208] Example 8: Preparation of compound A15

[0209]

[0210] Compound A15 was prepared by referring to the synthesis of compound A14, except that starting material L-23 was replaced with L-24, and all other steps remained the same. ESI-MS: 869.2 [M+H] + .

[0211] Example 9: Preparation of compounds A16-A21 and A22-A27

[0212] The preparation of compounds A16-A21 was carried out with reference to the synthesis of compound A1, using warhead-1 as a common starting material. L-1 was replaced with L-5, L-6, L-7, L-8, L-9, and L-10 respectively, while other steps remained the same, to prepare compounds A16-A21.

[0213] The preparation of compounds A22-A27 was carried out with reference to the synthesis of compound A14, using warhead-8 as a common starting material. L-23 was replaced with L-25, L-26, L-27, L-28, L-29, and L-30, respectively, while other steps remained the same, to obtain compounds A22-A27.

[0214] The structural formulas of compounds A16-A21 and A22-A27 are shown in Table 13 below.

[0215] Table 13

[0216]

[0217] Example 10: Preparation of compounds A28-A39

[0218] The preparation of compounds A28-A39 was performed following the synthesis of compound A1, using L-1 as a common starting material. Warhead-1 was replaced with warhead-9, warhead-10, warhead-11, warhead-12, warhead-13, warhead-14, warhead-15, warhead-16, warhead-17, warhead-18, warhead-19, and warhead-20, respectively, while maintaining the same procedure. The structural formulas of compounds A28–A39 are shown in Table 14 below.

[0219] Table 14

[0220]

[0221] Example 11: Preparation of compounds B1-B6, B7-B8, B9-B11, and B12-B13

[0222] The preparation of compounds B1-B6 was carried out with reference to the synthesis of compound A1, using warhead-21 as a common starting material. L-1 was replaced with L-12, L-11, L-13, L-14, and L-15 respectively, while other steps remained the same, to prepare compounds B1-B6.

[0223] The preparation of compounds B7-B8 was carried out with reference to the synthesis of compound A1, using L-12 as a common starting material. Warhead-21 was replaced with warhead-22 and warhead-23 respectively, and the rest were the same, to prepare compounds B7-B8.

[0224] The preparation of compounds B9-B11 was carried out with reference to the synthesis of compound A14, using warhead-24 as a common starting material, and replacing L-23 with L-25, L-26 and L-27 respectively, while keeping other aspects the same, to prepare compounds B9-B11;

[0225] The preparation of compound B12 was the same as that of compound A14, except that the starting material warhead-7 was replaced with warhead-24.

[0226] The preparation of compound B13 was carried out with reference to the synthesis of compound A14. Warhead-24 was used as the starting material, and L-23 was replaced with L-24. All other steps were the same, and compound B13 was prepared.

[0227] The structural formulas of compounds B1-B13 are shown in Table 15 below.

[0228] Table 15

[0229]

[0230]

[0231] Example 12: Preparation of compounds B14-B18, B19-B21, and B22-B27

[0232] The preparation of compounds B14-B18 was carried out with reference to the synthesis of compound A1, using warhead-21 as a common starting material. L-1 was replaced with L-18, L-19, L-20, L-21 and L-22 respectively, and the rest were the same, to prepare compounds B14-B18.

[0233] The preparation of compounds B19-B21 was carried out with reference to the synthesis of compound A14, using warhead-24 as a common starting material, and replacing L-23 with L-28, L-29 and L-30 respectively, while keeping other aspects the same, to prepare compounds B19-B21;

[0234] The preparation of compounds B22-B27 was carried out with reference to the synthesis of compound A1, using L-1 as a common starting material. Warhead-1 was replaced with warhead-26, warhead-27, warhead-28, warhead-29, warhead-30, and warhead-31, respectively, while other steps remained the same. The structural formulas of compounds B14-B27 are shown in Table 16 below.

[0235] Table 16

[0236]

[0237]

[0238] Example 13: Assay of the inhibitory activity of selected compounds against POLθ helicase (ADP-Glo ​​assay)

[0239] The ability of compounds to bind to and inhibit Polθ helicase activity in vitro was tested using the ADP Glo assay. Compound solution preparation: The compounds were first dissolved in DMSO, and then serially diluted 3-fold with sterile deionized ultrapure water to obtain eight concentrations of compound solutions. A 2×helicase domain Polθ enzyme and DNA mixture was prepared in buffer (25 mM Tris-HCl pH 7.5, 6 mM NaCl, 1.5 mM MgCl2, 5% (v / v) glycerol, 0.01% (v / v) Triton X-100, 0.01% (w / v) Bovine γ-Globulin, 1 mM dithiothreitol). A substrate solution containing 2×ATP was prepared in buffer. 1 μL of each concentration of compound solution was added to a 384-well plate, centrifuged, and then 2 μL of the 2×helicase domain Polθ enzyme and DNA mixture and the enzyme-free buffer containing DNA were added. The plate was centrifuged again and pre-incubated for 30 minutes. Subsequently, 2 μL of 2×ATP solution was added to each well, mixed, centrifuged, and incubated at room temperature for 60 minutes. Then, 5 μL of ADP-Glo ​​reagent was added to each well to stop the reaction, mixed, centrifuged, and incubated at room temperature for 60 minutes. Next, 10 μL of ADP-Glo ​​Kinase Detection Reagent was added to each well, centrifuged, and after equilibration for 60 minutes, the inhibition rate of each compound was measured using a microplate reader. The experimental results are shown in Table 17.

[0240] Table 17 shows the inhibitory activity of some compounds on POLθ helicase.

[0241] serial number <![CDATA[IC 50 ]]> A1 ++++ A2 +++ A3 ++

[0242] Where "++++" represents IC 50 Value ≤ 10nM; "+++" indicates 10nM ≤ IC 50 Value ≤ 30nM; "++" indicates 30nM ≤ IC 50 Value ≤ 50 nM. As can be seen from Table 17, the compounds of the present invention have good inhibitory activity against POLθ enzyme.

[0243] Example 14: Determination of the inhibitory effect of some compounds on the formation of DLD-1BRCA2(- / -) cell clones.

[0244] DLD-1BRCA2(- / -) cells were cultured and seeded at a density of 1000 cells / well. The culture plates were incubated overnight at 37°C, 5% CO2, and 100% relative humidity. Then, DLD-1BRCA2(- / -) cells were treated with different concentrations of the compound and incubated for 144 hours at 37°C, 5% CO2, and 100% relative humidity. After equilibration to room temperature, 50 μL / well of CellTiter-Glo working solution was added, and the cells were incubated at room temperature for 10 minutes in the dark. Fluorescence was then measured using a chemiluminescence module on a TECAN microplate reader, and the data were read. The IC50 was obtained by four-parameter fitting of the data. 50 The values ​​were used to calculate the biological activity of the compounds. The experimental results are shown in Table 18.

[0245] Table 18 shows the inhibitory effects of some compounds on DLD-1BRCA2(- / -) cell colony formation.

[0246] serial number <![CDATA[IC 50 ]]> A1 +++ A2 ++ A3 ++

[0247] Where "++" indicates IC 50 Value ≤ 100nM; "++" indicates 100nM ≤ IC 50 Value ≤ 300nM.

[0248] As can be seen from Table 18, the compounds of the present invention have a good inhibitory effect on the proliferation of DLD-1BRCA2(- / -) cells.

[0249] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit the technical solutions. Those skilled in the art should understand that any modifications or equivalent substitutions to the technical solutions of the present invention without departing from the spirit and scope of the present invention should be covered within the scope of the claims of the present invention.

Claims

1. A compound targeting the POLθ helicase domain, characterized in that, The compound has a structure of general formula (I) or (II): in: W, X, Y, and Z are each independently selected from N or CR. X ;R X Selected from H, D, halogens, OH, NH2, CN, C 1-4 Alkyl or C 1-4 Alkoxy; R A1 R A2 R A3 R A4 Each is independently selected from H, D, halogens, OH, CN, NH2, SF5, and C. 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, deuterated C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-10 The heterocyclic alkyl group or 5-10 heteroaryl group contains 1-3 heteroatoms selected from N, S, and O; the heterocyclic alkyl group, aryl group, and heteroaryl group are optionally surrounded by 1-5 R atoms. 1a replace; R 1a Each is independently selected from D, halogens, CN, =O, OH, NH2, C 1-4 Alkyl or C 1-4 Alkoxy; B is selected from C. 3-10 Cycloalkyl, 4-10 membered heterocyclic alkyl, C 6-12 The heterocyclic alkyl group or 5-12 heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, and the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are optionally surrounded by 1-5 R atoms. 1b replace; R 1b Each is independently selected from D, halogen, CN, =O, OH, NH2, COOH, C 1-4 Alkyl or C 1-4 Alkoxy; L is a linking group, selected from one or more of the following groups: straight-chain or branched alkyl, alkoxy, alkylamine, haloheterocyclic, alkenyl, alkynyl, alkynoxy, alkynamine, cycloalkyl, heterocycloalkyl, spirocycloalkyl, heterospirocycloalkyl, phencycloalkyl, heterophenocycloalkyl, aryl, haloaryl, heteroaryl. -CO(CH2) n -、-CO(CH2) n O-、-(CH2) n NH2-、-(CH2) n NR L -、-CO(CH2) n NH-、-CO(CH2) n NR L - -(CH2) n CONH(CH2) n -、-(CH2) n CONH(CH2) n NH-、-(CH2) n CONH(CH2) n NR L -、-CO(CH2) n NHCO(CH2) n -、-CO(CH2) n NHCO(CH2) n NH-、-CO(CH2) n NHCO(CH2)nNR L -、-CO(CH2OCH2) n CH2NHCO(CH2) n -、-CO(CH2OCH2) n CH2NHCO(CH2) n NH-、-CO(CH2OCH2) n CH2NHCO(CH2) n NR L -、-CH2(CH2OCH2) n CH2-、-CH2(CH2OCH2) n CH2NH-、-CH2(CH2OCH2) n CH2NR L -、-CH2(CH2OCH2) n CH2O-、-CH2CONHCH2(CH2OCH2) n CH2NH-、-CH2CONHCH2(CH2OCH2) n CH2NR L -、-CH2CONHCH2(CH2OCH2) n CH2NHCO(CH2) n NH- -CH2CONHCH2(CH2OCH2) n CH2NHCO(CH2) n NR L -, -CH2CONHCH2(CH2OCH2) n CO-, -CH2(CH2OCH2) n CH2CO- or any combination thereof; n represents a natural number from 1 to 20; R L For H or C 1-10 alkyl; E3 ligand is the E3 ligase ligand for CRBN or VHL.

2. The compound according to claim 1, characterized in that, It can be any of the following structural formulas:

3. The compound according to claim 1, characterized in that, It can be any of the following structural formulas:

4. The compound according to claim 1, characterized in that, It can be any of the following structural formulas:

5. The compound according to claim 1, characterized in that, B is preferred from R 1b The following heterocyclic alkyl, aryl, or heteroaryl groups are substituted:

6. The compound according to claim 1, characterized in that, R 1b It is selected from any one of hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyano, and ethynyl.

7. The compound according to claim 1, characterized in that, L is selected from any of the following structures: acetylene, propyne, -O-, -CONH-, -CH2CH2-.

8. The compound according to claim 1, characterized in that, In the general formula, E3 Ligand is selected from any of the following structures:

9. The compound according to claim 1, characterized in that, The compound has any one of the following structures:

10. An application of a compound, characterized in that, The compound of any one of claims 1-9, its isomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, may be used to prepare a drug targeting the POLθ helicase domain.

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