CN117362277A - Benzamide compound containing imidazolone structure, and preparation method and application thereof - Google Patents

Benzamide compound containing imidazolone structure, and preparation method and application thereof Download PDF

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CN117362277A
CN117362277A CN202311323884.XA CN202311323884A CN117362277A CN 117362277 A CN117362277 A CN 117362277A CN 202311323884 A CN202311323884 A CN 202311323884A CN 117362277 A CN117362277 A CN 117362277A
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宫平
秦铭泽
吴迪
赵燕芳
刘亚婧
侯云雷
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Shenyang Pharmaceutical University
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Abstract

Benzamide compound containing imidazolone structure and preparation method and application thereof, belonging to the field of medicines and the inventionTo benzamide compounds containing an imidazolinone structure represented by the general formula I or pharmaceutically acceptable salts thereof, wherein the substituent R 1 、R 2 、R 3 、R 4 And R is 5 The meaning of (c) is set forth in the present specification. The compound of the general formula I or the pharmaceutically acceptable salt thereof has remarkable inhibition effect on wild type and mutant EZH2, and can be used for preparing medicines for inhibiting the EZH2, in particular medicines for preventing and/or treating tumors.

Description

Benzamide compound containing imidazolone structure, and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to benzamide compounds containing an imidazolinone structure, and a preparation method and application thereof.
Background
The polycomb repression complex 2, PRC2 (polycomb repressive complex 2), is a polyprotein complex with the function of catalyzing the methylation of lysine at position 27 (H3K 27) of histone H3, thus causing silencing of the relevant gene. PRC2 consists of four core parts: EZH1 or EZH2 (SET domain with histone methyltransferase activity), EED, SUZ12 and RbAp48 (histone binding domain). EZH2 is the core catalytic subunit of PRC2, which needs to interact with EED and then rely on stabilization by SUZ12 to exert methyltransferase activity. EZH2 is often overexpressed in prostate, breast, kidney, lung, myeloma and lymphoma. The wild-type EZH2 shows the best catalytic efficiency for the monomethylation of the unmethylated H3K27 site and its catalytic efficiency decreases with increasing methylation status of the lysine amino acids. In addition, Y641 mutants within the EZH2 catalytic domain have been identified in non-hodgkin lymphomas such as diffuse large B cell lymphomas, follicular lymphomas, and disease-associated EZH 2Y 641 mutants can effectively catalyze both dimethyl and trimethyl reactions. Thus, wild-type EZH2 and mutant EZH2 synergistically result in increased levels of H3K27Me3, resulting in silencing of target genes that promote normal cell differentiation and inhibit proliferation. Therefore, it would be interesting to develop EZH2 inhibitors with high activity against both wild type and mutant for the treatment of non-hodgkin lymphomas like DLBCL.
Over the years of effort, a number of EZH2 inhibitors have entered clinical research stages in succession, including Tazemetostat, GSK126, CPI1209, CPI0209, SHR2554, PF06821497, DS3201b, and the like. Wherein tazemetastat has been approved by the FDA for the treatment of metastatic/locally advanced epithelioid sarcoma adult patients who cannot be completely resected and pediatric patients over 16 years old, is the first epithelioid sarcoma therapeutic drug approved by the FDA, and then is also the first approved EZH2 inhibitor for the batch treatment of follicular lymphoma. However, currently, tazemetostat in combination with R-CHOP chemotherapy for DLBCL indications is still in the clinical stage of research. These inhibitors require further clinical trials to assess potential use in the treatment of DLBCL. Therefore, there is a need to develop novel EZH2 inhibitors to address the limitations of DLBCL clinical therapies.
Disclosure of Invention
The invention provides a series of benzamide compounds containing an imidazolinone structure with novel structures. Researches show that the compounds can obviously inhibit enzyme activities of EZH2 WT and EZH2 mutants. The invention relates to benzamide compounds containing an imidazolinone structure shown in a general formula I or pharmaceutically acceptable salts thereof, a preparation method thereof and a pharmaceutical composition containing the compounds, wherein a substituent R 1 、R 2 、R 3 、R 4 、R 5 The meaning of (c) is set forth in the specification. The invention relates to a compound which has high level of inhibitory activity on EZH2WT and EZH2 mutant enzyme, and a benzamide compound containing an imidazolinone structure or a pharmaceutically acceptable salt thereof is used for preparing medicines for treating diseases related to abnormal expression of EZH2, such as cancers and autoimmune diseases.
The invention relates to benzamide compounds containing an imidazolinone structure shown in a general formula I or pharmaceutically acceptable salts thereof,
wherein the method comprises the steps of
R 1 Is (C1-C3) alkyl or (C1-C3) alkoxy;
R 2 、R 3 each independently selected from hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C3-C6) cycloalkylacyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O and S, wherein said (C3-C8) cycloalkyl is optionally substituted with 1-3R 6 Substitution; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S is a heterocycloalkyl group containing a sulfur atom, the sulfur atom thereof can be oxidized to sulfone; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S atoms is a heterocycloalkyl group containing a nitrogen atom, the nitrogen atom may be optionally substituted with 1 to 2R 7 Substitution;
R 4 、R 5 each independently selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C8) cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O and S atoms, six-to eight-membered bicyclic ring containing 1-2 nitrogen atoms, wherein said (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C8) cycloalkyl may optionally be substituted with 1-3R 6 Substitution; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S atoms is a heterocycloalkyl group containing a sulfur atom, the sulfur atom can be oxidized to form sulfone; where the 1-2 4-7 membered heterocycloalkyl groups containing 1-2 nitrogen atoms selected from N, O and S atoms and the six-to eight-membered bicyclic ring containing 1-2 nitrogen atoms is a heterocycloalkyl group containing a nitrogen atom, the nitrogen atom may optionally be substituted with 1-2R 7 Substitution;
R 6 selected from hydrogen, halogen, hydroxy, cyano, (C1-C3) alkyl, (C1-C3) alkoxy, (C3-C6) cycloalkyl, optionally substituted with 1-2R 7 Substituted amino groups;
R 7 selected from hydrogen, halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy (C1-C4) alkyl, (C4-C6) cycloalkyl, (C1-C4) acyl, (C3-C6) cycloalkylacyl, (C1-C4) sulfonyl, cyclopropylsulfonyl, (C1-C4) alkyl substituted by 1-3 cyano groups or fluorine atoms.
The present invention preferably relates to an imidazolinone structure-containing benzamide compound of the general formula I or a pharmaceutically acceptable salt thereof, wherein,
R 1 methyl or methoxy;
selected from:
selected from:
the imidazolinone structure-containing benzamide compounds of the present invention or pharmaceutically acceptable salts thereof are finally preferably selected from the compounds (I-1 to I-75), but these compounds are not meant to limit the present invention:
Benzamide compounds containing an imidazolinone structure of formula I described above, or pharmaceutically acceptable salts thereof, including salts with inorganic and organic acids; the mineral acid is selected from the group consisting of: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid; the organic acid is selected from the group consisting of: succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid;
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "heterocycloalkyl" means a monocyclic ring system containing N, O and/or S atoms;representing the substituent linkage.
The invention can be prepared into a composition by taking the benzamide compound containing the imidazolinone structure of the general formula I or the pharmaceutically acceptable salt thereof as an active ingredient and mixing with a pharmaceutically acceptable carrier or excipient. The carrier or excipient comprises diluents, binders, wetting agents, disintegrants, lubricants, glidants, which are known in the art. Diluents include starch, dextrin, sucrose, dextrose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate; the wetting agent comprises water, ethanol, isopropanol, etc.; the binder comprises starch slurry, dextrin, syrup, mel, glucose solution, acacia pulp, gelatin slurry, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and polyethylene glycol; the disintegrating agent comprises dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sodium dodecyl sulfate; lubricants and glidants include talc, silicon dioxide, polyethylene glycol.
The pharmaceutical composition of the present invention may be formulated into several dosage forms including injections, tablets, capsules.
The benzamide compound containing the imidazolinone structure or the pharmaceutically acceptable salt thereof can be combined with other active ingredients for use, so that a better therapeutic effect is achieved.
The invention also provides application of the benzamide compound containing the imidazolinone structure in the general formula I or pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to abnormal expression of EZH 2. The diseases related to the abnormal expression of the EZH2 are cancers and autoimmune diseases. The cancer is lymphoma, non-small cell lung cancer, head and neck cell cancer, bladder cancer, gastric cancer, colon cancer, colorectal cancer, kidney cancer, bile duct cancer, gastric cancer, esophageal squamous carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, glioblastoma, leukemia or cervical cancer; the autoimmune disease is inflammatory enteritis, autoimmune encephalomyelitis or multiple sclerosis.
The invention has the positive progress effects that: the benzamide compound containing the imidazolinone structure has a novel chemical structure, and most of the compounds have remarkable inhibitory activity on EZH2 WT and EZH2 mutants in-vitro biological activity research and have strong antiproliferative activity on Karpas-422 cells. The compounds are useful for the treatment and prevention of various diseases such as cancer.
Detailed Description
Route one:
(a) 4-bromo-1-fluoro-2-nitrobenzene is taken as a raw material, and is subjected to nucleophilic substitution reaction with fatty amine to obtain an intermediate 2;
(b) Intermediate 2 is taken as a raw material, and intermediate 3 is obtained through nitroreduction reaction;
(c) Intermediate 3 is taken as a raw material, and intermediate 4 is obtained through CDI-mediated clasp reaction;
(d) Taking the intermediate 5 as a raw material, condensing with tetrahydropyranone and preparing an intermediate 6 under the action of sodium triacetoxyborohydride;
(e) An intermediate 6 is taken as a raw material, condensed with acetaldehyde and subjected to the action of sodium triacetoxyborohydride to prepare an intermediate 7;
(f) Intermediate 7 is taken as a raw material, and intermediate 8 is prepared by Miyaura boric acid esterification reaction with pinacol ester of biboronate;
(g) Intermediate 8 is taken as a raw material, and intermediate 9 is prepared by Suzuki-Miyaura coupling reaction with intermediate 4;
(h) Intermediate 9 is taken as a raw material, and is subjected to nucleophilic substitution reaction with methyl iodide or ethyl iodide to obtain intermediate 10;
(i) Taking the intermediate 10 as a raw material, and obtaining an intermediate 11 through ester hydrolysis under the action of NaOH;
(j) The intermediate 11 is used as a raw material, and is subjected to amide condensation reaction with 3- (aminomethyl) -4, 6-dimethyl-1H-pyridin-2-one hydrochloride or 3- (aminomethyl) -4-methoxy-6-methylpyridin-2 (1H) -one hydrochloride under the condition of a condensing agent to obtain the target compound in the general formula I.
Route two:
referring to schemes one (g), (h), (I) and (j), intermediate 12 is reacted in four steps (a), (b), (c) and (d) to give the target compounds of formula I.
Route three:
wherein ring A is an aliphatic heterocyclic ring containing nitrogen atoms, as defined in formula I.
Similarly, referring to the reaction of scheme one, intermediate 14 is reacted in four steps (a), (b), (c) and (d) to provide intermediate 18.
(e) Taking the intermediate 18 as a raw material, and removing the Boc protecting group under an acidic condition to obtain an intermediate 19;
(f) The intermediate 19 is used as a raw material, and is subjected to N-acylation or N-sulfonylation reaction with acyl chloride or sulfonyl chloride, or is condensed with fatty aldehyde or ketone and subjected to sodium triacetoxyborohydride to prepare the target compound in the general formula I.
Route four:
similarly, referring to scheme four, intermediate 20 is reacted in six steps (a), (b), (c), (d), (e) and (f) to provide the target compound of formula I.
Route five:
(a) Intermediate 14 is taken as a raw material, and is subjected to nucleophilic substitution reaction with methyl iodide or ethyl iodide to obtain an intermediate 26;
(b) Starting from intermediate 26, removing the Boc protecting group under acidic conditions to afford intermediate 27;
(c) Intermediate 27 is used as a raw material, condensed with formaldehyde solution and is prepared into intermediate 28 under the action of sodium triacetoxyborohydride;
Similarly, referring to the reaction in scheme three, intermediate 28 is reacted in five steps (d), (e), (f), (g) and (h) to give the target compound in formula I.
Route six:
wherein ring B is a cycloalkane as defined in formula I.
Similarly, referring to the reaction in scheme five, intermediate 34 is reacted in five steps (a), (b), (c), (d) and (e) to give the target compound in formula I.
Route seven:
(a) Intermediate 5 is used as a raw material, condensed with acetaldehyde and subjected to the action of cyano sodium borohydride to prepare intermediate 39;
(b) Intermediate 39 is taken as a raw material and reacts with cycloalkyl formyl chloride to prepare intermediate 7 through N-acylation reaction;
similarly, referring to the reaction in scheme six, intermediate 7 is reacted in four steps (c), (d), (e) and (f) to give the target compound of formula I.
Example 1: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-2-oxo-1- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-1)
Step one: 5-bromo-2-methyl-3- ((tetrahydro 2H-pyran-4-yl) amino) benzoic acid methyl ester
Methyl 3-amino-5-bromo-2-methylbenzoate (10 g,40.97 mmol) was dissolved in DCM (150 mL), tetrahydropyranone (12.3 g,122.91 mmol) and acetic acid (7.35 g,122.91 mmol) were added sequentially, stirred at room temperature for 1h, and sodium triacetoxyborohydride (26.05 g,122.91 mmol) was added and stirred at room temperature for 3h. TLC monitored reaction was complete. The reaction solution was poured into water, extracted with dichloromethane for 3 times, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to give a yellow solid (13 g,39.76 mmol), which was directly put into the next step without purification, yield: 98.0%. ESI-MS m/z 328.23[ M+H ] ] + 。
Step two: 5-bromo-3- (ethyl (tetrahydro 2H-pyran-4-yl) amino) -2-methylbenzoic acid methyl ester
The compound from step one (13 g,39.76 mmol) was dissolved in DCM (150 mL), acetaldehyde (3.5 g,79.51 mmol) and acetic acid (14.32 g,238.53 mmol) were added sequentially, stirred at room temperature for 1h, sodium triacetoxyborohydride (25.28 g,119.27 mmol) was added and stirred at room temperature for 6h. TLC monitored reaction was complete. The reaction solution was poured into water, extracted with dichloromethane for 3 times, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous ammonium sulfate and concentrated, and purified by column chromatography to give a pale yellow solid (11.46 g,32.17 mmol), yield: 81.0%. ESI-MS m/z 357.25[ M+H ]] + 。
Step three: 3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid methyl ester
The compound from step two (5 g,14.03 mmol) was dissolved in 1, 4-dioxane (75 mL) and added sequentiallyPinacol ester of diboronic acid (5.35 g,21.05 mmol), pd (dppf) Cl 2 (0.51 g,0.70 mmol) and KOAc (4.13 g,42.10 mmol), then N 2 Heating to 100 ℃ under the protection condition and refluxing for 3 hours. TLC monitored reaction was complete. Cooled to room temperature, 80mL of water was added, the mixture was filtered with celite, the filtrate was extracted 3 times with EA, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a pale yellow solid (5.39 g,13.36 mmol), yield: 95.2%. ESI-MS m/z 404.32[ M+H ] ] + 。
Step four: n- (4-bromo-2-nitrophenyl) tetrahydro-2H-pyran-4-amine
4-bromo-1-fluoro-2-nitrobenzene (10 g,45.45 mmol) was dissolved in DMF (100 mL) and 4-aminotetrahydropyran (6.90 g,68.18 mmol) and potassium carbonate (12.56 g,90.91 mmol) were added sequentially. Heating to 60 ℃ for reaction for 3 hours. TLC monitored reaction was complete. 600mL of water was added and after stirring for 30min, a yellow solid (13.41 g,44.55 mmol) was obtained by suction filtration, yield: 98.0%. ESI-MS m/z 301.12[ M+H ]] + 。
Step five: 4-bromo-N 1 - (tetrahydro 2H-pyran-4-yl) benzene-1, 2-diamine
NH is added to 4 Cl (14.30 g,267.27 mmol) was dissolved in 67mL of water and iron powder (14.97 g,267.27 mmol) was added in portions. And heating to 80 ℃ to activate the iron powder for 30min. Thereafter, the compound obtained in the fourth step (13.41 g,44.55 mmol) and EtOH (201 mL) were added in this order, and the reaction was continued for 1h. TLC monitored reaction was complete. 100mL of ethyl acetate and 100mL of water were added, the mixture was filtered through celite, extracted 3 times with EA, the organic layers were combined, washed 2 times with saturated sodium chloride, and dried and evaporated to dryness to give a purple solid (9.08 g,33.49 mmol). Yield: 75.2%. ESI-MS m/z 271.12[ M+H ]] + 。
Step six: 5-bromo-1- (tetrahydro-2H-pyran-4-yl) -1, 3-dihydro-2H-benzo [ d ] imidazol-2-one
The compound from step five (9.08 g,33.49 mmol) was dissolved in redistilled dioxane (136 mL) and CDI (16.29 g,100.46 mmol) was added in portions. The reaction was carried out at room temperature for 3 hours. TLC monitored reaction was complete. Evaporated to dryness, water was added, filtered off with suction and dried, and slurried with diethyl ether to give a grey solid (7.78 g,26.19 mmol), yield: 78.2%. ESI-MS m/z 297.08[ M+H ] ] + 。
Step seven: 3- (Ethyl (tetrahydro 2H-pyran-4-yl) amino) -2-methyl-5- (2-oxo-1- (tetrahydro 2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzoic acid methyl ester
Dissolving the compound (0.71 g,1.77 mmol) obtained in step three in 1, 4-dioxane (6 mL), and sequentially adding the compound (0.71 g,1.77 mmol) obtained in step six and Pd (dppf) Cl 2 (0.12g，0.17mmol)、K 2 CO 3 (0.70 g,5.05 mmol) and H 2 O(2mL)。N 2 Under the protection condition, heating to 100 ℃ for reaction for 3 hours. TLC monitored reaction was complete. After cooling to room temperature, 20mL of water was added, the mixture was filtered with celite, the filtrate was extracted 3 times with EA, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a pale yellow solid (0.51 g,1.04 mmol), yield: 62.1%. ESI-MS m/z 494.35[ M+H ]] + 。
Step eight: 3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-2-oxo-1- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzoic acid methyl ester
The compound from step seven (0.51 g,1.04 mmol) was dissolved in DMF (5 mL) and NaH (0.083 g,2.08 mmol) was added in portions at 0deg.C and stirred at room temperature for 30min. Methyl iodide (0.29 g,2.08 mmol) was added thereto, and the reaction was continued at room temperature for 2 hours. TLC monitored reaction was complete. 50mL of water was added, stirred for 10min, extracted 3 times with EA, the organic phases were combined, washed twice with water, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, and evaporated to dryness to give a pale yellow solid (0.49 g,0.96 mmol), yield: 92.6%. ESI-MS m/z 508.23[ M+H ] ] + 。
Step nine: 3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-2-oxo-1- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzoic acid
The compound from step eight (0.49 g,0.96 mmol) was dissolved in methanol (8 mL) and NaOH (0.15 g,3.84 mmol) and water (2 mL) were added sequentially. The temperature was raised to 66℃and the reaction was continued for 3h. TLC monitored reaction was complete. After cooling to room temperature, 10mL of water was added, pH was adjusted to 4 with 2N HCl aqueous solution, DCM was added for extraction 3 times, the organic phases were combined, washed with saturated sodium chloride for 2 times, dried over anhydrous sodium sulfate, evaporated to dryness to give a pale solutionYellow solid (0.45 g,0.91 mmol), yield: 95.2%. ESI-MS m/z 494.30[ M+H ]] + 。
Step ten: preparation of Compound I-1
The compound (0.15 g,0.30 mmol) obtained in step nine was dissolved in DMF (2 mL), and 3- (aminomethyl) -4, 6-dimethyl-1H-pyridin-2-one hydrochloride (0.057 g,0.30 mmol), HATU (0.15 g,0.40 mmol), DIPEA (0.20 g,1.52 mmol) and reacted at room temperature for 1H were added sequentially. TLC monitored reaction was complete. 20mL of water is added, after stirring for 10min, EA is added for extraction for 3 times, the organic phases are combined, water washing is carried out for two times, saturated sodium chloride is used for washing for 2 times, anhydrous sodium sulfate is dried, and the target compound I-1 (0.088 g,0.14 mmol) is obtained through column chromatography after evaporation to dryness, and the yield is: 45.2%. ESI-MS m/z 628.25[ M+H ] ] + ； 1 H NMR(600MHz,DMSO-d 6 )δ11.46(s,1H),8.18(t,J＝4.5Hz,1H),7.40(d,J＝7.2Hz,2H),7.36(d,J＝8.2Hz,1H),7.30(d,J＝7.9Hz,1H),7.27(s,1H),5.86(s,1H),4.49–4.44(m,1H),4.30(d,J＝4.6Hz,2H),4.02–3.98(m,2H),3.86–3.82(m,2H),3.49(t,J＝11.4Hz,2H),3.39(s,3H),3.25(t,J＝11.3Hz,2H),3.13–3.08(m,2H),3.05–2.99(m,1H),2.42–2.36(m,2H),2.24(s,3H),2.22(s,3H),2.11(s,3H),1.67(s,4H),1.57–1.51(m,2H),0.85(t,J＝6.8Hz,3H)。
The title compound of examples 2-4, 43, 71 and 72 was obtained according to the synthesis method of example 1.
Example 2: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (oxetan-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-2)
ESI-MS m/z:600.22[M+H] + 。
Example 3: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (1- (2-methoxyethyl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-3)
ESI-MS m/z:602.23[M+H] + 。
Example 4: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro 2H-pyran-4-yl) amino) -5- (1-ethyl-2-oxo-3- (tetrahydro 2H-pyran-4-yl) -2, 3-dihydro 1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-4)
ESI-MS m/z:642.10[M+H] + 。
Example 5:5- (1- (1-Acetylpiperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-5)
Step one: 4- (5- (3- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methylphenyl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
According to the synthesis method of the target compound I-1, 4-aminopiperidine-1-carboxylic acid tert-butyl ester is used for replacing 4-aminotetrahydropyran to prepare a light yellow solid. ESI-MS m/z 593.23[ M+H ]] + 。
Step two: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-2-oxo-1- (piperidin-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide
The compound from step one of example 5 (1.64 g,2.25 mmol) was dissolved in DCM (16 mL) and TFA (8 mL) was added. The reaction was carried out at room temperature for 1h. TLC monitored reaction was complete. 30mL of water was added, the pH was adjusted to 10 with 2N aqueous NaOH, extracted 3 times with DCM, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness to give a white solid (1.34 g,2.14 mmol), yield: 95.2%. ESI-MS m/z 627.35[ M+H ]] + 。
Step three: preparation of Compound I-5
The compound obtained in step two of example 5 (0.1 g,0.16 mmol), NEt 3 (0.049 g,0.48 mmol) in THF (2 mL), at 0deg.C,a solution of acetyl chloride (0.015 g,0.192 mmol) in THF was slowly added dropwise. The reaction was carried out at room temperature for 30min. TLC monitored reaction was complete. Water (20 mL) was added, extracted 3 times with DCM, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and chromatographed to give a white solid, yield: 35.2%. 1 H NMR(600MHz,DMSO-d 6 )δ11.49(s,1H),8.19(s,1H),7.42–7.39(m,2H),7.36(d,J＝7.9Hz,1H),7.30–7.26(m,2H),5.86(s,1H),4.57(d,J＝11.6Hz,1H),4.50–4.46(m,1H),4.31(d,2H),3.97(d,J＝12.2Hz,1H),3.84(d,J＝9.0Hz,2H),3.39(s,3H),3.26(d,J＝11.1Hz,2H),3.20(d,J＝12.7Hz,1H),3.12–3.08(m,2H),3.05–3.01(m,1H),2.66(t,J＝12.2Hz,1H),2.34–2.30(m,1H),2.24(s,3H),2.22(s,3H),2.11(s,3H),2.07(s,3H),1.76(d,J＝10.6Hz,1H),1.72(d,J＝12.5Hz,1H),1.67(d,J＝11.3Hz,2H),1.56–1.51(m,2H),1.09(t,J＝6.7Hz,1H),0.85(t,J＝5.9Hz,3H)；ESI-MS m/z:669.25[M+H] + 。
The title compounds of examples 6-11, 19-21, 27, 44-46 and 53-62 were obtained according to the synthesis method of example 5.
Example 6:5- (1- (1- (cyclopropanecarbonyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-6)
ESI-MS m/z:695.38[M+H] + 。
Example 7: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3-methyl-2-oxo-1- (1-propionylpiperidin-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-7)
ESI-MS m/z:683.25[M+H] + 。
Example 8: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (1- (1-isobutyrylpiperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-8)
ESI-MS m/z:697.30[M+H] + 。
Example 9: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (1- (methylsulfonyl) piperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-9)
ESI-MS m/z:705.32[M+H] + 。
Example 10: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (1- (1- (ethylsulfonyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (compound I-10)
ESI-MS m/z:719.32[M+H] + 。
Example 11: (1- (1- (cyclopropylsulfonyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-11)
ESI-MS m/z:731.25[M+H] + 。
Example 12: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-12)
The compound (0.1 g,0.16 mmol) obtained in step two of example 5 was dissolved in DCM (2 mL), 40% aqueous formaldehyde (0.036 g,0.48 mmol) was added sequentially, acetic acid (0.029 g,0.48 mmol) was stirred at room temperature for 30min. Sodium Triacetoxyborohydride (STAB) (0.10 g,0.48 mmol) was added in portions and reacted at room temperature for 1h. TLC monitored reaction was complete. Water was added, the pH was adjusted to 10 with 2N NaOH, extracted 3 times with DCM, the organic layers were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and column chromatographed to give a white solid (0.075 g,0.12 mmol), yield: 72.6%. 1 H NMR(600MHz,DMSO-d 6 )δ11.46(s,1H),8.18(t,J＝4.8Hz,1H),7.40(s,1H),7.39(s,1H),7.33(d,J＝8.2Hz,1H),7.30–7.28(m,1H),7.26(s,1H),5.86(s,1H),4.30(d,J＝4.8Hz,2H),4.19(ddd,J＝12.4,7.2,3.5Hz,1H),3.84(d,J＝9.9Hz,2H),3.38(s,3H),3.25(t,J＝11.2Hz,2H),3.10(q,J＝6.5Hz,2H),3.04–3.00(m,1H),2.93(d,J＝9.0Hz,2H),2.39(d,J＝9.2Hz,2H),2.24(s,3H),2.23(s,3H),2.22(s,3H),2.11(s,3H),2.08(s,2H),1.67(d,J＝9.2Hz,4H),1.56–1.51(m,2H),0.84(t,J＝7.0Hz,3H)；ESI-MS m/z:641.30[M+H] + 。
The title compounds of examples 13-15, 22, 24, 29, 47-50 and 63-66 were obtained according to the synthesis method of example 12.
Example 13:5- (1- (1- (cyclopropylmethyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-13)
ESI-MS m/z:681.32[M+H] + 。
Example 14: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (1- (1-ethylpiperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-14)
ESI-MS m/z:655.35[M+H] + 。
Example 15: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (1- (oxetan-3-yl) piperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-15)
ESI-MS m/z:683.35[M+H] + 。
Example 16:5- (1- (1- (2, 2-difluoroethyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-16)
The compound obtained in step two of example 5 was dissolved in DMF (2 mL), and potassium carbonate (0.044 g,0.32 mmol) and 2, 2-difluoroethyl trifluoromethanesulfonate (0.043 g,0.20 mmol) were added sequentially. The reaction was carried out at 40℃for 2 hours. TLC monitored reaction was complete. 20mL of water was added thereto, and the mixture was stirred,after stirring for 30min, extracted 3 times with EA, the organic phases were combined, washed 3 times with water, 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and column chromatographed to give a white solid (0.039 g,0.057 mmol), yield: 35.6%. 1 H NMR(600MHz,DMSO-d 6 )δ11.48(s,1H),8.19(t,J＝4.8Hz,1H),7.40(d,J＝7.5Hz,2H),7.31(d,J＝3.7Hz,2H),7.27(s,1H),6.28–6.09(m,1H),5.86(s,1H),4.31(d,J＝4.8Hz,2H),4.23–4.18(m,1H),3.84(d,J＝10.5Hz,2H),3.39(s,3H),3.25(t,J＝11.2Hz,2H),3.12–3.08(m,2H),3.05(d,J＝6.9Hz,2H),3.03–2.99(m,1H),2.83–2.77(m,2H),2.40–2.34(m,4H),2.24(s,3H),2.22(s,3H),2.11(s,3H),1.67(d,J＝11.0Hz,4H),1.56–1.51(m,2H),0.85(t,J＝6.9Hz,3H)；ESI-MS m/z:691.35[M+H] + 。
The title compounds of examples 17, 18, 23, 25, 26, 28, 51, 52 and 67-70 were obtained according to the synthesis method of example 16.
Example 17: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-2-oxo-1- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-17)
ESI-MS m/z:709.35[M+H] + 。
Example 18:5- (1- (1- (cyanomethyl) piperidin-4-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-18)
ESI-MS m/z:666.37[M+H] + 。
Example 19: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (1- (methylsulfonyl) azetidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-19)
ESI-MS m/z:677.30[M+H] + 。
Example 20:5- (1- (1-Acetylazetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-20)
ESI-MS m/z:641.30[M+H] + 。
Example 21:5- (1- (1- (cyclopropanecarbonyl) azetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-21)
ESI-MS m/z:667.30[M+H] + 。
Example 22:5- (1- (1- (cyclopropylmethyl) azetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-22)
ESI-MS m/z:653.37[M+H] + 。
Example 23:5- (1- (1- (2, 2-difluoroethyl) azetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-23)
ESI-MS m/z:663.30[M+H] + 。
Example 24: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylazetidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-24)
ESI-MS m/z:613.34[M+H] + 。
Example 25: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (1- (1- (2-hydroxyethyl) azetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-25)
ESI-MS m/z:643.35[M+H] + 。
Example 26:5- (1- (1- (cyanomethyl) azetidin-3-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-26)
ESI-MS m/z:638.33[M+H] + 。
Example 27: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (3- (methylsulfonyl) -3-azabicyclo [3.1.0] hexane-6-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-27)
ESI-MS m/z:703.32[M+H] + 。
Example 28:5- (1- (3- (2, 2-difluoroethyl) -3-azabicyclo [3.1.0] hexane-6-yl) -3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-28)
ESI-MS m/z:689.35[M+H] + 。
Example 29: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (3-methyl-1- (3-methyl-3-azabicyclo [3.1.0] hexan-6-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-29)
ESI-MS m/z:639.35[M+H] + 。
Example 30:3- ((1-Acetylpiperidin-4-yl) (ethyl) amino) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-30)
Step one: 4- (5-bromo-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Following the same procedure as in steps four, five and six of example 1 substituting tert-butyl 4-aminopiperidine-1-carboxylate for 4-aminotetrahydropyran, ash was obtainedColor solids. ESI-MS m/z 395.10[ M+H ]] + 。
Step two: 4- (5-bromo-3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Prepared by the method of step eight in example 1 starting from the compound obtained in step one of example 30 (5 g,12.62 mmol), yield: 92.6%. ESI-MS m/z 410.10[ M+H ] ] + 。
Step three: 5-bromo-3-methyl-1- (piperidin-4-yl) -1, 3-dihydro 2H-benzo [ d ] imidazol-2-one
Prepared by the method of step two of example 5 starting from the compound obtained in step two of example 30 (4.80 g,11.69 mmol), yield: 88.5%. ESI-MS m/z 310.05[ M+H ]] + 。
Step four: 5-bromo-3-methyl-1- (1-methylpiperidin-4-yl) -1, 3-dihydro 2H-benzo [ d ] imidazol-2-one
Prepared by the method of example 12 using the compound obtained in step three of example 30 (3.18 g,10.27 mmol), yield: 85.6%. ESI-MS m/z 324.06[ M+H ]] + 。
Step five: 4- (Ethyl (3- (methoxycarbonyl) -2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) amino) piperidine-1-carboxylic acid tert-butyl ester
The same preparation method as in step one, two and three of example 1 was followed by substituting N-t-butoxycarbonyl-4-piperidone for tetrahydropyranone to give a gray solid, ESI-MS m/z:395.10[ M+H ]] + 。
Step six: 4- (ethyl (3- (methoxycarbonyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) phenyl) amino) piperidine-1-carboxylic acid tert-butyl ester
Using the compound obtained in step five and the compound obtained in step four in example 30 as raw materials, a yellow solid was obtained in the same manner as in step seven in example 1. ESI-MS m/z 620.30[ M+H ] ] + 。
Step seven: 3- ((1- (tert-Butoxycarbonyl) piperidin-4-yl) (ethyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzoic acid
The same procedure as in step nine of example 1 was followed except for using the compound obtained in step six of example 30 to give a pale yellow solid. ESI-MS m/z 605.30[ M+H ]] + 。
Step eight: 4- ((3- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) phenyl) (ethyl) amino) piperidine-1-carboxylic acid tert-butyl ester
Using the compound obtained in step seven in example 30, a yellow solid was obtained in the same manner as in step ten in example 1. ESI-MS m/z 739.20[ M+H ]] + 。
Step nine: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (piperidin-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro 1H-benzo [ d ] imidazol-5-yl) benzamide
The same procedures as in step two of example 5 were repeated except for using the compound obtained in step eight of example 30 to give a pale yellow solid. ESI-MS m/z 639.10[ M+H ] ] + 。
Step ten: preparation of Compound I-30
Using the compound obtained in step nine of example 30, according to the same preparation method as in step three of example 5, a white solid was obtained by column chromatography, yield: 32.5%. 1 H NMR(600MHz,DMSO-d 6 )δ11.47(s,1H),8.18(t,J＝4.8Hz,1H),7.40(d,J＝3.6Hz,2H),7.33(d,J＝8.2Hz,1H),7.30(d,J＝8.1Hz,1H),7.27(s,1H),5.86(s,1H),4.30(d,J＝4.7Hz,2H),4.21–4.17(m,1H),3.76(d,J＝12.9Hz,1H),3.39(s,3H),3.11–3.07(m,2H),3.05–3.02(m,1H),3.02–2.95(m,2H),2.92(d,J＝10.4Hz,2H),2.54(d,J＝11.8Hz,1H),2.41–2.36(m,2H),2.24(s,6H),2.22(s,3H),2.11(s,3H),2.07(d,J＝10.5Hz,2H),1.97(s,3H),1.77–1.72(m,2H),1.65(d,J＝10.6Hz,2H),1.51–1.47(m,1H),1.37–1.33(m,1H),0.84(t,J＝7.0Hz,3H)；ESI-MS m/z:682.40[M+H] + 。
The title compound in examples 31, 32 and 41 was obtained by the synthesis method in step ten of example 30.
Example 31:3- ((1- (cyclopropanecarbonyl) piperidin-4-yl) (ethyl) amino) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-31)
ESI-MS m/z:708.42[M+H] + 。
Example 32: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (1-propionylpiperidin-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro 1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-32)
ESI-MS m/z:696.42[M+H] + 。
Example 33: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (1-methylpiperidin-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-33)
Prepared by the method of example 12 starting from the compound of step nine of example 30 (0.1 g,0.16 mmol), yield: 65.2%. ESI-MS m/z 653.41[ M+H ] ] + 。
Examples 34 and 35 were prepared according to the synthesis method of example 33.
Example 34:3- ((1- (cyclopropylmethyl) piperidin-4-yl) (ethyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (compound I-34)
ESI-MS m/z:694.44[M+H] + 。
Example 35: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (1- (oxetan-3-yl) piperidin-4-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-35)
ESI-MS m/z:696.42[M+H] + 。
Example 36: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (N-ethylcyclopropanecarboxamide) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-36)
Step one: 5-bromo-3- (ethylamino) -2-methylbenzoic acid methyl ester
Methyl 3-amino-5-bromo-2-methylbenzoate (3 g,12.29 mmol) was dissolved in methanol (30 mL), and acetaldehyde (0.54 g,12.29 mmol), acetic acid (0.74 g,12.29 mmol) were added in this order to react for 30min at room temperature. After which NaBH is added in portions 3 CN (2.32 g,36.87 mmol), at room temperature for 2h. TLC monitored reaction was complete. Water was added, extracted 3 times with DCM, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and chromatographed on column to give a yellow solid (1.18 g,4.33 mmol), yield: 35.2%. ESI-MS m/z 272.02[ M+H ]] + 。
Step two: 5-bromo-3- (N-ethylcyclopropane-carboxamide) -2-methylbenzoic acid methyl ester
5-bromo-3- (ethylamino) -2-methylbenzoic acid methyl ester (1.18 g,4.33 mmol) was dissolved in DCM (15 mL) and NEt was added 3 (1.31 g,12.99 mmol) and a solution of cyclopropylcarbonyl chloride (0.68 g,6.50 mmol) in DCM was slowly added dropwise at 0deg.C. The reaction was carried out at room temperature for 2 hours. TLC monitored reaction was complete. Water was added and extracted 3 times with DCM, the organic phases were combined, washed 2 times with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness to give a yellow solid (1.41 g,4.14 mmol), yield: 95.6%. ESI-MS m/z 340.05[ M+H ]] + 。
Step three: preparation of Compound I-36
Using the compound obtained in step two in example 36 and the compound obtained in step four in example 30 as raw materials, a white solid was obtained by column chromatography with reference to the synthetic method of example 1. 1 H NMR(600MHz,DMSO-d 6 )δ11.50(s,1H),8.38(t,J＝4.9Hz,1H),7.61(d,J＝10.2Hz,2H),7.54(s,1H),7.42–7.39(m,1H),7.36(d,J＝8.2Hz,1H),5.87(s,1H),4.35–4.30(m,2H),4.21(t,J＝12.1Hz,1H),3.39(s,3H),2.94(d,J＝10.3Hz,2H),2.79(s,2H),2.42–2.38(m,2H),2.26(s,3H),2.23(s,3H),2.19(s,3H),2.11(s,3H),1.67(d,J＝10.5Hz,2H),1.24–1.22(m,1H),1.09–1.08(m,2H),1.05(t,J＝7.1Hz,3H),0.77(t,J＝3.5Hz,2H),0.62–0.54(m,2H)；ESI-MS m/z:625.34[M+H] + 。
Example 37: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- ((4- (dimethylamino) cyclohexyl) (ethyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-37)
Step one: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (4- (methylamino) cyclohexyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide
A pale yellow solid was prepared according to the synthetic method of step one to step nine of example 30. 668.12[ M+H ] ESI-MS m/z] + 。
Step two: preparation of Compound I-37
The compound obtained in step one of example 37 was purified by column chromatography according to the synthetic method of example 12 to give a white solid, yield: 65.4%. 1 H NMR(600MHz,DMSO-d 6 )δ11.46(s,1H),8.18(t,J＝5.0Hz,1H),7.38–7.35(m,2H),7.32(d,J＝8.1Hz,1H),7.28–7.26(m,1H),7.23(d,J＝3.3Hz,1H),5.86(s,1H),4.30(d,J＝4.8Hz,2H),4.19–4.15(m,1H),3.38(s,3H),3.16–3.06(m,2H),3.05–3.01(m,1H),2.90(d,J＝10.9Hz,2H),2.69–2.64(m,1H),2.39–2.36(m,2H),2.23(s,3H),2.21(s,6H),2.17(s,3H),2.15(s,3H),2.11(s,3H),2.05(t,2H),1.85–1.78(m,4H),1.65(d,J＝10.7Hz,2H),1.40–1.34(m,2H),1.15(q,J＝11.6Hz,2H),0.84(t,J＝6.4Hz,3H)；ESI-MS m/z:682.44[M+H] + 。
Examples 38-40 and 42 were prepared according to the procedure for the synthesis of example 37.
Example 38: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (4- (ethyl (methyl) amino) cyclohexyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-38)
ESI-MS m/z:696.45[M+H] + 。
Example 39:3- ((4- ((cyclopropylmethyl) (methyl) amino) cyclohexyl) (ethyl) amino) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (compound I-39)
ESI-MS m/z:722.47[M+H] + 。
Example 40: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (4- (methyl (oxetan-3-yl) amino) cyclohexyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-40)
ESI-MS m/z:724.45[M+H] + 。
Example 41: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (4- (N-methylcyclopropanecarboxamide) cyclohexyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-41)
ESI-MS m/z:736.45[M+H] + 。
Example 42: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (4- ((2-methoxyethyl) (methyl) amino) cyclohexyl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-42)
1 H NMR(600MHz,DMSO-d 6 )δ11.47(s,1H),8.17(t,J＝4.8Hz,1H),7.39–7.35(m,2H),7.32(d,J＝8.2Hz,1H),7.28(d,J＝7.4Hz,1H),7.25–7.22(m,1H),5.86(s,1H),4.30(d,J＝4.7Hz,2H),4.20–4.15(m,1H),3.38(s,3H),3.33(t,J＝6.0Hz,2H),3.20(s,3H),3.12–3.08(m,2H),2.91(d,J＝10.6Hz,2H),2.66(t,J＝11.3Hz,1H),2.59–2.54(m,1H),2.41–2.34(m,2H),2.23(s,3H),2.22(s,6H),2.21(s,3H),2.15(s,2H),2.11(s,3H),2.06(t,J＝11.6Hz,2H),1.83(d,J＝11.1Hz,2H),1.71(d,J＝10.7Hz,2H),1.65(d,J＝10.8Hz,2H),1.38(q,J＝11.0Hz,2H),1.19(q,J＝11.3Hz,2H),0.84(t,J＝6.6Hz,3H)；ESI-MS m/z:726.46[M+H] + 。
Example 43: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-2-oxo-3- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-43)
ESI-MS m/z:628.34[M+H] + 。
Example 44:5- (3- (1-Acetylpiperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-44)
ESI-MS m/z:669.37[M+H] + 。
Example 45: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1- (methylsulfonyl) piperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-45)
ESI-MS m/z:705.34[M+H] + 。
Example 46:5- (3- (1- (cyclopropanecarbonyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-46)
ESI-MS m/z:695.38[M+H] + 。
Example 47: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1- (oxetan-3-yl) piperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-47)
ESI-MS m/z:683.38[M+H] + 。
Example 48: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-48)
ESI-MS m/z:641.37[M+H] + 。
Example 49: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3- (1-ethylpiperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-49)
ESI-MS m/z:655.39[M+H] + 。
Example 50:5- (3- (1- (cyclopropylmethyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-50)
ESI-MS m/z:681.40[M+H] + 。
Example 51:5- (3- (1- (2, 2-difluoroethyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro 2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-51)
ESI-MS m/z:691.37[M+H] + 。
Example 52: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-2-oxo-3- (1- (2, 2-trifluoroethyl) piperidin-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-52)
ESI-MS m/z:709.36[M+H] + 。
Example 53: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3- (1- (ethylsulfonyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-53)
ESI-MS m/z:719.35[M+H] + 。
Example 54:5- (3- (1- (cyclopropylsulfonyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-54)
ESI-MS m/z:731.35[M+H] + 。
Example 55: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-2-oxo-3- (1-propionylpiperidin-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-55)
ESI-MS m/z:683.38[M+H] + 。
Example 56: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3- (1-isobutyrylpiperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-56)
ESI-MS m/z:697.40[M+H] + 。
Example 57:5- (3- (1-Acetylazetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-57)
ESI-MS m/z:641.34[M+H] + 。
Example 58: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1- (methylsulfonyl) azetidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-58)
ESI-MS m/z:677.30[M+H] + 。
Example 59: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-2-oxo-3- (1-propionylazetidin-3-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-59)
ESI-MS m/z:655.35[M+H] + 。
Example 60:5- (3- (1- (cyclopropylsulfonyl) azetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-60)
ESI-MS m/z:703.32[M+H] + 。
Example 61:5- (3- (1- (cyclopropanecarbonyl) azetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro 2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-61)
ESI-MS m/z:667.30[M+H] + 。
Example 62: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3- (1-isobutyrylazetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-62)
ESI-MS m/z:669.37[M+H] + 。
Example 63: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1-methylazetidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-63)
ESI-MS m/z:613.34[M+H] + 。
Example 64: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3- (1-ethylazetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-64)
ESI-MS m/z:627.36[M+H] + 。
Example 65: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-3- (1- (oxetan-3-yl) azetidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-65)
ESI-MS m/z:655.35[M+H] + 。
Example 66:5- (3- (1- (cyclopropylmethyl) azetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (Compound I-66)
ESI-MS m/z:653.37[M+H] + 。
Example 67:5- (3- (1- (2, 2-difluoroethyl) azetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-67)
ESI-MS m/z:663.34[M+H] + 。
Example 68: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (1-methyl-2-oxo-3- (1- (2, 2-trifluoroethyl) azetidin-3-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-68)
ESI-MS m/z:681.33[M+H] + 。
Example 69:5- (3- (1- (cyanomethyl) azetidin-3-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-69)
ESI-MS m/z:638.34[M+H] + 。
Example 70:5- (3- (1- (cyanomethyl) piperidin-4-yl) -1-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (compound I-70)
ESI-MS m/z:666.37[M+H] + 。
Example 71: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (3-ethyl-2-oxo-1- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-methylbenzamide (Compound I-71)
ESI-MS m/z:642.36[M+H] + 。
Example 72: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (2-oxo-1- (tetrahydro-2H-pyran-4-yl) -2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-72)
ESI-MS m/z:614.33[M+H] + 。
Example 73:3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -N- ((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro 1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-73)
Following the synthesis of example 1 and example 36, a white solid was prepared in yield: 32.2%. ESI-MS m/z 657.35[ M+H ]] + 。
Example 74: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (1-methylpyrrolidin-3-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro 1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-74)
Following the synthesis of example 33, a white solid was prepared in yield: 22.5%. ESI-MS m/z 640.0[ M+H ]] + 。
Example 75: n- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (1- (oxetan-3-yl) pyrrolidin-3-yl) amino) -2-methyl-5- (3-methyl-1- (1-methylpiperidin-4-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) benzamide (Compound I-75)
Prepared according to the synthesis method of example 33To a white solid, yield: 15.8%. ESI-MS m/z 682.0[ M+H ]] + 。
Biological Activity assay:
experiment one, determination of enzyme Activity of Compounds of the invention on EZH2 WT, Y641F and Y641N mutants
According to the instructions, 1x assay buffer (modified Tris buffer) was prepared, and the enzyme and substrate were diluted with this assay buffer. The compounds were diluted with the appropriate concentration gradient, after which 100nL of compound dilution was transferred to 384 well plates per well. After this, 5. Mu.L of enzyme solution was transferred to the assay plate and for the low control 5. Mu.L of 1 Xassay buffer was transferred. Incubate at room temperature for 15min. After incubation, 5 μl of substrate solution was added to each well, the reaction was started and incubated for 45min at room temperature. Then 15. Mu.L of the acceptor and donor solutions were added after dilution with 1 Xassay buffer and incubated at room temperature for 60min under low light. The endpoint was read on EnSpire using Alpha mode. (this experiment was performed by Shanghai Ming's chemical research Co., ltd. By the method AlphaLISA). The results of the inhibitory activity of the compounds on EZH2 WT are shown in table 1. The results of the inhibitory activity on the EZH 2Y 641 mutant are shown in table 2.
Inhibitory Activity of the compounds of Table 1 on EZH2 WT
The test results show that the example compounds have significant inhibition of EZH2 WT at the level of biochemical.
TABLE 2 inhibitory Activity of partial Compounds against Y641F and Y641N mutants
Numbering of compounds Y641F Y641N
12 0.028 0.05
37 0.034 0.083
42 0.14 0.20
EPZ-6438 0.37 0.85
GSK-126 0.33 0.52
The results show that preferred compounds 12, 37 and 42 have a strong inhibitory effect on EZH 2Y 641F and EZH 2Y 641N.
Experiment two proliferation assay of the Compounds of the invention on human diffuse Large B cell lymphodynia cells (Karpas 422 cells)
Experiments CCK-8 assays were performed on Karpas-422 (cellhook) cells to assess the antiproliferative activity of the compounds of interest. Karpas 422 cells (about 3000 cells/well) were seeded into RPMI 1640 (Gibco) 96-well plates containing 20% FBS (Celcook) and 1% penicillin-streptomycin (Gibco). The cells are then sequentially treated with a compound having a concentration gradient. First, 50. Mu.L of test compound was added to the cell plates of each well, and the cell culture was incubated at 37℃and 5% CO 2 Culturing for 72h. After the incubation was completed, the compounds were diluted again with growth medium and 50 μl was added to the cell plates of each well. The plates were then incubated at 37℃with 5% CO 2 Under the condition thatCulturing was continued for 96 hours. Then, 50. Mu.L of CCK-8 diluent (including 20. Mu.L of CCK-8 and 30. Mu.L of medium) was added to each well, and further cultured for 4 hours. The plates were then shaken for 5min and read at 450nm using a microplate reader (Multiskan FC). All experiments were repeated at least 3 times. Dose-response curves were obtained by Prism 5.0 (GraphPad software), and the antiproliferative activity results of some examples on Karpas-422 cells are shown in table 3.
Inhibition of Karpas-422 proliferation by the compounds of Table 3
Cell test results show that the compounds of the examples have certain antiproliferative activity on Karpas-422. In comparison with EPZ-6438 (IC) 50 =35.01 nM), some compounds exhibited stronger antiproliferative activity.

Claims (10)

1. Benzamide compounds containing an imidazolinone structure shown in the general formula I or pharmaceutically acceptable salts thereof,
wherein the method comprises the steps of
R 1 Is (C1-C3) alkyl or (C1-C3) alkoxy;
R 2 、R 3 each independently selected from hydrogen, (C1-C4) alkyl, (C3-C8) cycloalkyl, (C3-C6) cycloalkylacyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O and S, wherein said (C3-C8) cycloalkyl is optionally substituted with 1-3R 6 Substitution; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S is a heterocycloalkyl group containing a sulfur atom, the sulfur atom thereof can be oxidized to sulfone; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S atoms is a heterocycloalkyl group containing a nitrogen atom, the nitrogen atom may be optionally substituted with 1 to 2R 7 Substitution;
R 4 、R 5 each of which is a single pieceIndependently selected from hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C8) cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 atoms selected from N, O and S atoms, six-to eight-membered bicyclic ring containing 1-2 nitrogen atoms, wherein said (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C8) cycloalkyl may optionally be substituted with 1-3R 6 Substitution; when the 4-7 membered heterocycloalkyl group containing 1 to 2 atoms selected from N, O and S atoms is a heterocycloalkyl group containing a sulfur atom, the sulfur atom can be oxidized to form sulfone; where the 1-2 4-7 membered heterocycloalkyl groups containing 1-2 nitrogen atoms selected from N, O and S atoms and the six-to eight-membered bicyclic ring containing 1-2 nitrogen atoms is a heterocycloalkyl group containing a nitrogen atom, the nitrogen atom may optionally be substituted with 1-2R 7 Substitution;
R 6 selected from hydrogen, halogen, hydroxy, cyano, (C1-C3) alkyl, (C1-C3) alkoxy, (C3-C6) cycloalkyl, optionally substituted with 1-2R 7 Substituted amino groups;
R 7 selected from hydrogen, halogen, hydroxy, (C1-C4) alkyl, (C1-C4) alkoxy, hydroxy (C1-C4) alkyl, (C4-C6) cycloalkyl, (C1-C4) acyl, (C3-C6) cycloalkylacyl, (C1-C4) sulfonyl, cyclopropylsulfonyl, (C1-C4) alkyl substituted by 1-3 cyano groups or fluorine atoms.
2. The benzamide compound having an imidazolinone structure or a pharmaceutically acceptable salt thereof according to claim 1,
R 1 methyl or methoxy;
selected from:
3. the benzamide compound having an imidazolinone structure or a pharmaceutically acceptable salt thereof according to claim 1,
selected from:
4. the benzamide compound containing an imidazolinone structure according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds I-1 to I-75:
5. The process for producing an imidazolinone-containing benzamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound production route is selected from route one to route seven;
route one:
(a) 4-bromo-1-fluoro-2-nitrobenzene is taken as a raw material, and is subjected to nucleophilic substitution reaction with fatty amine to obtain an intermediate 2;
(b) Intermediate 2 is taken as a raw material, and intermediate 3 is obtained through nitroreduction reaction;
(c) Intermediate 3 is taken as a raw material, and intermediate 4 is obtained through CDI-mediated clasp reaction;
(d) Taking the intermediate 5 as a raw material, condensing with tetrahydropyranone and preparing an intermediate 6 under the action of sodium triacetoxyborohydride;
(e) An intermediate 6 is taken as a raw material, condensed with acetaldehyde and subjected to the action of sodium triacetoxyborohydride to prepare an intermediate 7;
(f) Intermediate 7 is taken as a raw material, and intermediate 8 is prepared by Miyaura boric acid esterification reaction with pinacol ester of biboronate;
(g) Intermediate 8 is taken as a raw material, and intermediate 9 is prepared by Suzuki-Miyaura coupling reaction with intermediate 4;
(h) Intermediate 9 is taken as a raw material, and is subjected to nucleophilic substitution reaction with methyl iodide or ethyl iodide to obtain intermediate 10;
(i) Taking the intermediate 10 as a raw material, and obtaining an intermediate 11 through ester hydrolysis under the action of NaOH;
(j) Taking an intermediate 11 as a raw material, and carrying out an amide condensation reaction with 3- (aminomethyl) -4, 6-dimethyl-1H-pyridin-2-one hydrochloride or 3- (aminomethyl) -4-methoxy-6-methylpyridin-2 (1H) -one hydrochloride under the condition of a condensing agent to obtain a target compound in a general formula I;
route two:
adopting the four steps of reaction of the intermediates 12 (a), (b), (c) and (d) in the first route (g), (h), (I) and (j) to obtain the target compound in the general formula I;
route three:
wherein, the ring A is an aliphatic heterocyclic ring containing nitrogen atoms, and is defined in a general formula I;
adopting the reaction of the first route, obtaining an intermediate 18 from the intermediate 14 through four steps of reactions of (a), (b), (c) and (d);
(e) Taking the intermediate 18 as a raw material, and removing the Boc protecting group under an acidic condition to obtain an intermediate 19;
(f) The intermediate 19 is used as a raw material, and is subjected to N-acylation or N-sulfonylation reaction with acyl chloride and sulfonyl chloride, or is condensed with fatty aldehyde or ketone and subjected to sodium triacetoxyborohydride to prepare a target compound in a general formula I;
route four:
adopting a reaction of a route IV, and obtaining a target compound in a general formula I through six steps of reactions of (a), (b), (c), (d), (e) and (f) of the intermediate 20;
route five:
(a) Intermediate 14 is taken as a raw material, and is subjected to nucleophilic substitution reaction with methyl iodide or ethyl iodide to obtain an intermediate 26;
(b) Starting from intermediate 26, removing the Boc protecting group under acidic conditions to afford intermediate 27;
(c) Intermediate 27 is used as a raw material, condensed with formaldehyde solution and is prepared into intermediate 28 under the action of sodium triacetoxyborohydride;
adopting the reaction in the route III, and obtaining the target compound in the general formula I through five steps of reactions of (d), (e), (f), (g) and (h) of the intermediate 28;
route six:
wherein ring B is a cycloalkane as defined in formula I;
adopting the reaction in the fifth route, and obtaining the target compound in the general formula I through five steps of reactions of (a), (b), (c), (d) and (e) of the intermediate 34;
route seven:
(a) Intermediate 5 is used as a raw material, condensed with acetaldehyde and subjected to the action of cyano sodium borohydride to prepare intermediate 39;
(b) Intermediate 39 is taken as a raw material and reacts with cycloalkyl formyl chloride to prepare intermediate 7 through N-acylation reaction;
the reaction in the route six is adopted, and the intermediate 7 is subjected to four-step reactions of (c), (d), (e) and (f) to obtain the target compound in the general formula I.
6. A pharmaceutical composition comprising the imidazolinone-containing benzamide compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt, carrier or excipient thereof as an active ingredient; the pharmaceutical composition is in the form of injection, tablet or capsule.
7. Use of the benzamide compound containing an imidazolinone structure according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of a disease associated with abnormal expression of EZH 2.
8. Use of the pharmaceutical composition according to claim 6 for the preparation of a medicament for the prevention and/or treatment of a disease associated with abnormal expression of EZH 2.
9. The use according to claim 7 or 8, wherein the disease associated with abnormal expression of EZH2 is cancer or autoimmune disease.
10. The use according to claim 9, wherein the cancer is lymphoma, non-small cell lung cancer, head and neck cell cancer, bladder cancer, gastric cancer, colon cancer, colorectal cancer, renal cancer, cholangiocarcinoma, gastric cancer, esophageal squamous carcinoma, ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, brain cancer, melanoma, multiple myeloma, glioblastoma, leukemia or cervical cancer; the autoimmune disease is inflammatory enteritis, autoimmune encephalomyelitis or multiple sclerosis.
CN202311323884.XA 2023-10-13 2023-10-13 Benzamide compound containing imidazolone structure, and preparation method and application thereof Pending CN117362277A (en)

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