CN116768906B - Tri-fused ring compound and preparation method and application thereof - Google Patents

Tri-fused ring compound and preparation method and application thereof Download PDF

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CN116768906B
CN116768906B CN202310613031.3A CN202310613031A CN116768906B CN 116768906 B CN116768906 B CN 116768906B CN 202310613031 A CN202310613031 A CN 202310613031A CN 116768906 B CN116768906 B CN 116768906B
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CN116768906A (en
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丁宗保
程斌斌
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Zhuhai Campus Of Zunyi Medical University
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Abstract

The invention belongs to the technical field of compounds, and provides a tri-fused ring compound, and a preparation method and application thereof. The invention provides a tri-parallel compound with a molecular structure shown in a formula I, which has excellent activity of inhibiting USP1 and growth inhibition effect on MDA-MB-436 cells, has good application prospect, and can be used for preparing medicines for treating and/or preventing diseases related to USP1 of mammals.

Description

Tri-fused ring compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of compounds, in particular to a tri-fused ring compound, a preparation method and application thereof.
Background
USP1 (Ubiquitin specific protease, ubiquitin-specific protease 1) is a deubiquitinase that is located in the nucleus and involved in DNA repair processes, and plays a role in the Fanconi anemia pathway (FANCD 2 and FANC 1) and the trans-injury synthesis (TLS) pathway (PCNA (proliferating cell nuclear antigen)). It catalyzes a specific monoubiquitin signaling removal process and is a key regulator to ensure genome integrity. USPl is a cysteine isopeptidase of the USP (ubiquitin specific protease) subfamily in DUBs (deubiquitinase). Full length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, his593 and Asp 751. USP1 plays a role in DNA damage repair, blocks USP1 to inhibit DNA repair, can induce apoptosis in multiple myeloma cells, and can also enhance sensitivity of lung cancer cells to cis-clamp. USP1 dysfunction is closely related to the development and progression of cancer in the treatment of tumors. Furthermore, USP1 is a novel synthetic lethal component of BRCA1 deletion mutations, with potential to treat cancer patients resistant to PARP inhibitors.
Patent WO2020132269 discloses a compound, code KSQ-4279, as an inhibitor of USP1, which is useful as an inhibitor of USP1 in the treatment of tumors, but is currently under clinical phase I studies. The specific structure of the compound KSQ-4279 is as follows:
the USP1 inhibitor has great application prospect, so that the synthesis of the compound with a novel structure and remarkable inhibition effect on USP1 has great significance.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides a tri-fused ring compound, and a preparation method and application thereof. The tricyclic compound provided by the invention has excellent activity of inhibiting USP1 and growth inhibition effect on MDA-MB-436 cells, and can be used for preparing medicaments for treating and/or preventing related diseases mediated by the USP1 of mammals, such as solid tumors, adenocarcinomas and hematological cancers, particularly breast cancers, multiple bone marrow cancers and the like.
A first aspect of the invention provides a tricyclic compound.
Specifically, a tricyclic compound has a molecular structure shown in the following formula I:
wherein,is a single bond or a double bond;
Z 1 selected from CR 1 or-C (=o) -; r is R 1 Selected from H, CH 3 ；
Z 2 Selected from N, NH or CH;
ring A is selected from a 6-10 membered aromatic ring or a 6-10 membered heteroaryl, said ring A being substituted with one or more R a Substitution, wherein R a Selected from H, halogen, -CN, -OH, -NH 2 、C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups;
ring B is selected from a 6-10 membered aromatic ring or a 6-10 membered heteroaryl, said ring B being substituted with one or more R b Substitution, wherein R b Selected from H, halogen, -CN, -OH, -NH 2 At least one of (a) and (b);
ring C is selected from a 4-6 membered aromatic ring or a 4-6 membered heteroaryl, said ring C being substituted with one or more R c Substitution, wherein R c Selected from H, halogen, -CN, -CF 3 、C l -C 6 Alkyl group,C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups.
Preferably, the tricyclic compound has any one of the following formulas ia, ib, ic:
wherein R1 is selected from H, CH 3 ；
Ring A is selected from a 6-10 membered aromatic ring or a 6-10 membered heteroaryl, said ring A being substituted with one or more R a Substitution, wherein R a Selected from H, halogen, -CN, -OH, -NH 2 、C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups;
ring B is selected from a 6-10 membered aromatic ring or a 6-10 membered heteroaryl, said ring B being substituted with one or more R b Substitution, wherein R b Selected from H, halogen, -CN, -OH, -NH 2 At least one of (a) and (b);
ring C is selected from a 4-6 membered aromatic ring or a 4-6 membered heteroaryl, said ring C being substituted with one or more R c Substitution, wherein R c Selected from halogen H, halogen, -CN, -CF 3 、C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups.
Further preferably, the tricyclic compound has any one of the structural formulas la, lb, ic shown below:
wherein R is 1 Selected from H, CH 3 ；
X 1 ，X 2 Each independently selected from CH or N;
R a selected from C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups;
R b selected from H or F;
R c selected from C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups.
More preferably, the tricyclic compound has any one of the structural formulas shown in the following formulas 1 to 12:
in a second aspect, the invention provides a method of preparing a tricyclic compound.
A method for preparing a tri-fused ring compound, comprising the steps of:
the intermediate 2 is generated by utilizing the reductive amination reaction of ethyl aminoacetate hydrochloride and substituted aldehyde group compounds, the intermediate 2 and 2, 4-dichloro-5-nitropyrimidine are generated by nucleophilic substitution reaction to generate the intermediate 3, the intermediate 3 is generated by ring closure reaction under the action of iron powder and acetic acid to generate the intermediate 4, the intermediate 4 is generated by the action of phosphorus pentasulfide to generate the intermediate 5, the intermediate 5 is reacted with amino compound to generate the intermediate 6, and the intermediate 6 and substituted boric acid are subjected to coupling reaction to generate the tricyclic compound.
Preferably, the reaction temperature of the reductive amination reaction is 0-4 ℃ and the reaction time is 1-3 hours.
Preferably, the nucleophilic substitution reaction is carried out at a reaction temperature of 0-4 ℃ for a reaction time of 1-3 hours.
Preferably, the reaction temperature of the ring closure reaction is 80-100 ℃ and the reaction time is 11-13 hours.
Preferably, the reaction is carried out for 3 to 5 hours at 70 to 90 ℃ under the action of phosphorus pentasulfide.
Preferably, the amino compound comprises at least one of aminoglyoxal dimethyl ester, hydrazide, ethyl hydrazinoformate.
Preferably, the hydrazide is a formylhydrazine and/or an acetylhydrazine.
Preferably, the amino compound is aminoglyoxal dimethyl ester, the intermediate 5 and aminoglyoxal dimethyl ester are reacted in triethylamine and ethanol at 60-80 ℃ for 1-3 hours, or the intermediate 5 and aminoglyoxal dimethyl ester are reacted in glacial acetic acid at 90-110 ℃ for 0.1-3 hours.
Preferably, the amino compound is a hydrazide, and the intermediate 5 and the hydrazide react for 10 to 15 hours at the temperature of 110 to 130 ℃.
Preferably, the amino compound is ethyl hydrazine formate, and the intermediate 5 and ethyl hydrazine formate are reacted at 110-130 ℃ for 10-15 hours.
Preferably, the tricyclic compound has any one of the structural formulas Ia, ib and ic, and the preparation method of the formulas Ia, ib and ic comprises the following steps:
the method comprises the steps of firstly, carrying out reductive amination reaction on ethyl carbamate hydrochloride and a substituted aldehyde group compound to generate an intermediate 2 (corresponding to the compound with the number 2 in the following reaction formula), carrying out nucleophilic substitution reaction on the intermediate 2 and 2, 4-dichloro-5-nitropyrimidine to generate an intermediate 3 (corresponding to the compound with the number 3 in the following reaction formula), carrying out ring closure reaction on the intermediate 3 under the action of iron powder and acetic acid to generate an intermediate 4 (corresponding to the compound with the number 4 in the following reaction formula), carrying out coupling reaction on the intermediate 4 under the action of phosphorus pentasulfide to generate an intermediate 5 (corresponding to the compound with the number 5 in the following reaction formula), and carrying out reaction on the intermediate 5 with aminoglyoxal dimethyl ester, hydrazide and ethyl hydrazinoformate respectively to generate an intermediate 6i, an intermediate ii or an intermediate iii (corresponding to the compound with the number 6i, 6ii and 6iii in the following reaction formula) respectively, and carrying out coupling reaction on the intermediate 6i, the intermediate ii or the intermediate iii and the substituted boric acid respectively to generate a compound Ia, ib or Ic respectively.
The above reaction schemes for preparing formulas Ia, ib, ic are as follows:
wherein, the reaction conditions and reagents involved above are as follows: a. sodium cyanoborohydride, dichloromethane, 0 ℃ for 2 hours; b. potassium carbonate, azotemamide, 0 ℃ for 2 hours; c. iron powder, acetic acid, 90 ℃ for 12 hours; d. phosphorus pentasulfide, triethylamine, acetonitrile, 80 ℃ for 4 hours; ei, triethylamine, ethanol, 70 ℃ for 2 hours; II. Glacial acetic acid at 100deg.C for 1 hr; eii. cyclohexanol, 120 ℃, for 12 hours; f. cesium carbonate, palladium acetate, xantphos (5-bis-diphenylphosphine-9, 9-dimethylxanthene), dioxane and water (volume ratio of dioxane to water=10/1), 100 ℃,2 hours.
A third aspect of the invention provides the use of a tri-fused ring compound.
Use of a tricyclic compound in the preparation of a medicament for preventing and/or treating a disease associated with USP 1.
A medicament for preventing and/or treating diseases associated with USP1, comprising the tricyclic compound.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier and/or adjuvant.
A USP1 inhibitor comprising the tricyclic compound.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a tri-parallel compound with a molecular structure shown in a formula I, which has excellent activity of inhibiting USP1 and growth inhibition effect on MDA-MB-436 cells, has good application prospect, and can be used for preparing medicaments for treating and/or preventing diseases related to USP1 of mammals, such as solid tumors, adenocarcinoma and hematological cancers, particularly breast cancer, multiple bone marrow cancers and the like.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic ring radical having a conjugated pi-electron system.
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being aromatic ring groups of C.
The term "C 1 -C 6 Alkyl "means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
The term "C 1 -C 6 Alkoxy "means C 1 -C 6 alkyl-O-formed radicals, where "C 1 -C 6 The definition of alkyl "is as described above.
The term "C 3 -C 10 Cycloalkyl "means a cyclic alkyl or cyclic heteroalkyl group containing the specified number of C atoms and having no aromaticity, which may be a single ring (e.g., C 3- C 6 Cycloalkyl) may also be in the form of a bicyclic ring.
The present invention includes all possible stereoisomers of the compounds of the invention, which may be single stereoisomers, or any mixture of said stereoisomers in any ratio, for example the R or S isomer, or the E or Z isomer. Separation of individual stereoisomers of the compounds of the invention, e.g., individual enantiomers or individual diastereomers, may be achieved using any suitable method described in the art, e.g., chromatography, particularly chiral chromatography.
The invention also relates to useful forms of the compounds disclosed herein, e.g., metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and co-precipitates.
The compounds of the invention may exist in the form of a hydrate or solvate, wherein the compounds of the invention contain a polar solvent, in particular water, methanol or ethanol, for example as structural elements of the crystal lattice of the compound. The polar solvent, in particular the amount of water, may be present in stoichiometric or non-stoichiometric proportions. In the case of stoichiometric solvent compounds, such as hydrates, it may be a half (part), one and one half, two, three, four, five solvent compounds or hydrates, respectively, and so on. The present invention includes all such hydrates or solvates.
Further, the compounds of the present invention may exist in free form, e.g., as a free base or free acid or zwitterionic, or may exist in salt form. The salt may be any salt commonly used in pharmacy, organic or inorganic addition salts, in particular any pharmaceutically acceptable organic or inorganic addition salt.
Pharmaceutically acceptable salts of the compounds of the invention may be, for example, acid addition salts of the compounds of the invention which carry a nitrogen atom in the chain or ring, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example, acid addition salts with inorganic acids, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid, or acid addition salts with organic acids, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanoic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.
The compounds of the invention may contain non-natural proportion isotopes on one or more of the atoms making up the compound, for example substitution of hydrogen with deuterium to form deuterated drugs.
In the context of the present invention, the term "treatment" includes inhibiting, delaying, examining, alleviating, attenuating, limiting, reducing, suppressing, counteracting, or curing a disease (the term "disease" includes but is not limited to a condition, disorder, loss, or health problem), or the development, progression, or progress of such a condition and/or symptoms of such a condition, the term "therapy" is understood herein as synonymous with the term "treatment".
The terms "prevent", "preventing" or "preventing" are used synonymously in the context of the present invention and refer to avoiding or reducing the risk of infection, experiencing, suffering from or having a disease or the development or progression of symptoms of this and/or this state. Treatment or prevention of a disease may be partial or complete.
In the following specific examples, the liquid phase conditions identified for the detection of the preparation compounds were: island LCMS2020, G1322A degasser, G1312 binary high pressure pump, G1329A autosampler, G1316A column oven, G4212B diode array detector. The column was Xbridge C18 (50 mm. Times.4.6 mm,5.0 μm) with deionized water as mobile phase A and acetonitrile containing 0.1% trifluoroacetic acid as mobile phase B, and the gradient elution was performed as follows:
the flow rate was 1.5mL/min, the column temperature was 40℃and the detection wavelength was 254nm.
Example 1
A tricyclic compound, named 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -5, 6-dihydroimidazo [1,2-f ] pteridine (abbreviated as compound 1), having the molecular structure shown below:
the preparation method of the compound 1 comprises the following steps:
(1) 4- (1-isopropyl-4- (trifluoromethyl) -1H-imidazol-2-yl) benzaldehyde (1 g,3.54 mmol), dichloromethane (50 mL), glacial acetic acid (2 mL) and ethyl glycinate hydrochloride (741.74 mg,5.31 mmol) were added to a reaction flask, cooled to 0 ℃ with stirring, sodium cyanoborohydride (445.27 mg,7.09 mmol) was added in portions, the addition was completed, the reaction was kept at 0 ℃ for 2 hours, thin Layer Chromatography (TLC) was performed to monitor the complete reaction of the starting material, then the ph=7 of the reaction solution was adjusted with saturated sodium bicarbonate solution, the solution was separated, extracted three times with dichloromethane (30 ml×3), the organic phases were combined, washed once with saturated saline, and purified by silica gel column chromatography (ethyl acetate: petroleum ether=1:1) to give intermediate 2 (1.1 g, yield 84.06%) as a colorless oil. LCMS: (MS-ESI, M/z) [ M+H ]] + ＝370.2。
(2) 2, 4-dichloro-5-nitropyrimidine (500.00 mg,2.58 mmol) and azomethide (30 mL) were added to the reaction flask, stirred and cooled to 0deg.C, intermediate 2 (952.17 mg,2.58 mmol), potassium carbonate (534.38 mg,3.87 mmol) were added, the reaction was stirred for 30min, the TLC plate monitored, the reaction was stopped after completion, 50mL water was added to quench the reaction, the solution was separated, ethyl acetate was extracted 3 times (30 mL. Times.3), the ethyl acetate phases were combined, concentrated under reduced pressure, the column was passed through silica gel column chromatography, ethyl acetate: petroleum ether system elution (PE: EA volume ratio = 3:1) afforded intermediate 3 as a yellowish green powder (1.1 g, 80.99% yield). Liquid Chromatography Mass Spectrometry (LCMS) test results: (MS-ESI, M/z) [ M+H ]] + ＝527.2。
(3) At room temperature, add intermediate 3 (1.1 g,2.09 mmol) and acetic acid (20 mL) into a reaction flask, stir and dissolve, add iron powder (349.76 mg,6.26 mmol), raise to 90 ℃ for 2 hours, monitor by TLC, cool to 25 ℃ after the raw materials are reacted completely, concentrate to remove acetic acid, thenTo the concentrate was added 100mL of water, extracted 3 times with ethyl acetate (30 mL x 3), the ethyl acetate phases were combined, concentrated under reduced pressure, and slurried with methanol (5 mL) to give intermediate 4 (0.9 g, yield 95.62%) as a white powdery solid. LCMS: (MS-ESI, M/z) [ M+H ]] + ＝450.2。
(4) Triethylamine (20 mL) and acetonitrile (30 mL) are added into a reaction bottle at room temperature for stirring and dissolution, phosphorus pentasulfide (665.49 mg,2.99 mmol) is added in batches, after the phosphorus pentasulfide is completely dissolved, intermediate 4 (900.00 mg,2.00 mmol) is added, the reaction is continued for 5 hours at 80 ℃ under the protection of nitrogen, TLC monitoring is carried out, after the raw materials are completely reacted, the temperature is reduced to 25 ℃, silica gel is added for mixing and concentrating, column chromatography silica gel is used for passing through a column, and ethyl acetate is used for: petroleum ether system elution (PE: EA=5:1) afforded intermediate 5 as a bright yellow powder (850.00 mg, 91.02% yield). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝467.2。
(5) Intermediate 5 (100 mg, 214.17. Mu. Mol) and ethanol (5 mL) were added to the flask at room temperature and dissolved with stirring, followed by aminoglyoxal dimethyl ester (33.78 mg, 321.26. Mu. Mol) and 0.5mL triethylamine, and the reaction was continued at 70℃for 2 hours under TLC monitoring, after the completion of the reaction of the starting materials, the temperature was lowered to 25℃and the reaction solution was concentrated under reduced pressure. Subsequently, the concentrated reaction solution was dissolved with acetic acid (5 mL), reacted for 2 hours at 100 ℃, monitored by TLC, after the reaction of the raw materials was completed, cooled to 25 ℃, concentrated by adding silica gel as a sample, passing through a column chromatography silica gel column, passing through methylene chloride: the methanol system eluted (DCM: meoh=20:1) to afford intermediate 6i (70.00 mg, yield 68.97%) as a yellow solid. LCMS: (MS-ESI, M/z) [ M+H ]] + ＝474.2。
(6) To the flask was added intermediate 6 (70.00 mg, 147.71. Mu. Mol), (2-cyclopropyl-6-methoxypyrimidine) boric acid (34.11 mg, 221.57. Mu. Mol), palladium acetate (3.32 mg, 14.77. Mu. Mol), cesium carbonate (40.22 mg, 295.43. Mu. Mol), xantphos (8.55 mg, 14.77. Mu. Mol) and dioxane (5 mL), the mixture was replaced 3 times with nitrogen under vacuum, and the mixture was stirred and heated to 100℃for 2 hours under nitrogen protection, monitored by TLC, and after the reaction of the starting materials was completed, the mixture was cooled to 25℃and then passed through a column chromatography silica gel column using methylene chloride: methanol system elution (DCM: meOH volume ratio = 10:1) afforded compound 1 as a white solid (40 mg, 46.08% yield). LCMS: (MS-ESI, m/z) [M+H] + Nuclear magnetic hydrogen spectrum = 588.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.69(s,1H),8.24(s,1H),7.93(s,1H),7.69(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),7.21(d,J＝8.1Hz,1H),7.01(d,J＝8.1Hz,1H),4.83(s,2H),4.25(s,2H),4.01(m,1H),3.89(s,3H),1.79(m,1H),1.62(m,6H),1.00(m,2H),0.84(m,2H)。
The preparation process of the compound 1 has the following reaction formula:
wherein the corresponding reaction conditions and reagents in the above reaction formula are as follows: a. sodium cyanoborohydride, dichloromethane, 0 ℃ for 2 hours; b. potassium carbonate, azotemamide, 0 ℃ for 2 hours; c. iron powder, acetic acid, 90 ℃ for 12 hours; d. phosphorus pentasulfide, triethylamine, acetonitrile, 80 ℃ for 4 hours; ei. glacial acetic acid, 100deg.C, for 1 hr; f. cesium carbonate, palladium acetate, xantphos, dioxane/water volume ratio = 10/1, 100 ℃,2 hours.
Example 2
A tricyclic compound, named 3- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-methyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -5, 6-dihydroimidazo [1,2-f ] pteridine (abbreviated as compound 2), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (1)Replaced by->
Compound 2 (40 mg, 40.1% yield). LCMS: (MS-ESI, M/z) [ M+H ]] + Nuclear magnetic hydrogen spectrum =560.2 1 HNMR：(400MHz,DMSO-d 6 ,ppm):δ8.64(s,1H),8.16(s,1H),7.93(s,1H),7.67(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),7.22(d,J＝8.1Hz,1H),7.02(d,J＝8.1Hz,1H),4.81(s,2H),4.23(s,2H),3.86(s,3H),3.76(s,3H),1.79(m,1H),1.00(m,2H),0.82(m,2H)。
Example 3
A tricyclic compound, named 5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -3- (2-isopropylphenyl) -5, 6-dihydroimidazo [1,2-f ] pteridine (abbreviated as compound 3), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (6)Replaced by->
Compound 3 (37 mg, 39.2% yield). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝558.3 1 HNMR：(400MHz,DMSO-d 6 ,ppm):δ8.68(s,1H),7.91(s,1H),7.68(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.41(m,4H),7.21(d,J＝8.1Hz,1H),7.01(d,J＝8.1Hz,1H),4.83(s,2H),4.25(s,2H),4.01(m,1H),2.88(m,1H),1.62(m,12H)。
Example 4
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 4), having the molecular structure shown below:
process for preparing the above tricyclic compounds, andexample 1 differs in that in step (5)Replaced by->
Compound 4 (43 mg, yield 52.6%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝589.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.69(s,1H),8.24(s,1H),7.93(s,1H),7.69(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),7.21(s,1H),4.81(s,2H),4.24(s,2H),4.01(m,1H),3.89(s,3H),1.80(m,1H),1.62(m,6H),1.02(m,2H),0.82(m,2H)。
Example 5
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-methyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 5), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (1)Replaced by->And +.>Replaced by
Compound 5 (39 mg, yield 39.2%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝560.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.67(s,1H),8.17(s,1H),7.93(s,1H),7.67(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),7.22(s 1H),4.81(s,2H),4.21(s,2H),3.86(s,3H),3.76(s,3H),1.79(m,1H),1.02(m,2H),0.84(m,2H)。
Example 6
A tricyclic compound, named 5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -7- (2-isopropylphenyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 6), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (5)Replaced by->And +.in step (6)>Replaced by->
Compound 6 (42 mg, yield 49.1%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝559.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.64(s,1H),7.91(s,1H),7.64(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.41(m,4H),7.23(s,1H),4.85(s,2H),4.25(s,2H),4.01(m,1H),2.88(m,1H),1.67(m,12H)。
Example 7
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -1-methyl-4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 7), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (5)Replaced by->
Compound 7 (39 mg, yield 47.6%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝603.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.63(s,1H),8.24(s,1H),7.93(s,1H),7.69(d,J＝8.1Hz,2H),7.44(d,J＝8.1Hz,2H),4.81(s,2H),4.24(s,2H),4.01(m,1H),3.89(s,3H),3.01(s,3H),1.81(m,1H),1.62(m,6H),1.00(m,2H),0.86(m,2H)。
Example 8
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -1-methyl-5- (4- (1-methyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] butterfly (abbreviated as compound 8), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (1)Replaced by->Step five +.>Replaced by->/>
Compound 8 (44 mg, yield 48.6%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝575.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.63(s,1H),8.24(s,1H),7.93(s,1H),7.69(d,J＝8.1Hz,2H),7.44(d,J＝8.1Hz,2H),4.81(s,2H),4.24(s,2H),3.79(s,3H),4.01(m,1H),3.89(s,3H),3.01(s,3H),1.81(m,1H),1.01(m,2H),0.82(m,2H)。
Example 9
A tricyclic compound, named 5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -7- (2-isopropylphenyl) -1-methyl-4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 9), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (5)Replaced by->The +.6 of step (6)>Replaced by->
Compound 9 (39 mg, yield 38.4%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝573.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ8.65(s,1H),7.91(s,1H),7.67(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.41(m,4H),4.83(s,2H),4.25(s,2H),4.01(m,1H),3.79(s,3H),2.88(m,1H),1.62(m,12H)。
Example 10
A tricyclic compound, named 5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -7- (2-isopropylphenyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridin-1 (2-hydro) -one (abbreviated as compound 10), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that step (5) in step (1) is carried outReplaced by->The +.6 of step (6)>Replaced by->
Compound 10 (55 mg, yield 48.2%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝575.2 1 H NMR：(400MHz,DMSO-d6,ppm):δ11.63(s,1H)，8.68(s,1H),7.94(s,1H),7.63(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.43(m,4H),4.83(s,2H),4.25(s,2H),4.01(m,1H),2.88(m,1H),1.60(m,12H)。
Example 11
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-isopropyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridin-1 (2-hydro) -one (abbreviated as compound 11), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (5)Replaced by->
Compound 11 (47 mg, yield 48.9%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝605.2 1 H NMR：(400MHz,DMSO-d6,ppm):δ11.68(s,1H)，8.61(s,1H),8.25(s,1H),7.91(s,1H),7.67(d,J＝8.2Hz,2H),7.45(d,J＝8.2Hz,2H),4.79(s,2H),4.30(s,2H),4.01(m,1H),3.89(s,3H),1.80(m,1H),1.62(m,6H),1.02(m,2H),0.82(m,2H)。
Example 12
A tricyclic compound, named 7- (4-cyclopropyl-6-methoxypyrimidin-5-yl) -5- (4- (1-methyl-4- (trifluoromethyl) -1-hydro-imidazol-2-yl) benzyl) -4, 5-dihydro- [1,2,4] triazolo [4,3-f ] pteridine (abbreviated as compound 12), having the molecular structure shown below:
the process for preparing the above-mentioned tricyclic compound is different from example 1 in that in step (1)Replaced by->The +.5 of step (5)>Replaced by->
Compound 12 (39 mg, yield 37.3%). LCMS: (MS-ESI, M/z) [ M+H ]] + ＝577.2 1 H NMR：(400MHz,DMSO-d 6 ,ppm):δ11.67(s,1H)，8.69(s,1H),8.20(s,1H),7.92(s,1H),7.67(d,J＝8.2Hz,2H),7.48(d,J＝8.2Hz,2H),4.81(s,2H),4.21(s,2H),3.86(s,3H),3.76(s,3H),1.79(m,1H),1.00(m,2H),0.87(m,2H)。
Product effect test
1. USP1 in vitro enzymatic assay
The inhibition of USP1 enzyme activity by the compounds 1-12 of the present invention was examined by the following method:
USP1 enzyme (Recombinant Human His6-USPl/His6-UAFl Complex Protein, R&D, cat No. E-568-050), detection kit (Ub-CHOP 2-Reporter Deubiquitination Assay Kit, life sensors, cat No. PR1101) melted on ice, the kit comprising a ubiquitinated reporter enzyme, when deubiquitinated by USP1/UAF1, generating an activity, catalyzing the substrate, and subjecting the substrate to 485nm laser excitation to generate 531nm emission light signal. Adding 1 μl/Kong Daice compound (compound 1-12 and positive control (USP 1 inhibitor of KSQ Therapeutics Co., ltd., code of KSQ-4279)) working solution into 384 microwell plates, adding freshly prepared reaction solution (20 mM Tris-HCl (pH 8.0), 2mM CaCl) 2 2mM beta-mercaptoethanol, 0.05% CHAPS, deionized water) to dilute the USP1 enzyme. 5. Mu.L of diluted enzyme reaction solution was added to each well, and the mixture of enzyme and compound was centrifuged and shaken. The kit system and the substrate were diluted with the reaction solution, 5. Mu.L of the diluted liquid was added to each well, and the mixture was centrifuged and mixed, and incubated at room temperature for 30 minutes, followed by measurement. Fluorescence signal the fluorescence signal in each well was measured using an Envision reader (PerkinEhner excitation wavelength 480nm, emission wavelength 540 nm). Luminescence values (RLU) were read using Nivo for Luminescence detection. The inhibition ratio was calculated as follows (inhibition)% = (1- (signal value of 531nm/485nm per well-low control mean)/(high control mean-low control mean)) x 100. Wherein the high control group is a group which is not treated by adding a compound and is added with the USP1 enzyme reaction solution with the same concentration; the low control group was without USP1 enzyme reaction, and only an equal amount of freshly prepared reaction was added. Fitting dose-response curve: the log value of the concentration is taken as an X axis, the percent inhibition rate is taken as a Y axis, and a log (inhibitor) vs. response Variable slope fit quantitative response curve of analysis software GraphPad Prism 5 is adopted, so that the pair of each compound is obtainedIC of enzyme Activity 50 Values.
The experimental results are shown in table 1.
TABLE 1 measurement of USP1 kinase Activity
Numbering of compounds IC 50 (nM)
Compound 1 12
Compound 2 14.5
Compound 3 22.1
Compound 4 27.2
Compound 5 26.5
Compound 6 33.9
Compound 7 41.4
Compound 8 45.4
Compound 9 67.2
Compound 10 9.9
Compound 11 7.6
Compound 12 5.2
KSQ-4279 32.9
As is clear from the table above, the compounds of the present invention have excellent inhibitory effect on the enzyme activity of USP 1.
2. MTT cytotoxicity test
The inhibition of MDA-MB-436 cell (human breast cancer cell) growth by compounds 1-12 was measured using MTT (chemical name 3- (4, 5-dimethylthiazole-2) -2, 5-diphenyltetrazolium bromide, trade name thiazole blue) assay. The experimental procedure was as follows:
MDA-MB-436 cells were seeded at 4000 cells/well in 96-well plates, 150. Mu.L/well, and incubated at 37℃for 24 hours. The preparation of the compounds 1-12 was carried out according to the concentration setting, and the compounds 1-12 were diluted in a gradient with serum-free medium, and the dosage was 50. Mu.L/well. After 72h of drug treatment, 10. Mu.L MTT solution was added to each well and incubated for 4h at 37 ℃. The supernatant was carefully aspirated, 150 μl DMSO was added to each well, and gently shaken to dissolve the formazan. OD value was measured with an ELISA reader at 570nm of detection wavelength within 1 h. Analytical calculations were performed using Graphpad Prism software.
The inhibition rate was calculated as follows:
inhibition (%) = (100-OD Sample of /OD Solvent(s) ) X 100%, where OD Sample of For absorbance values detected after addition of each concentration of the test substance, OD Solvent(s) Absorbance values detected for vehicle group (vehicle added, no test substance added).
semi-Inhibitory Concentration (IC) 50 ) Can be used as an index of antitumor activity of a drug, and can indicate that a certain drug or inhibitor is inhibiting half-amount of certain substances such as enzymes, cell receptors or microorganisms. Determination of IC 50 For the values, the drug concentration at 50% Inhibition can be obtained by diluting the drug to different concentrations, calculating the respective Inhibition ratios, using the drug concentration as the abscissa and the Inhibition ratio as the ordinate, and plotting Log (inhibitor) vs. response-Variable slope (four parameters) under the Dose-response-Inhibition option of the graphic prism software.
The cytotoxicity test results of compounds 1-12 on MDA-MB-231 cells are shown in Table 2. The positive control was KSQ-4279.
TABLE 2 MTT cytotoxicity test results
Compounds of formula (I) IC 50 (nM)
Compound 1 78.6
Compound 2 159.4
Compound 3 177.3
Compound 4 415.6
Compound 5 519.1
Compound 6 385.6
Compound 7 201.5
Compound 8 233.7
Compound 9 176.9
Compound 10 32.8
Compound 11 41.7
Compound 12 59.6
KSQ-4279 81.9
As shown in the table above, the compounds of the present invention have excellent inhibitory activity on MDA-MB-436 cell growth.
The result shows that compared with a positive control KSQ-4279, the compound has quite better effect of inhibiting the activity of USP1 kinase and inhibiting the growth of MDA-MB-436 cells, and has better application prospect.

Claims (7)

1. A tricyclic compound characterized by having any one of the following structural formulas la, ib, ic:
wherein R is 1 Selected from H, CH 3 ；
X 1 、X 2 Each independently selected from CH or N;
R a selected from C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups;
R b selected from H or F;
R c selected from C l -C 6 Alkyl, C l -C 6 Alkoxy, C 3 -C 10 At least one of cycloalkyl groups.
2. The tricyclic compound of claim 1, wherein said tricyclic compound has any one of the structural formulas shown in the following formulas 1 to 12:
3. a process for the preparation of a tri-fused ring compound according to claim 1 or 2, characterized by comprising the steps of:
firstly, carrying out reductive amination reaction on ethyl aminoacetate hydrochloride and a substituted aldehyde compound to generate an intermediate 2, carrying out nucleophilic substitution reaction on the intermediate 2 and 2, 4-dichloro-5-nitropyrimidine to generate an intermediate 3, carrying out ring closure reaction on the intermediate 3 under the action of iron powder and acetic acid to generate an intermediate 4, carrying out ring closure reaction on the intermediate 4 under the action of phosphorus pentasulfide to generate an intermediate 5, respectively carrying out reaction on the intermediate 5 and methyl aminoglyoxalate, hydrazide and ethyl hydrazinoformate to respectively generate an intermediate 6i, an intermediate ii or an intermediate iii, and carrying out coupling reaction on the intermediate 6i, the intermediate ii or the intermediate iii and substituted boric acid to respectively generate a compound Ia, ib or Ic;
the structures of the substituted aldehyde compound, the intermediate 2, the intermediate 3, the intermediate 4, the intermediate 5, the aminoglyoxal dimethyl ester, the intermediate 6i, the intermediate ii, the intermediate iii and the substituted boric acid are respectively shown as follows:
4. a process according to claim 3, wherein the reductive amination reaction is carried out at a temperature of 0-4 ℃ for a time period of 1-3 hours.
5. Use of the tricyclic compound of claim 1 or 2 in the preparation of a medicament for preventing and/or treating a disease associated with USP 1.
6. A medicament for preventing and/or treating diseases associated with USP1, comprising the tri-fused ring compound according to claim 1 or 2.
7. An inhibitor of USP1 comprising the tri-fused ring compound of claim 1 or 2.
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CN111217815A (en) * 2018-11-27 2020-06-02 沈阳药科大学 Compound containing pteridinone skeleton and preparation method and application thereof
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CN103403010A (en) * 2010-10-08 2013-11-20 依兰制药公司 Inhibitors of polo-like kinase
CN111217815A (en) * 2018-11-27 2020-06-02 沈阳药科大学 Compound containing pteridinone skeleton and preparation method and application thereof
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