Acetylenic compounds, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application discloses an alkyne compound, a preparation method, a pharmaceutical composition and an application thereof. The structure of the compound is shown as (I), and the compound also comprises stereoisomers, pharmaceutically acceptable salts or mixtures thereof. The compound can effectively inhibit the activity of Pol theta protein, thereby effectively inhibiting the proliferation of tumor cells. The compound has definite biological activity, can be prepared into a medicine for treating breast cancer, ovarian cancer and other cancers, and has wide application. The preparation method of the compound has strong applicability and is easy to expand to multiple types of chemical structures.

Description

Technical Field

[0001] This invention relates to an alkyne compound, its preparation method, pharmaceutical composition, and application, and particularly to an alkyne compound with Polθ inhibitory activity, its preparation method, pharmaceutical composition, and application. Background Technology

[0002] Targeting cancer cells through synthetic lethal mechanisms is an emerging therapeutic strategy. Polθ (DNA polymerase θ) is a large, multifunctional DNA repair protein encoded by the POLQ gene. Composed of 2590 amino acids, it contains three domains: an N-terminal SF2 helicase domain (Polθ-hel, residues 32-899), a non-structural central domain, and a C-terminal A-family polymerase domain (Polθ-pol, residues 1819-2590). Polθ has a synthetic lethal relationship with cancers deficient in homologous recombination (HR), including genes such as BRCA1 / 2, ATM, ATR, and TP53BP1. Polθ is a protein that repairs DNA double-strand breaks and plays a crucial role in the microhomology-mediated end-linking pathway. The survival of HR-deficient cancer cells is more dependent on Polθ activity. Polθ has been found to be overexpressed in various human malignancies, including those of the lung, stomach, small intestine, rectum, breast, ovary, and head and neck, promoting cancer cell growth and survival, and may be a factor contributing to more aggressive and recurrent tumors. It is expressed at low levels or not at all in most normal cells, making this enzyme an ideal anti-tumor target. Currently, no Polθ inhibitors have been approved for marketing, and several are in clinical trials. Summary of the Invention

[0003] Objectives of the Invention: The first objective of this invention is to provide an alkyne compound with Polθ inhibitory activity; the second objective is to provide a method for preparing the compound; the third objective is to provide a pharmaceutical composition comprising the compound; and the fourth objective is to provide a pharmaceutical application of the compound and the pharmaceutical composition thereof.

[0004] Technical solution: The alkyne compounds of the present invention have the structure of formula (I), and also include their stereoisomers, pharmaceutically acceptable salts, or mixtures thereof.

[0005]

[0006] in:

[0007] A is selected from

[0008] X is selected from NH, O, or S;

[0009] R 1Selected from H, halogens, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, OH, NR 2 R 3 CN, CO2H, CO2CH3, CONH2 or NO2;

[0010] R 2 R 3 Selected from H, C1-C6 alkyl or COR 4 ;

[0011] R 4 Selected from H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0012] L is selected from the substituted C1 to C2. 10 Alkyl groups, substituted phenyl or aromatic heterocyclic groups, substituted C3-C6 cycloalkyl groups, substituted C4-C6 heterocyclic alkyl groups, n is selected from any integer from 1 to 10; the aromatic heterocyclic group is selected from five-membered or six-membered rings or 8- to 14-membered bicyclic aromatic heterocycles containing 1 to 3 O, N, or S atoms; the C4 to C6 heterocyclic alkyl group is tetrahydrofuranyl, hexahydropyranyl, morpholinyl, tetrahydropyrroleyl, piperidinyl, piperazineyl, or aziridine; the substituent is selected from at least one H, halogen, CN, NO2, OH, or NR. 2 R 3 C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, CO2H, CO2CH3 or CONR 5 R 6 ;

[0013] Ar is selected from substituted phenyl or aromatic heterocyclic groups, wherein the aromatic heterocyclic group is selected from five-membered or six-membered rings or 8- to 14-membered bicyclic aromatic heterocycles containing 1 to 3 O, N, or S atoms; the substituent is selected from at least one H, halogen, CN, NO2, OH, or NR. 2 R 3 C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkenyl, CO2H, CO2CH3 or CONR 5 R 6 ;

[0014] R 5 R 6 Selected from H, C1-C6 alkyl or C3-C6 cycloalkyl.

[0015] Preferably, in the structure:

[0016] A is selected from

[0017] X is selected from NH or O;

[0018] R 1 Selected from H, halogens, OH, CN, CO2H, CO2CH3, CONH2, or NO2;

[0019] L is selected from n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0020] Preferably, in the structure:

[0021] R 1 Selected from H;

[0022] L is selected from n is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; n is more preferably selected from 1, 2, 3, 4, 5, 6 or 7.

[0023] Ar is selected from substituted phenyl, pyrimidinyl, pyridazinyl, or pyridinyl groups, wherein the substituent is selected from at least one H, halogen, CN, NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy groups; more preferably, Ar is 3,6-pyridazinyl, 2,5-pyridinyl, 1,4-phenyl, or 2,5-pyridinyl.

[0024] Preferably, the alkyne compound is selected from any of the following compounds:

[0025]

[0026]

[0027]

[0028]

[0029] This invention designs a class of small Polθ inhibitory molecules containing alkyne structures. Polθ participates in microhomology-mediated end joining, thereby repairing DNA double-strand breaks. It is overexpressed in various HR-deficient tumors and presents at low levels in normal cells, making it a promising new drug target for cancer treatment discovered in recent years. To date, no Polθ inhibitor drugs have been approved for marketing.

[0030] Preferably, the pharmaceutically acceptable salt of the present invention is a salt formed by the alkyne compound and an acid selected from any of the following:

[0031] Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.

[0032] "Pharmaceutically acceptable salts" refer to salts of compounds prepared by reacting a compound with a relatively non-toxic acid or base, containing specific substituents. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bisulfates), hydroiodic acid, phosphorous acid, etc.); and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid. Acids such as citric acid, tartaric acid, and methanesulfonic acid; organic acid salts also include salts of organic acids such as amino acids (e.g., arginine) and glucuronic acid. Certain compounds contain both basic and acidic functional groups, thus allowing them to be converted into either a base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0033] Pharmaceutically acceptable salts can be synthesized from parent compounds containing an acid radical or a base using conventional chemical methods. Generally, such salts are prepared by reacting these compounds, in their free acid or base form, with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred.

[0034] Preferably, the stereoisomers of the present invention are chiral isomers introduced by the chiral carbon in the central nitrogen-containing heterocyclic ketone ring system.

[0035] The method for preparing the alkyne compounds of the present invention is selected from the following methods:

[0036] When L is The preparation method of compound IA is as follows:

[0037]

[0038] Where: A and Ar are defined as described above, and n is selected from any integer from 1 to 10;

[0039] The corresponding acid is salted with the alkyne compound prepared by the above method to obtain the pharmaceutically acceptable salt described in this invention.

[0040] Specifically, the preparation method of compound IA includes the following steps:

[0041] Compound IV was prepared from compound II and p-fluoroaniline (III), using a condensing agent selected from N,N'-carbonyldiimazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (HATU), 1H-benzotriazol-1-yloxytripyrrolidinylhexafluorophosphate (PyBOP), or N N,N',N'-Tetramethylchloroformamidine hexafluorophosphate (TCFH), preferably TCFH; the base is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, N-methylimidazolium (NMI), N,N-diisopropylethylamine (DIPEA) or triethylamine, preferably NMI; the solvent is selected from N,N-dimethylformamide (DMF), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 1,4-dioxane or any mixture of both, preferably acetonitrile; the reaction temperature is 25-80℃, preferably 25℃.

[0042] Compound VI was prepared from compounds IV and V, using a catalyst selected from cuprous iodide, cuprous oxide, Pd(PPh3)2Cl2, Pd(OAc)2, or Pd2(dba)3, preferably cuprous iodide; the ligand was selected from (1S,2S)-(+)-1,2-cyclohexanediamine, 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (Ruphos), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (Xphos), 2-(di-tert-butylphosphine) The reaction mixture is selected from benzene (Johnphos) or 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos), preferably (1S,2S)-(+)-1,2-cyclohexanediamine; the base is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, potassium phosphate or cesium carbonate, preferably potassium carbonate; the solvent is selected from DMF, toluene, N,N-dimethylacetamide (DMAc), 1,4-dioxane, THF, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP), preferably 1,4-dioxane; the reaction temperature is 60–150 °C, preferably 100 °C.

[0043] Compound VII is prepared from compound VI and 3-bromopropyne. The base is selected from sodium hydride, potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, triethylamine, potassium tert-butoxide, or cesium carbonate, preferably cesium carbonate; the solvent is selected from NMP, DMAc, DMSO, DMF, THF, acetonitrile, acetone, toluene, or a mixture of two solvents, preferably DMF; the reaction temperature is 0–70°C, preferably 25°C.

[0044] Compound IX is prepared by reacting compound VII with compound (VIII). The solvent used is selected from THF, acetonitrile, NMP, DMAc, DMSO, DMF or 1,4-dioxane, preferably DMF; the base used is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, triethylamine or DIPEA, preferably triethylamine; the catalyst used is Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, Pd2(dba)3 or Pd(PPh3)2Cl2, preferably Pd(PPh3)2Cl2; the reaction temperature is 25-150℃, preferably 100℃.

[0045] Compound XI is prepared by reacting compound IX and compound (X). The condensing agent used is selected from CDI, DCC, DIC, EDCI, HATU, PyBOP or TCFH, preferably HATU; the base is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, NMI, DIPEA or triethylamine, preferably DIPEA; the solvent is selected from DMF, acetonitrile, dichloromethane, THF, 1,4-dioxane or a mixture of any two, preferably DMF; the reaction temperature is 25-80℃, preferably 25℃.

[0046] Compound IA is obtained by reacting compound XI under acidic conditions. The acid used is selected from hydrochloric acid / dioxane, hydrochloric acid / ethyl acetate, hydrochloric acid / methanol, or trifluoroacetic acid, preferably trifluoroacetic acid; the solvent is selected from dioxane, methanol, ethyl acetate, dichloromethane, or THF, preferably dichloromethane; the reaction temperature is -20 to 50°C, preferably 25°C.

[0047] The corresponding acid is salted with the alkyne compound prepared by the above method to obtain the pharmaceutically acceptable salt described in this invention.

[0048] The pharmaceutical composition of the present invention comprises the alkyne compound of the present invention and a pharmaceutically acceptable carrier.

[0049] Preferably, the formulation of the drug combination is selected from tablets, capsules, powders, pills, granules, injections, oral liquids, syrups, inhalers, ointments, patches, or suppositories.

[0050] "Pharmaceutically acceptable carriers" are excipients widely used in the pharmaceutical manufacturing industry. Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition, and may also provide methods to facilitate the dissolution of the active ingredient at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after administration to a subject. The pharmaceutical excipients may be inert fillers or provide a function, such as stabilizing the overall pH of the composition or preventing the degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulators, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0051] The pharmaceutical compositions described in this invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0052] The pharmaceutical compositions of this invention can be administered in any form, including by injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical, or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical compositions of this invention can also be controlled-release or sustained-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral formulations include, but are not limited to, solutions for injection, dry powder formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and tablets.

[0053] The alkyne compounds or pharmaceutical compositions thereof described in this invention are used in the preparation of drugs for Polθ inhibitors.

[0054] Preferably, the drug is a drug for treating tumors.

[0055] Further preferably, the drug is a drug for treating ovarian cancer, colon cancer, or breast cancer.

[0056] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0057] The compound designed in this invention can effectively inhibit Polθ enzyme activity, with molecular-level inhibition of IC50. 50 The value reached nanomolar levels, and the inhibitory IC50 value on the proliferation of related cancer cells reached nanomolar levels. 50 The values ​​reach single-digit micromolar levels. It possesses definite biological activity and can be used to prepare drugs for treating cancers such as breast cancer and ovarian cancer, with wide applications. The compound preparation method is highly adaptable and easily expands to various types of chemical structures. Detailed Implementation

[0058] The technical solution of the present invention will be further described below with reference to the embodiments.

[0059] Example 1: Synthesis of (4S)-N-(3-(6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-1)

[0060] (1) Synthesis of (S)-4-((4-fluorophenyl)carbamoyl)-2-oxoimidazolidine-1-carboxylic acid tert-butyl ester (IV)

[0061] Compound II (920 mg, 4 mmol), 4-fluoroaniline (476 mg, 4 mmol), and N-methylimidazole (692 mg, 8.4 mmol) were added to acetonitrile (10 mL) and stirred. TCFH (1.23 g, 4.4 mmol) was then added, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete, the turbid liquid was directly filtered to give 857 mg of a white solid, with a yield of 66.3%. 1 H NMR(400MHz,DMSO-d6)δ(ppm):10.21(s,1H),7.73(s,1H),7.66-7.58(m,2H),7.22-7.13(m,2H), 4.20(dd,J=10.0,4.4Hz,1H), 4.00(t,J=10.2Hz,1H), 3.71(dd,J=10.6,4.5Hz,1H), 1.44(s,9H).

[0062] (2) Synthesis of (S)-4-((4-fluorophenyl)carbamoyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylic acid tert-butyl ester (VI)

[0063] Compound IV (809 mg, 2.5 mmol), compound V (600 mg, 2.5 mmol), cuprous iodide (48 mg, 0.25 mmol), (1S,2S)-(+)-1,2-cyclohexanediamine (29 mg, 0.25 mmol), and potassium carbonate (691 mg, 5 mmol) were added to a reaction flask. After adding 6 mL of 1,4-dioxane, the mixture was purged with nitrogen three times. The mixture was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 8:1–2:1) to obtain 683 mg of a white solid, with a yield of 56.6%. 1 H NMR(300MHz,DMSO-d6)δ(ppm):10.56(s,1H),8.29(s,1H),7.64-7.51(m,2H),7.36(s,1H),7.23-7.09(m,2H), 5.08(dd,J=10.1,3.5Hz,1H),4.13(t,J=10.3Hz,1H),3.76(dd,J=10.6,3.5Hz,1H),2.39(s,3H),1.50(s,9H).

[0064] (3) Synthesis of (S)-4-((4-fluorophenyl)(prop-2-yn-1-yl)carbamoyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylic acid tert-butyl ester (VII)

[0065] Compound VI (241 mg, 0.5 mmol) was dissolved in DMF (2 mL), and cesium carbonate (489 mg, 1.5 mmol) and 3-bromopropyne (90 mg, 0.75 mmol) were added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 8:1 to 5:1) to give 250 mg of white solid, yield 96.2%, MS (ESI+) m / z 521.2 [M+H]. + .

[0066] (4) Synthesis of (S)-4-((3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)(4-fluorophenyl)carbamoyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-1-carboxylic acid tert-butyl ester (IX-1)

[0067] Compound VII (250 mg, 0.48 mmol), 6-bromopyridazine-3-amine (VIII-1, 84 mg, 0.48 mmol), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), and cuprous iodide (10 mg, 0.048 mmol) were placed in a reaction flask. Triethylamine (134 μL, 0.96 mmol) and DMF (2 mL) were added, followed by purging with nitrogen three times. The mixture was then heated to 100 °C and stirred for 2 hours. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 2:1 to 1:2) to give 250 mg of a brown solid, with a yield of 78.4%. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.29 (s, 1H), 7.69 (dd, J = 8.0, 4.9Hz, 2H), 7.64 (s, 1H), 7.45 (t, J = 8.7Hz, 2H), 7.27-7.16 (m, 2H), 6.85-6.72 (m, 3H) ), 4.96 (d, J = 17.7Hz, 1H), 4.79 (dd, J = 10.0, 4.0Hz, 1H), 4.46 (d, J = 17.7Hz, 1H), 3.40 (dd, J = 9.4, 4.1Hz, 1H), 3.33 (t, J = 9.7Hz, 1H), 2.50 (s, 3H).

[0068] (5) Synthesis of (4S)-N-(3-(6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-1)

[0069] Compound IX-1 (100 mg, 0.16 mmol) and 3-((2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propionic acid (X-1, 84 mg, 0.24 mmol) were dissolved in DMF (2 mL), followed by the addition of DIPEA (63 mg, 0.49 mmol). The reaction mixture was stirred in an ice-water bath. HATU (93 mg, 0.24 mmol) was added, and the mixture was heated to room temperature and stirred for 12 hours. After the reaction was complete, water was added, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed once with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 1:1 to 1:2) to obtain 124 mg of a yellow-green solid, with a yield of 81.05%. MS (ESI+) m / z 963.4 [M+Na] + The above product was dissolved in DCM (4 mL), and 4 mL of a trifluoroacetic acid-DCM mixed solvent (v / v = 1:1) was added dropwise under ice bath. After the addition was complete, the mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction. The mixture was extracted three times with DCM, and the combined organic phases were washed once with saturated sodium chloride. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 1:2-EA), and then slurried with ethyl acetate:diethyl ether = 1:3 to obtain 24 mg of a yellow-green solid, with a yield of 26.86%. MS (ESI+) m / z 841.4 [M+H] + . 1 H NMR (300MHz, Chloroform-d) δ (ppm): 11.04 (s, 1H), 8.79 (d, J = 9.4Hz, 1H), 8.54 (s, 1 H),8.38(s,1H),7.65(s,2H),7.51-7.36(m,3H),7.22(s,1H),7.03(d,J=7.0Hz,1H) ,6.97-6.90(m,2H),6.54(s,2H),5.16-5.00(m,2H),4.92(s,1H),4.38(d,J=17.3Hz ,1H),3.71(s,3H),3.57-3.46(m,1H),2.94(s,2H),2.90-2.66(m,4H),2.54(s,3H).

[0070] Example 2: Synthesis of (4S)-N-(3-(6-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyramido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-2)

[0071] Compound IA-2 was prepared from compound IX-1 and compound 4-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)butyric acid (X-2) according to the method of Example 1. MS (ESI+) m / z 855.4 [M+H] + . 1 H NMR(300MHz,Chloroform-d)δ(ppm):10.75(s,1H),8.78(s,1H),8.53(s,1H),8.41 (s,1H),7.69(s,2H),7.47(s,2H),7.24(s,1H),7.04(d,J=6.6Hz,1H),6.96(s,1H), 6.90(d,J=7.4Hz,1H),6.37(s,1H),5.13(s,1H),5.04(s,1H),4.87(s,1H),4.39(s ,1H),3.73-3.55(m,1H),3.39(s,2H),2.90-2.66(m,5H),2.55(s,3H),2.13(s,5H).

[0072] Example 3: Synthesis of (4S)-N-(3-(6-(5-((2-(2,6-dioxopiridin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)pentamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-3)

[0073] Compound IA-3 was prepared from compound IX-1 and compound 5-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)valeric acid (X-3) according to the method of Example 1. MS (ESI+) m / z 869.4 [M+H] + . 1H NMR(300MHz,Chloroform-d)δ(ppm):10.14(s,1H),8.70-8.46(m,2H),8.41(s,1H),7.65(s, 2H),7.48(t,J=7.5Hz,2H),7.24(s,1H),7.07(d,J=6.9Hz,1H),6.97(s,1H),6.91-6.85(m,1H ),6.22(s,1H),6.09(s,1H),5.05(s,2H),4.93(s,1H),4.49(s,1H),3.64(s,1H),3.50(s,1H ),3.28(s,2H),2.94-2.71(m,3H),2.62-2.50(m,4H),2.12(s,1H),1.84(s,4H),1.48(s,2H).

[0074] Example 4: Synthesis of (4S)-N-(3-(6-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-4)

[0075] Compound IA-4 was prepared from compound IX-1 and compound 6-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexanoic acid (X-4) according to the method of Example 1. MS (ESI+) m / z 883.4 [M+H] + . 1 H NMR(300MHz,Chloroform-d)δ(ppm):10.14(s,1H),8.62-8.46(m,2H),8.41(s,1H),7.65( s,2H),7.48(t,J=7.5Hz,2H),7.23(s,1H),7.07(d,J=6.9Hz,1H),6.97(s,1H),6.87(d,J=8 .3Hz,1H),6.16(d,J=40.1Hz,2H),4.99(d,J=36.5Hz,4H),4.49(s,1H),3.57(d,J=42.9Hz ,2H),3.28(s,2H),2.88-2.70(m,3H),2.55(s,4H),2.12(s,1H),1.84(s,5H),1.51(s,2H).

[0076] Example 5: Synthesis of (4S)-N-(3-(6-(7-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-5)

[0077] Compound IA-5 was prepared from compound IX-1 and compound 7-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)heptanoic acid (X-5) according to the method of Example 1. MS (ESI+) m / z 897.4 [M+H] + . 1 H NMR (300MHz, Chloroform-d) δ (ppm): 10.24 (s, 1H), 8.53 (d, J = 8.8Hz, 1H), 8.40 (s, 1H), 7. 65(s,2H),7.53-7.46(m,2H),7.23(s,1H),7.11(d,J=7.0Hz,1H),6.97-6.90(m,2H),6.30( s,1H),5.03(s,2H),4.92(s,1H),4.62(s,1H),3.59(s,1H),3.50(s,1H),3.32(d,J=33.6Hz ,3H),2.98-2.74(m,4H),2.55(s,4H),2.50(s,2H),2.17(s,1H),1.70(s,3H),1.43(s,5H).

[0078] Example 6: Synthesis of (4S)-N-(3-(6-(8-((2-(2,6-dioxopiridine-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-6)

[0079] Compound IA-6 was prepared from compound IX-1 and compound 8-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)octanoic acid (X-6) according to the method of Example 1. MS (ESI+) m / z 911.4 [M+H] + . 1H NMR (300MHz, Chloroform-d) δ (ppm): 10.30 (s, 1H), 8.85 (d, J = 11.7Hz, 1H), 8.55 (d, J = 9.0Hz, 1H), 8 .41(s,1H),7.66(s,2H),7.54-7.43(m,2H),7.22(s,1H),7.08(d,J=7.1Hz,1H),6.97(s,1H),6.88( d,J=8.5Hz,1H),6.25(s,1H),5.09-4.93(m,3H),4.50(d,J=17.2Hz,1H),3.58(d,J=35.6Hz,2H),3. 27(s,2H),2.91-2.73(m,3H),2.59-2.50(m,5H),2.20-2.05(m,3H),1.78-1.60(m,4H),1.40(s,6H).

[0080] Example 7: Synthesis of (4S)-N-(3-(6-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)amino)heptamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-7)

[0081] Compound IA-7 was prepared from compound IX-1 and compound 7-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)heptanoic acid (X-7) according to the method of Example 1. MS (ESI+) m / z 883.4 [M+H] + . 1 H NMR (300MHz, Chloroform-d) δ (ppm): 10.74 (s, 1H), 8.57 (d, J = 6.7Hz, 2H), 8.40 (s, 1H), 7.67 (s, 2H) ),7.53(t,J=10.1Hz,2H),7.22(s,1H),6.93(d,J=11.0Hz,2H),6.81(s,1H),6.68(d,J=8.3Hz,1H) ,5.18-5.02(m,2H),4.94(s,1H),4.42(d,J=17.5Hz,1H),3.66(s,1H),3.53(s,1H),3.12(s,2H),2 .99-2.67(m,4H),2.66-2.44(m,6H),2.12(d,J=9.3Hz,1H),1.76(s,2H),1.61(s,2H),1.42(s,4H).

[0082] Example 8: Synthesis of (4S)-N-(3-(6-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pentamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-8)

[0083] Compound IA-8 was prepared from compound IX-1 and compound 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)valerate (X-8) according to the method of Example 1. MS (ESI+) m / z 870.4 [M+H] + . 1 HNMR (300MHz, Chloroform-d) δ (ppm): 10.04 (s, 1H), 9.12 (s, 1H), 8.45 (d, J = 9.2Hz, 1H), 8.36 (s, 1H), 7. 72-7.55(m,3H),7.45(d,J=7.2Hz,1H),7.40(d,J=9.2Hz,1H),7.24-7.18(m,2H),6.94(s,1H),5.80(s,1H ),5.05-4.96(m,2H),4.86(d,J=17.4Hz,1H),4.77-4.58(m,1H),4.27-4.22(m,1H),3.79(d,J=6.8Hz,1H ),3.55(s,1H),3.50-3.36(m,1H),2.96-2.77(m,5H),2.53(s,3H),2.33-2.16(m,2H),2.05-1.88(m,4H).

[0084] Example 9: Synthesis of (4S)-N-(3-(6-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)octamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-9)

[0085] Compound IA-9 was prepared from compound IX-1 and compound 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)octanoic acid (X-9) according to the method of Example 1. MS (ESI+) m / z 912.4 [M+H] + . 1HNMR(400MHz,Chloroform-d)δ(ppm):10.29(s,1H),9.14(s,1H),8.64-8.54(m,1H),8.40( s,1H),7.76-7.59(m,3H),7.52-7.42(m,2H),7.24-7.18(m,2H),6.97(s,1H),5.78(s,1H),5 .15-4.97(m,3H),4.54(d,J=17.6Hz,1H),4.24-4.15(m,2H),3.64(s,1H),3.52(s,1H),2.91 -2.75(m,3H),2.55(s,4H),2.15-1.99(m,4H),1.87(s,2H),1.75(s,2H),1.44-1.32(m,4H).

[0086] Example 10: Synthesis of (4S)-N-(3-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)acetamyl)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-10)

[0087] Compound IA-10 was prepared from compound IX-1 and compound 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)acetic acid (X-10) according to the method of Example 1. MS (ESI+) m / z 828.5 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ (ppm): 11.62 (s, 1H), 11.14 (s, 1H), 8.32-8.28 (m, 2H), 7.88 (d, J=8.3Hz, 1H), 7.76 (d, J= 9.3Hz,1H),7.73-7.69(m,2H),7.63(s,1H),7.53(d,J=2.3Hz,1H),7.48(s,1H),7.46-7.42(m,2H),7.17(s,1H),5. 15(s,2H),5.12(d,J=5.4Hz,1H),5.03(d,J=17.8Hz,1H),4.81(dd,J=10.1,3.9Hz,1H),4.55(d,J=17.9Hz,1H),3.4 5-3.41(m,1H),3.33(d,J=9.6Hz,1H),2.95-2.85(m,1H),2.64-2.52(m,4H),2.10-2.02(m,1H),1.31-1.22(m,1H).

[0088] Example 11: Synthesis of (4S)-N-(3-(6-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-11)

[0089] Compound IA-11 was prepared from compound IX-1 and compound 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyric acid (X-11) according to the method of Example 1. MS (ESI+) m / z 856.4 [M+H] + . 1HNMR(300MHz,Chloroform-d)δ(ppm):10.81(s,1H),8.75(d,J=12.6Hz,1H),8.53(d,J=9.1Hz,1H) ,8.39(s,1H),7.74-7.58(m,3H),7.49(d,J=9.2Hz,1H),7.21(d,J=9.0Hz,2H),7.12(d,J=8.3Hz,1H ),6.95(s,1H),6.62(s,1H),5.11-4.90(m,3H),4.46(d,J=17.4Hz,1H),4.16(s,2H),3.56(d,J=33. 3Hz,2H),3.03-2.88(m,1H),2.90-2.63(m,5H),2.54(s,3H),2.28-2.24(m,3H),2.18-2.08(m,1H).

[0090] Example 12: Synthesis of (4S)-N-(3-(6-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-12)

[0091] Compound IA-12 was prepared from compound IX-1 and compound 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)valerate (X-12) according to the method of Example 1. MS (ESI+) m / z 870.4 [M+H] + . 1 HNMR (300MHz, Chloroform-d) δ (ppm): 10.75 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 8.8Hz, 1H), 8.39 (s, 1H),7.72-7.60(m,3H),7.47(d,J=9.0Hz,1H),7.23(s,1H),7.14(d,J=8.3Hz,1H),6.95(s,1H),6. 80(s,1H),5.11(d,J=20.9Hz,2H),4.96(s,1H),4.40(d,J=17.3Hz,1H),4.09(s,2H),3.73-3.53( m,2H),3.12(s,1H),2.79-2.67(m,3H),2.54(s,3H),2.45-2.26(m,2H),2.13(s,1H),1.93(s,5H).

[0092] Example 13: Synthesis of (4S)-N-(3-(6-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)heptamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-13)

[0093] Compound IA-13 was prepared from compound IX-1 and compound 7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)heptanoic acid (X-13) according to the method of Example 1. MS (ESI+) m / z 898.4 [M+H] + . 1 HNMR(400MHz,Chloroform-d)δ(ppm):10.44(s,1H),8.64-8.51(m,2H),8.41(s,1H),7.73(d,J=8.3Hz,1H) ,7.64(s,2H),7.46(d,J=9.3Hz,1H),7.29(s,1H),7.22(d,J=8.0Hz,1H),7.14(d,J=8.3Hz,1H),6.96(s,1H ),,5.08(d,J=17.3Hz,2H),5.00-4.94(m,1H),4.46(d,J=17.4Hz,1H),4.05(s,2H),3.65(s,1H),3.53(s,1 H),2.97-2.71(m,4H),2.59(s,2H),2.54(s,3H),2.20-2.09(m,2H),1.85-1.76(m,4H),1.54-1.44(m,4H).

[0094] Example 14: Synthesis of (4S)-N-(3-(6-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)octamido)pyridazin-3-yl)prop-2-yn-1-yl)-N-(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-14)

[0095] Compound IA-14 was prepared from compound IX-1 and compound 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)octanoic acid (X-14) according to the method of Example 1. MS (ESI+) m / z 912.4 [M+H] + . 1HNMR (300MHz, Chloroform-d) δ (ppm): 10.41 (s, 1H), 8.70 (d, J = 9.4Hz, 1H), 8.52 (d, J = 9.2Hz, 1H), 8.41 (s, 1H), 7.75 (d ,J=8.3Hz,1H),7.62(s,1H),7.45(d,J=9.2Hz,1H),7.31(s,1H),7.23(s,1H),7.17-7.14(m,1H),6.96(s,1H),6.71(s,1 H),5.08-4.93(m,4H),4.52(d,J=17.4Hz,1H),4.08-4.00(m,3H),3.61(s,1H),3.51(t,J=9.6Hz,1H),2.93-2.74(m,4H) ,2.60-2.45(m,7H),2.30(t,J=7.1Hz,1H),2.17-2.12(m,1H),1.83-1.70(m,5H),1.66-1.56(m,1H),1.35-1.33(m,1H).

[0096] Example 15: Evaluation of the inhibitory activity of the compound against Polθ enzyme

[0097] 1. Experimental Materials

[0098] POLQ-C was purchased from ICE, FITC-dATP from Perkin, dCTP, dGTP and dTTP from Roche, dsDNA from Genscript, and Streptavidin-Tb cryptate from Cisbio.

[0099] 2. Experimental Methods

[0100] (1) Experimental steps

[0101] Dissolve the compound sample in DMSO to prepare a 10 mM stock solution. Add 60 μL of the compound solution to a 384-well dilution plate; serially dilute to the desired concentration in DMSO; transfer 0.15 μL of diluted compound solution per row to a 384-well detection plate using Echo, with two replicates per concentration; add 5 μL of enzyme working solution to the 384-well detection plate and centrifuge at 1000 rpm for 1 minute; incubate at 25°C for 10 minutes; add 5 μL of substrate (dNTP and dsDNA) working solution to start the reaction; add 5 μL of Streptavidin-Tb cryptate working solution to start the reaction; incubate at 25°C for 60 minutes; read the fluorescence signals at 490 nm and 520 nm (ratio 520 / 490) using BMG.

[0102] (2) Experimental data processing

[0103] Enzyme activity inhibition rate (%) = 100 * (ave High control - cpd well) / (ave High control - ave Low control).

[0104] Using XLfit 5.5.0 to fit the IC of the compound from the nonlinear regression equation 50 value.

[0105] 3. Experimental Results

[0106] The specific results are shown in Table 1. IC 50 <10nM (denoted as: A); IC 50 =10~100nM (denoted as: B); IC 50 >100nM (denoted as: C).

[0107] Table 1. Results of inhibitory activity of some compounds on Polθ enzyme.

[0108] Number <![CDATA[IC 50 ]]> Number <![CDATA[IC 50 ]]> I-A-1 B I-A-8 B I-A-2 B I-A-9 B I-A-3 B I-A-10 B I-A-4 B I-A-11 B I-A-5 B I-A-12 B I-A-6 B I-A-13 B I-A-7 B I-A-14 B

[0109] Table 1 shows that some of the compounds of this invention exhibit good inhibitory activity against Polθ enzyme, inhibiting IC50. 50 The value reached the nanomolar concentration level.

[0110] Example 16: Evaluation of the inhibitory activity of the compound on tumor cell proliferation

[0111] 1. Experimental Methods

[0112] (1) The breast cancer cell line (MDA-MB-436) cultured to the logarithmic growth phase was plated into 96-well plates at a pre-specified density in a medium containing fetal bovine serum;

[0113] (2) Cells were treated with a compound or medium (DMSO) 24 hours later, and day 0 plates were collected for analysis;

[0114] (3) After the drug was applied, the 96-well plate was placed in a constant temperature incubator at 37°C and 5% CO2. After 7 days, 20 μL of 1.0% MTT thiazolyl blue solution was added to each well.

[0115] (4) Continue to place in a constant temperature incubator. After 4 hours, use a suction device to remove the supernatant culture medium, add 150 μL DMSO to each well, and place on a decolorizing shaker to mix until the crystals dissolve.

[0116] (5) Measure the absorbance at 570 nm using a multi-functional microplate reader and calculate the IC50 using the modified Kohl's method. 50 Value: lgIC 50=Xm-I[P-(3-Pm-Pn) / 4].

[0117] 2. Experimental Results

[0118] The specific results are shown in Table 2. IC 50 <1μM (denoted as: A); IC 50 =1~10μM (denoted as: B); IC 50 >10μM (denoted as: C).

[0119] Table 2. Results of the inhibitory activity of some compounds on the MDA-MB-436 cell line.

[0120] Number <![CDATA[IC 50 ]]> Number <![CDATA[IC 50 ]]> I-A-1 B I-A-8 C I-A-2 C I-A-9 C I-A-3 C I-A-10 C I-A-4 C I-A-11 C I-A-5 C I-A-12 C I-A-6 C I-A-13 B I-A-7 C I-A-14 B

[0121] Table 2 shows that some of the compounds of this invention exhibit good inhibitory activity against the breast cancer MDA-MB-436 cell line, inhibiting IC50. 50 The value reached the micromolar concentration level.

Claims

1. An alkyne compound, characterized in that, Having the structure of formula (I), or a pharmaceutically acceptable salt thereof, ， in: A is selected from , ; X is selected from NH and O; R 1 Selected from H; L is selected from n is selected from 1, 2, 3, 4, 5, 6, or 7; Ar is selected from 3,6-pyridazinyl.

2. The alkyne compound according to claim 1, characterized in that, Compounds selected from any of the following: (4 S )- N -(3-(6-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)amino)propamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-1). (4 S )- N -(3-(6-(4-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindololin-4-yl)amino)butyramido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-2). (4 S )- N -(3-(6-(5-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-3). (4 S )- N -(3-(6-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindololin-4-yl)amino)hexamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-4). (4 S )- N -(3-(6-(7-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)heptanamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-5). (4 S )- N -(3-(6-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-6). (4 S )- N -(3-(6-(7-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)heptanamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-7). (4 S )- N -(3-(6-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentamido)pyridazine-3-yl)prop-2-yn-1-yl)- N -(4-fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-8). (4 S )- N -(3-(6-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)octamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-9). (4 S )- N -(3-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamyl)pyridazine-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-10). (4 S )- N -(3-(6-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyramido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-11). (4 S )- N -(3-(6-(5-((2-(2,6-dioxoperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-12). (4 S )- N -(3-(6-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)heptanamido)pyridazine-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-13). (4 S )- N -(3-(6-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)octamido)pyridazin-3-yl)prop-2-yn-1-yl)- N -(4-Fluorophenyl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-oxoimidazolidine-4-carboxamide (IA-14).

3. The alkyne compound according to claim 1, characterized in that, The acceptable salt is a salt formed by the compound and an acid selected from any of the following: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.

4. A method for preparing the alkyne compound according to claim 1, characterized in that, The preparation method of compound IA is as follows: ， Wherein: the definitions of A, Ar, and n are as described in claim 1; The corresponding acid is salted with the alkyne compound prepared by the above method to obtain the pharmaceutically acceptable salt.

5. A pharmaceutical composition, characterized in that, It comprises the alkyne compound of claim 1 and a pharmaceutically acceptable carrier.

6. The use of an alkyne compound of claim 1 or a pharmaceutical composition of claim 5 in the preparation of a Polθ inhibitor drug.

7. The application according to claim 6, characterized in that, The drug mentioned is a drug for treating tumors.

8. The application according to claim 7, characterized in that, The medication mentioned is for the treatment of ovarian cancer, colon cancer, or breast cancer.

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