CN118146197A - Alkyne compound and preparation method, pharmaceutical composition and application thereof - Google Patents
Alkyne compound and preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN118146197A CN118146197A CN202410263852.3A CN202410263852A CN118146197A CN 118146197 A CN118146197 A CN 118146197A CN 202410263852 A CN202410263852 A CN 202410263852A CN 118146197 A CN118146197 A CN 118146197A
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Abstract
The invention discloses an alkyne compound, a preparation method, a pharmaceutical composition and application thereof. The structure of the compound is shown as (I), and the compound also comprises stereoisomers, pharmaceutically acceptable salts or mixtures thereof. It can effectively inhibit the activity of Pol theta protein, thereby effectively inhibiting the proliferation of tumor cells. Has definite biological activity, can be prepared into medicaments for treating cancers such as breast cancer, ovarian cancer and the like, and has wide application. The preparation method of the compound has strong applicability and is easy to expand various chemical structures.
Description
Technical Field
The invention relates to an alkyne compound and a preparation method, a pharmaceutical composition and application thereof, in particular to an alkyne compound with Pol theta inhibition activity and a preparation method, a pharmaceutical composition and application thereof.
Background
Targeting cancer cells through synthetic lethal mechanisms is an emerging therapeutic strategy. Pol theta (DNA polymerase theta) is a large multifunctional DNA repair protein encoded by the POLQ gene, consisting of 2590 amino acids, comprising three domains: n-terminal SF2 helicase domain (Pol θ -hel, residues 32-899), unstructured central domain, C-terminal A family polymerase domain (Pol θ -Pol, residues 1819-2590). Pol theta has a synthetic lethal relationship with cancers deficient in Homologous Recombination (HR), including BRCA1/2, ATM, ATR, and TP53BP1, among others. Pol theta is a protein that repairs DNA double strand break damage and plays an important role in the micro-homology mediated end-linked pathway, with HR-deficient cancer cells surviving more dependent on Pol theta activity. Pol theta is found to be overexpressed in a variety of human malignancies including lung, stomach, small intestine, colorectal, breast, ovarian and head and neck, promoting the growth and survival of cancer cells, possibly a factor that leads to more aggressive and easily recurrent tumors. And the low-level expression or even non-expression in most normal cells makes the enzyme an ideal antitumor target. Currently, no Pol theta inhibitors are approved for sale, and several Pol theta inhibitors are in clinical trial phase.
Disclosure of Invention
The invention aims to: the first object of the invention is to provide an alkyne compound with Pol theta inhibition activity, the second object is to provide a preparation method of the compound, the third object is to provide a pharmaceutical composition containing the compound, and the fourth object is to provide a pharmaceutical application of the compound and the pharmaceutical composition thereof.
The technical scheme is as follows: the alkyne compounds of the invention have the structure of formula (I), and also comprise stereoisomers, pharmaceutically acceptable salts or mixtures thereof,
Wherein:
A is selected from
X is selected from NH, O or S;
R 1 is selected from H, halogen, C 1～C6 alkyl, C 1～C6 alkoxy, C 3～C6 cycloalkyl, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, OH, NR 2R3、CN、CO2H、CO2CH3、CONH2, or NO 2;
R 2、R3 is selected from H, C 1～C6 alkyl or COR 4;
R 4 is selected from H, C 1～C6 alkyl or C 3～C6 cycloalkyl;
L is selected from substituted C 1～C10 alkyl, substituted phenyl or aromatic heterocyclic group substituted C 3～C6 cycloalkyl, substituted C 4～C6 heterocycloalkyl, N is selected from any integer from 1 to 10; the aromatic heterocyclic group is selected from five-membered, six-membered or 8-14 membered double-ring aromatic heterocyclic groups containing 1-3O, N or S atoms; the C 4～C6 heterocycloalkyl is tetrahydrofuranyl, hexahydropyranyl, morpholinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or azetidinyl; the substituent is selected from at least one of H, halogen, CN, NO 2、OH、NR2R3、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, C 2～C6 alkenyl, CO 2H、CO2CH3 or CONR 5R6;
Ar is selected from substituted phenyl or aromatic heterocyclic group, wherein the aromatic heterocyclic group is selected from five-membered, six-membered or 8-14 membered double-ring aromatic heterocyclic ring containing 1-3O, N or S atoms; the substituent is selected from at least one of H, halogen, CN, NO 2、OH、NR2R3、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, C 2～C6 alkenyl, CO 2H、CO2CH3 or CONR 5R6;
R 5、R6 is selected from H, C 1～C6 alkyl or C 3～C6 cycloalkyl.
Preferably, in the structure:
A is selected from
X is selected from NH or O;
R 1 is selected from H, halogen, OH, CN, CO 2H、CO2CH3、CONH2 or NO 2;
L is selected from N is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
Preferably, in the structure:
r 1 is selected from H;
L is selected from N is selected from 1,2, 3, 4, 5, 6, 7, 8, 9 or 10; n is more preferably 1,2, 3, 4, 5, 6 or 7.
Ar is selected from substituted phenyl, pyrimidinyl, pyridazinyl, pyridinyl, said substituents being selected from at least one of H, halogen, CN, NO 2、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl or C 1～C6 haloalkoxy; ar is more preferably 3, 6-pyridazinyl, 2, 5-pyridyl, 1, 4-phenyl or 2, 5-pyrazinyl.
Preferably, the alkyne compound is selected from any one of the following compounds:
The invention designs a class of Polθ inhibitory activity small molecules containing alkyne structures. Pol theta is involved in micro-homology mediated end-joining, thereby repairing DNA double strand breaks. It is over-expressed in various HR deficient tumors, has low content in normal cells, and is an emerging drug target for treating tumors in recent years. To date, no Pol theta inhibitor drugs have been approved for sale.
Preferably, the pharmaceutically acceptable salt of the present invention is a salt of the alkyne compound with an acid selected from any one 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.
"Pharmaceutically acceptable salts" refers to salts of compounds prepared from compounds having a particular substituent with a relatively non-toxic acid or base. When compounds contain relatively acidic functionalities, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and salts of organic acids including amino acids (such as arginine and the like), glucuronic acid, and the like.
"Pharmaceutically acceptable salts" can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
Preferably, the stereoisomers described herein are chiral isomers introduced by chiral carbon in the central aza ring ketone ring system.
The preparation method of the alkyne compound is selected from the following methods:
When L is In this case, the compounds of the formula I-A are prepared as follows:
Wherein: A. ar is defined as above, and n is selected from any integer from 1 to 10;
And salifying the corresponding acid with the alkyne compound prepared by the method to obtain the pharmaceutically acceptable salt.
Specifically, the preparation method of the compound of the formula I-A comprises the following steps:
The preparation of compound IV from compound II and p-fluoroaniline (III) using a condensing agent selected from N, N ' -Carbonyldiimidazole (CDI), N, N ' -Dicyclohexylcarbodiimide (DCC), N, N ' -Diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), urea N, N, N ', N ' -tetramethyl-O- (7-azabenzotriazol-1-yl) Hexafluorophosphate (HATU), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (PyBOP) or N, N, N ', N ' -tetramethyl chloroformidine hexafluorophosphate (TCFH), preferably TCFH; the base is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, N-methylimidazole (NMI), 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 a mixed solvent composed of any two, preferably acetonitrile; the reaction temperature is 25 to 80℃and preferably 25 ℃.
The preparation of the compound VI from the compound IV and the compound (V) takes place using a catalyst selected from the group consisting of cuprous iodide, cuprous oxide, pd (PPh 3)2Cl2、Pd(OAc)2 or Pd 2(dba)3, preferably cuprous iodide, a ligand selected from the group consisting of (1S, 2S) - (+) -1, 2-cyclohexanediamine, 1 '-binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1 '-biphenyl (Ruphos), 2-dicyclohexylphosphorus-2', 4',6' -triisopropylbiphenyl (Xphos), 2- (di-tert-butylphosphine) biphenyl (Johnphos) or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene (Xanthos), preferably (1S, 2) - (+) -1, 2-cyclohexanediamine, a base selected from the group consisting of potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, potassium phosphate or cesium carbonate, preferably potassium carbonate, a solvent selected from the group consisting of DMF, toluene, N-dimethylacetamide (DMAc), 1, 4-dimethylsulfoxide, hexamethylsulfoxide (N, N-dimethylsulfoxide) or 1, 4-dimethylsulfoxide (NMP) at a temperature of preferably from the range of about 150℃to about 150 ℃.
Preparing a compound VII from a compound VI and 3-bromopropyne, wherein 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 mixed solvent of the two solvents, preferably DMF; the reaction temperature is 0 to 70℃and preferably 25 ℃.
Preparing a compound IX by reacting a compound VII with a compound (VIII), the solvent used being selected from THF, acetonitrile, NMP, DMAc, DMSO, DMF or 1, 4-dioxane, preferably DMF; the base is selected from potassium bicarbonate, potassium carbonate, sodium bicarbonate, sodium carbonate, sodium acetate, triethylamine or DIPEA, preferably triethylamine; the catalysts used are Pd (PPh 3)4、Pd(dppf)Cl2、Pd(OAc)2、Pd2(dba)3 or Pd (PPh 3)2Cl2, preferably Pd (PPh 3)2Cl2; reaction temperature 25 to 150 ℃, preferably 100 ℃).
The compound XI is prepared by reacting compound IX with compound (X) using a condensing agent 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 mixed solvent composed of any two, preferably DMF; the reaction temperature is 25 to 80℃and preferably 25 ℃.
The compound X I is reacted under acidic conditions to obtain a compound I-A, wherein the acid 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℃and preferably 25 ℃.
And salifying the corresponding acid with the alkyne compound prepared by the method to obtain the pharmaceutically acceptable salt.
The pharmaceutical composition comprises the alkyne compound and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutical composition is in the form of a tablet, capsule, powder, pill, granule, injection, oral liquid, syrup, inhalant, ointment, patch or suppository.
The pharmaceutically acceptable carrier can be an auxiliary material widely used in the field of medicine production. Adjuvants are primarily used to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or sustained release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, 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 formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powder formulations which may 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 formulations; aerosols, such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The alkyne compound or the pharmaceutical composition thereof disclosed by the invention is applied to the preparation of medicines of Pol theta inhibitors.
Preferably, the medicament is a medicament for treating tumors.
Further preferably, the medicament is a medicament for treating ovarian cancer, colon cancer or breast cancer.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
The compound designed by the invention can effectively inhibit the activity of Pol theta enzyme, the inhibition IC 50 value of the molecular level reaches nanomolar level, and the inhibition IC 50 value of the proliferation of related cancer cells reaches single digit micromolar level. Has definite biological activity, can be used for preparing medicines for treating cancers such as breast cancer, ovarian cancer and the like, and has wide application. The preparation method of the compound has strong applicability and is easy to expand various chemical structures.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: synthesis of (4S) -N- (3- (6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-1)
(1) Synthesis of (S) -4- ((4-fluorophenyl) carbamoyl) -2-oxoimidazolidine-1-carboxylic acid tert-butyl ester (IV)
Compound II (920 mg,4 mmol), 4-fluoroaniline (470 mg,4 mmol) and N-methylimidazole (692 mg,8.4 mmol) were added to acetonitrile (10 mL) and stirred, and then TCFH (1.23 g,4.4 mmol) was added thereto and the mixture was reacted at room temperature for 5 hours. Directly suction-filtering the turbid liquid after the reaction is completed to obtain 857mg of white solid with yield 66.3％.1H 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).
(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)
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, 1, 4-dioxane (6 mL) was added, nitrogen was replaced three times, and the mixture was heated to 100℃and stirred for 4 hours. After the reaction is finished, the mixture is filtered by diatomite, the filtrate is taken and concentrated under reduced pressure to obtain a crude product, and the crude product is separated by column chromatography (PE: EA=8:1-2:1) to obtain 683mg of white solid with yield 56.6％.1H 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).
(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)
Compound VI (241 mg,0.5 mmol) was dissolved in DMF (2 mL), cesium carbonate (4819 mg,1.5 mmol) and 3-bromopropyne (90 mg,0.75 mmol) were added and the reaction stirred at room temperature for 12 hours. After the reaction, water was added, extraction was performed 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 give a crude product, which was purified by column chromatography (PE: ea=8:1 to 5:1) to give 250mg of a white solid with a yield of 96.2%, MS (esi+) m/z 521.2[ m+h ] +.
(4) Synthesis of tert-butyl (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-carboxylate (IX-1)
Compound VII (250 mg,0.48 mmol), 6-bromopyridazin-3-amine (VIII-1, 84mg,0.48 mmol), pd (PPh 3)2Cl2 (17 mg,0.024 mmol), cuprous iodide (10 mg,0.048 mmol) were placed in a reaction flask, triethylamine (134. Mu.L, 0.96 mmol) and DMF (2 mL) were added and replaced with nitrogen three times, then warmed to 100deg.C and stirred for 2 hours, water was added after completion of the reaction, extracted with ethyl acetate three times, the combined organic phases were washed once with saturated sodium chloride, dried over anhydrous sodium sulfate to give crude product, which was purified by column chromatography (PE: EA=2:1-1:2) to give 250mg of brown solid in yield 78.4％.1H 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).
(5) Synthesis of (4S) -N- (3- (6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-1)
Compound IX-1 (100 mg,0.16 mmol), 3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionic acid (X-1, 84mg,0.24 mmol) was dissolved in DMF (2 mL) and DIPEA (63 mg,0.49 mmol) was added and the reaction was stirred in an ice-water bath. HATU (93 mg,0.24 mmol) was added and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, water was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate to obtain a crude product, and separated by column chromatography (PE: ea=1:1 to 1:2) to obtain 124mg of a yellowish green solid in a yield of 81.05%. MS (ESI+) M/z963.4[ M+Na ] +. The above product was dissolved in DCM (4 mL), and 4mL of trifluoroacetic acid-DCM mixed solvent (v/v=1:1) was added dropwise in ice bath, and the reaction was stirred for 3 hours at room temperature after the addition. After the reaction is completed, saturated sodium bicarbonate is added for quenching, DCM is used for extraction for three times, the combined organic phases are washed once by saturated sodium chloride, anhydrous sodium sulfate is dried and then concentrated under reduced pressure to obtain a crude product, the crude product is separated by column chromatography (PE: EA=1:2-EA), and then ethyl acetate: diethyl ether=1:3 is used for pulping to obtain 24mg of yellowish green solid with the yield 26.86％.MS(ESI+)m/z 841.4[M+H]+.1H NMR(300MHz,Chloroform-d)δ(ppm):11.04(s,1H),8.79(d,J＝9.4Hz,1H),8.54(s,1H),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).
Example 2: synthesis of (4S) -N- (3- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyrylamino) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-2)
Preparation of Compounds from Compound IX-1 and Compound 4- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-4-yl) amino) butanoic acid (X-2) by the method of reference example 1 I-A-2.MS(ESI+)m/z 855.4[M+H]+.1H 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).
Example 3: synthesis of (4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-3)
Preparation of Compounds from Compound IX-1 and Compound 5- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-4-yl) amino) pentanoic acid (X-3) by the method of reference example 1 I-A-3.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).
Example 4: synthesis of (4S) -N- (3- (6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-4)
Preparation of Compounds from Compound IX-1 and Compound 6- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-4-yl) amino) hexanoic acid (X-4) by the method of reference example 1 I-A-4.MS(ESI+)m/z 883.4[M+H]+.1H 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).
Example 5: synthesis of (4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-5)
Preparation of Compounds from Compound IX-1 and Compound 7- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-4-yl) amino) heptanoic acid (X-5) by the method of reference example 1 I-A-5.MS(ESI+)m/z 897.4[M+H]+.1H 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).
Example 6: synthesis of (4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-6)
Preparation of Compounds from Compound IX-1 and Compound 8- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-4-yl) amino) octanoic acid (X-6) by the method of reference example 1 I-A-6.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).
Example 7: synthesis of (I-A-7) Synthesis of (4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindol-5-yl) amino) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide
Preparation of Compounds from Compound IX-1 and Compound 7- ((2- (2, 6-Dioxypiperidin-3-yl) -1, 3-Dioxyisoindolin-5-yl) amino) heptanoic acid (X-7) by the method of reference example 1 I-A-7.MS(ESI+)m/z 883.4[M+H]+.1H 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).
Example 8: synthesis of (4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-8)
Preparation of Compounds from Compound IX-1 and Compound 5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentanoic acid (X-8) by the method of reference example 1 I-A-8.MS(ESI+)m/z 870.4[M+H]+.1H NMR(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).
Example 9: synthesis of (4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-9)
Preparation of Compounds from Compound IX-1 and Compound 8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) octanoic acid (X-9) according to the procedure of example 1 I-A-9.MS(ESI+)m/z 912.4[M+H]+.1H NMR(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).
Example 10: synthesis of (4S) -N- (3- (6- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) acetamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-10)
Preparation of Compounds from Compound IX-1 and Compound 2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) acetic acid (X-10) by the method of reference example 1 I-A-10.MS(ESI+)m/z 828.5[M+H]+.1H NMR(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),3.45-3.41(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).
Example 11: synthesis of (4S) -N- (3- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) butyryl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-11)
Preparation of Compounds from Compound IX-1 and Compound 4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) butyric acid (X-11) according to the procedure of example 1 I-A-11.MS(ESI+)m/z 856.4[M+H]+.1H NMR(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).
Example 12: synthesis of (4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-12)
Preparation of Compounds from Compound IX-1 and Compound 5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) pentanoic acid (X-12) by the method of reference example 1 I-A-12.MS(ESI+)m/z 870.4[M+H]+.1H NMR(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).
Example 13: synthesis of (4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-13)
Preparation of Compounds from Compound IX-1 and Compound 7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) heptanoic acid (X-13) by the method of reference example 1 I-A-13.MS(ESI+)m/z 898.4[M+H]+.1H NMR(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,1H),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).
Example 14: synthesis of (4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-14)
Preparation of Compounds from Compound IX-1 and Compound 8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) octanoic acid (X-14) by the method of reference example 1 I-A-14.MS(ESI+)m/z 912.4[M+H]+.1H NMR(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,1H),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).
Example 15: evaluation of inhibitory Activity of Compounds on Pol theta enzyme
1. Experimental materials
POLQ-C was purchased from ICE, FITC-dATP from Perkin, dCTP, dGTP and dTTP from Roche, dsDNA from Genscript, strepitavidin-Tb cryptate from Cisbio.
2. Experimental method
(1) Experimental procedure
Compound samples were dissolved in DMSO to prepare 10mM stock solutions. mu.L of the compound solution was added to 384-well dilution plates; gradient dilution in DMSO to the desired concentration; transfer 0.15 μl of diluted compound solution per row onto 384 assay plates with Echo, 2 wells per concentration; 5. Mu.L of enzyme working solution is added into a 384-well detection plate, and the mixture is centrifuged at 1000rpm for 1 minute; incubation at 25 ℃ for 10 min; add 5. Mu.L of substrate (dNTP and dsDNA) working solution to start the reaction; adding 5 mu L STREPTAVIDIN-Tb cryptate working solution to start the reaction; incubation at 25 ℃ for 60 min; fluorescence signals at 490nm and 520nm were read with BMG (ratio 520/490).
(2) Experimental data processing
Enzyme activity inhibition (%) =100 x (ave High control-cpd well)/(ave High control-ave Low control).
IC 50 values of the compounds were fitted from a nonlinear regression equation using XLfit 5.5.0.
3. Experimental results
The specific results are shown in Table 1.IC 50 < 10nM (denoted as A); IC 50 = 10-100 nM (denoted as B); IC 50 > 100nM (denoted as C).
TABLE 1 results of inhibition of Pol theta enzyme by some of the Compounds
| Numbering device | IC50 | Numbering device | IC50 |
| 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 |
The results in Table 1 show that some of the compounds of the present invention exhibit good inhibitory activity against Pol theta enzymes and that the inhibitory IC 50 values reach nanomolar levels.
Example 16: evaluation of inhibitory Activity of Compounds on proliferation of tumor cells
1. Experimental method
(1) The breast cancer cell line (MDA-MB-436) cultured to the logarithmic growth phase was plated in 96-well plates at a pre-specified density in a medium containing fetal bovine serum;
(2) Cells were treated with compound or vehicle (DMSO) after 24 hours and day 0 plates were collected for analysis;
(3) After application, the 96-well plate is placed in a constant temperature incubator with 5% CO 2 at 37 ℃ for cultivation, and 20 mu L of 1.0% MTT thiazole blue solution is added into each well after 7 days;
(4) Continuously placing in a constant temperature incubator, sucking away the supernatant culture solution after 4 hours, adding 150 mu LDMSO into each hole, and uniformly mixing on a decolorizing shaking table until the crystals are dissolved;
(5) Measuring absorbance at 570nm by using a multifunctional enzyme-labeled instrument, and calculating IC 50 value according to modified kou method: lgIC 50 = Xm-I [ P- (3-Pm-Pn)/4 ].
2. Experimental results
The specific results are shown in Table 2.IC 50 < 1. Mu.M (denoted as A); IC 50 = 1-10 μm (noted: B); IC 50 > 10. Mu.M (denoted as C).
TABLE 2 results of inhibitory Activity of partial Compounds on MDA-MB-436 cell lines
| Numbering device | IC50 | Numbering device | IC50 |
| 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 |
The results in Table 2 show that some of the compounds of the present invention exhibit good inhibitory activity against breast cancer MDA-MB-436 cell lines, with the IC 50 values being inhibited to micromolar levels.
Claims (10)
1. An alkyne compound, characterized by having the structure of formula (I), further comprising stereoisomers, pharmaceutically acceptable salts or mixtures thereof,
Wherein:
A is selected from
X is selected from NH, O or S;
R 1 is selected from H, halogen, C 1～C6 alkyl, C 1～C6 alkoxy, C 3～C6 cycloalkyl, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, OH, NR 2R3、CN、CO2H、CO2CH3、CONH2, or NO 2;
R 2、R3 is selected from H, C 1～C6 alkyl or COR 4;
R 4 is selected from H, C 1～C6 alkyl or C 3～C6 cycloalkyl;
L is selected from substituted C 1～C10 alkyl, substituted phenyl or aromatic heterocyclic group substituted C 3～C6 cycloalkyl, substituted C 4～C6 heterocycloalkyl, N is selected from any integer from 1 to 10; the aromatic heterocyclic group is selected from five-membered and six-membered rings or 8-14 membered aromatic heterocyclic rings containing 1-3O, N or S atoms; the C 4～C6 heterocycloalkyl is tetrahydrofuranyl, hexahydropyranyl, morpholinyl, tetrahydropyrrolyl, piperidinyl, piperazinyl or azetidinyl; the substituent is selected from at least one of H, halogen, CN, NO 2、OH、NR2R3、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, C 2～C6 alkenyl, CO 2H、CO2CH3 or CONR 5R6;
Ar is selected from substituted phenyl or aromatic heterocyclic groups, wherein the aromatic heterocyclic groups are selected from five-membered, six-membered or 8-14 membered aromatic heterocyclic rings containing 1-3O, N or S atoms; the substituent is selected from at least one of H, halogen, CN, NO 2、OH、NR2R3、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl, C 1～C6 haloalkoxy, C 2～C6 alkenyl, CO 2H、CO2CH3 or CONR 5R6;
R 5、R6 is selected from H, C 1～C6 alkyl or C 3～C6 cycloalkyl.
2. The alkyne compound of claim 1, wherein in the structure:
A is selected from
X is selected from NH or O;
R 1 is selected from H, halogen, OH, CN, CO 2H、CO2CH3、CONH2 or NO 2;
L is selected from N is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
3. The alkyne compound of claim 1, wherein in the structure:
r 1 is selected from H;
L is selected from N is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
Ar is selected from substituted phenyl, pyrimidinyl, pyridazinyl, pyridinyl, said substituents being selected from at least one of H, halogen, CN, NO 2、C1～C6 alkyl, C 3～C6 cycloalkyl, C 1～C3 alkoxy, C 1～C6 haloalkyl or C 1～C6 haloalkoxy.
4. The alkyne compound according to claim 1, wherein the compound is selected from any one of the following:
(4S) -N- (3- (6- (3- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-1),
(4S) -N- (3- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyramide) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-2),
(4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-3),
(4S) -N- (3- (6- (6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-4),
(4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-5),
(4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-6),
(4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-7),
(4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-8),
(4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-9),
(4S) -N- (3- (6- (2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) acetamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-10),
(4S) -N- (3- (6- (4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) butyryl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-11),
(4S) -N- (3- (6- (5- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) pentanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-12),
(4S) -N- (3- (6- (7- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) heptanamid-yl) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-13),
(4S) -N- (3- (6- (8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) octanamido) pyridazin-3-yl) prop-2-yn-1-yl) -N- (4-fluorophenyl) -3- (6-methyl-4- (trifluoromethyl) pyridin-2-yl) -2-oxoimidazolidine-4-carboxamide (I-A-14).
5. The alkyne compound of claim 1, wherein the acceptable salt is a salt of the compound with an acid selected from any one 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.
6. A process for the preparation of an alkyne compound according to claim 1, selected from the group consisting of:
When L is In this case, the compounds of the formula I-A are prepared as follows:
wherein: A. ar is defined in claim 1, n is selected from any integer from 1 to 10;
Salifying the corresponding acid with the alkyne compound prepared by the method to obtain the pharmaceutically acceptable salt.
7. A pharmaceutical composition comprising an alkyne compound of claim 1 and a pharmaceutically acceptable carrier.
8. Use of an alkyne compound according to claim 1 or a pharmaceutical composition according to claim 7 in the manufacture of a Pol theta inhibitor medicament.
9. The use according to claim 8, wherein the medicament is a medicament for the treatment of tumors.
10. The use according to claim 9, wherein the medicament is a medicament for the treatment of ovarian, colon or breast cancer.
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