CN113248481A - EZH2 covalent irreversible inhibitor, preparation method and application thereof - Google Patents

EZH2 covalent irreversible inhibitor, preparation method and application thereof Download PDF

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CN113248481A
CN113248481A CN202110420163.5A CN202110420163A CN113248481A CN 113248481 A CN113248481 A CN 113248481A CN 202110420163 A CN202110420163 A CN 202110420163A CN 113248481 A CN113248481 A CN 113248481A
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王元相
黄洵
耿美玉
李冰冰
杨红
施琼宇
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Shanghai Institute of Materia Medica of CAS
Sun Yat Sen University
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Abstract

The invention discloses an EZH2 covalent irreversible inhibitor, a preparation method and application thereof. The EZH2 covalent irreversible inhibitor comprises a compound or salt thereof with a structure shown as formula (I) or formula (II)
Figure DDA0003027517060000011
The EZH2 covalent irreversible inhibitor provided by the invention has good specificity and strong drug effect, has high selectivity on histone methyltransferase EZH2, and can be used for preparing drugs for inhibiting EZH2 and drugs for preventing and/or treating tumors or cancers.

Description

EZH2 covalent irreversible inhibitor, preparation method and application thereof
Technical Field
The invention relates to the field of medicines, in particular to an EZH2 covalent irreversible inhibitor, a preparation method and application thereof.
Background
In eukaryotes, post-translational modifications of histones (such as methylation, acetylation, phosphorylation and ubiquitination) are critical for regulating chromatin structure and gene transcription. Among them, histone lysine methyltransferase EZH2, as a catalytic component of Polycomb inhibitory complex 2 (PRC 2), can inhibit the expression of a target gene by catalyzing trimethylation of lysine 27 of histone H3. In recent years, the research finds that EZH2 is highly expressed in various human solid tumors, and also has gain-of-function mutation in blood tumors such as non-Hodgkin lymphoma, melanoma and the like, so that the expression level of H3K27Me3 in a patient is increased, and the generation and development of tumors are promoted. Therefore, the development of EZH2 inhibitors has been a hot spot in the frontier of research on antitumor drugs.
Over the course of several years of effort, several EZH2 inhibitors were sequentially entered into clinical study sessions, including Tazemetostat, GSK126, CPI1209, CPI0209, SHR2554, PF06821497, DS3201b, and HH2853, among others. Of these, Tazemetostat, approved by the FDA for the treatment of metastatic/locally advanced epithelioid sarcoma adult patients who fail to resect completely and pediatric patients over 16 years of age, is the FDA-approved first drug for treatment of epithelioid sarcoma and also the first approved EZH2 inhibitor. However, the EZH2 inhibitors including Tazemetostat currently in clinical research are all non-covalent reversible inhibitors, and have the defects of large administration dosage, low drug effect and the like. For example, the clinically recommended amount of Tazemetostat is 800mg twice daily. Therefore, the development of an EZH2 inhibitor with a novel action mechanism is urgently needed, and the defect of low drug effect of a clinically researched drug is overcome.
Unlike non-covalent inhibitors, electrophilic active groups (commonly called warheads) of covalent inhibitors can form covalent structures with nucleophilic amino acid residues (such as cysteine) of target proteins, so that the covalent inhibitors have the advantages of long action time with targets, strong drug effect and the like. The covalent inhibitor developed by targeting EZH2 is expected to improve the dilemma that the non-covalent inhibitor is not good in drug effect in clinical research at present, and is beneficial to developing a new generation EZH2 inhibitor with strong drug effect and good drug success.
Analysis of the eutectic structure of the non-covalent inhibitor of EZH2 with the target protein (e.g., PDB ID: 5LS6, Journal of Medicinal chemistry 2016,59,9928-
Figure BDA0003027517040000013
Suitable as sites for covalent binding for the development of covalent inhibitors. Based on the design, the EZH2 covalent inhibitor with the characteristics of strong drug effect and drug success has important research significance and application value.
Disclosure of Invention
The invention aims to overcome the defects or shortcomings of large dosage, low drug effect and the like of the conventional EZH2 inhibitors which are non-covalent inhibitors, and provides an EZH2 covalent irreversible inhibitor. The EZH2 covalent irreversible inhibitor provided by the invention has good specificity and strong drug effect, has high selectivity on histone methyltransferase EZH2, and can be used for preparing drugs for inhibiting EZH2 and drugs for preventing and/or treating tumors or cancers.
Another object of the present invention is to provide a method for preparing the above EZH2 covalent irreversible inhibitor.
Another object of the present invention is to provide the use of the above EZH2 covalent irreversible inhibitor for the preparation of a medicament for inhibiting EZH 2.
The invention also aims to provide application of the EZH2 covalent irreversible inhibitor in preparing medicines for preventing and/or treating tumors or cancers.
In order to achieve the above purpose of the present invention, the present invention provides the following technical solutions:
an EZH2 covalent irreversible inhibitor comprises a compound or its salt having a structure shown in formula (I) or formula (II)
Figure BDA0003027517040000011
Wherein:
R1is selected from
Figure BDA0003027517040000012
RaSelected from hydrogen, halogen or Rd；
Rb、RcEach independently selected from hydrogen or Rd；
X is selected from halogen;
Rdis selected from C1-C6Alkyl and substituted C1-C6Alkyl radical, C2-C6Alkenyl and substituted C2-C6Alkenyl radical, C2-C6Alkynyl and substituted C2-C6Alkynyl, C3-C6Cycloalkyl and substituted C3-C6Cycloalkyl, 4-12 membered heterocyclyl and substituted 4-12 membered heterocyclyl;
or Ra、RbTogether with the carbon atom to which they are attached form a 2-5 membered heterocyclyl or substituted 2-5 membered heterocyclyl containing 0 or 1 additional heteroatoms;
R2selected from hydrogen, C1-C6Alkyl and deuterated or substituted C thereof1-C6Alkyl and deuterate thereof, C3-C6Cycloalkyl or substituted C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl or substituted C3-C6A heterocycloalkyl group;
y is selected from CH and N;
q is selected from NR3R4、OR3Or S (O)mNR3R4；
R3Selected from hydrogen, C1-C6Alkyl or substituted C1-C6Alkyl radical, C2-C6Alkenyl or substituted C2-C6Alkenyl radical, C2-C6Alkynyl or substituted C2-C6Alkynyl, C3-C6Cycloalkyl or substituted C3-C6Cycloalkyl, 4-12 membered heterocyclyl or substituted 4-12 heterocyclyl;
R4selected from hydrogen, C1-C6Alkyl or substituted C1-C6Alkyl radical, C3-C6Cycloalkyl or substituted C3-C6A cycloalkyl group;
R5selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C6Cycloalkyl radical, C3-C6Cycloalkyl, halogen, hydroxy, trifluoromethyl or heterocycloalkyl;
R6、R12each independently selected from hydrogen and C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6A heterocycloalkyl group;
or R5、R6Together with the carbon atom to which they are attached and the nitrogen atom form a 5-12 membered heterocyclic group or a substituted 5-12 membered heterocyclic group containing 0 or 1 additional heteroatom;
R7、R8、R10each independently selected from hydrogen, deuterium, halogen, C1-C3Alkyl or C3-C6A cycloalkyl group;
R9、R11each independently selected from hydrogen, halogen or Re；
ReSelected from the group consisting of substituted: c1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or 4-12 membered heterocyclyl and deutero;
or R9、R10Together with the carbon atom to which they are attached form a 5-12 membered heterocyclyl or substituted 5-12 membered heterocyclyl containing 0 or 1 additional heteroatoms;
m is 0, 1 or 2;
n is 0, 1,2, or 3;
r in the formulae (I) and (II) of the present invention1Is a common electrophilic active group, and can generate Michael addition reaction with cysteine C663 in EZH2 protein to form covalent bond to realize covalent bond;
preferably, RdThe substituents in (a) are one or more-J-T groups;
Ra、Rbthe substituent in the substituted 2-to 5-membered heterocyclic group in (A) is one or more-J1-T1A group;
R3c substituted in1-C6Alkyl, substituted C2-C6Alkenyl, substituted C2-C6Alkynyl, substituted C3-C6The substituents in the cycloalkyl, substituted 4-12 membered heterocyclyl are one or more-J-T groups;
R5、R6wherein the substituents in the substituted 5-to 12-membered heterocyclic group are one or more-J1-T1A group;
R9、R10wherein the substituents in the substituted 5-to 12-membered heterocyclic group are one or more-J1-T1A group;
wherein:
j is selected from a bond or substituted C1-C6An alkylene group;
t is selected from hydrogen, halogen, cyano, hydroxy, -NRfRg、-C(O)Rf、-ORf、-C(O)O-Rf、-C(O)NRfRg、-NRfC(O)Rg、-NRhC(O)NRfRg、-NRfC(O)ORhOr Ri；
Rf、Rg、RhEach independently selected from hydrogen or Rj，RjIs selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-or 6-membered heteroaryl or aryl, RjIs covered by one or more-J1-T1Substituted by groups;
or Rf、RgTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms, said 4-12 membered heterocyclyl being substituted with one or more-J1-T1Substituted by groups;
Riis selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or aryl, RiIs covered by one or more-J1-T1Substituted by groups;
J1selected from a bond or substituted C1-C6An alkylene group;
T1selected from hydrogen, halogen, cyano, hydroxy, -NRkRl、-C(O)Rk、-ORk、-C(O)O-Rk、-C(O)NRkRl、-NRkC(O)Rl、-NRoC(O)NRkRl、-NRkC(O)ORoOr Rp；
Rk、Rl、RoEach independently selected from hydrogen or Rq，RqSelected from the group consisting of substituted: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-or 6-membered heteroaryl or aryl;
or Rk、RlTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms, said heterocyclyl being optionally selected from halogen, hydroxy, oxo, C1-C6Alkyl, ORx、-NRxRy、-C(O)Rx、-O(CH2)nORxSubstituted with one or more groups of (a);
Rpis selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-to 6-membered heteroaryl, or aryl;
Rx、Ryeach independently selected from hydrogen or Rz，RzIs selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-or 6-membered heteroaryl or aryl; rzSubstituted by one or more of halogen, hydroxy, 5-or 6-membered heteroaryl or aryl or substituted 5-or 6-membered heteroaryl or aryl,
or Rx、RyTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms;
or-J1-T1Is an oxo group;
or-J-T is oxo.
More preferably, J or J1C substituted in1-C6The substituents in the alkylene group are independently selected from halogen, cyano, hydroxy or C1-C6One or more groups of alkoxy groups.
More preferably, the additional heteroatom is C, N, O, S or P.
More preferably, RqThe substituent in (1) is halogen, hydroxyl, 5-or 6-membered heteroaryl or aryl or substituted 5-or 6-membered heteroaryl or aryl.
Further preferably, the substituent in said substituted 5-or 6-membered heteroaryl or aryl is C1-C6One or more of alkyl, hydroxyl and oxo.
Preferably, R2C substituted in1-C6Alkyl and deuterated and substituted C thereof3-C6Cycloalkyl, substituted C3-C6In heterocycloalkyl groupsThe substituent is halogen, cyano, hydroxy, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkyl, amino, C1-C6Alkylamino, di-C1-C6Alkylamino or 4-12 membered heterocyclyl.
Preferably, R4C substituted in1-C6Alkyl, substituted C3-C6The substituents in cycloalkyl being halogen, cyano, hydroxy, amino or C3-C5One or more groups of cycloalkyl groups.
Preferably, ReWherein the substituent is deuterium atom, halogen, cyano, hydroxy, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkyl, -OC (O) -, amino, C1-C6Alkylamino, di-C1-C6One or more of alkylamino or 4-12 membered heterocyclyl.
Preferably, halogen is F, Br, Cl or I.
Preferably, the EZH2 covalent irreversible inhibitor is any one compound in the number of 1-100:
Figure BDA0003027517040000021
Figure BDA0003027517040000031
Figure BDA0003027517040000041
Figure BDA0003027517040000051
the application of the EZH2 covalent irreversible inhibitor in preparing the medicines for preventing and/or treating tumors or cancers is also within the protection scope of the invention.
Preferably, the medicament (including both the medicament for inhibiting EZH2 and the medicament for preventing and/or treating tumors or cancers) comprises an effective dose of a compound having a structure shown in formula (i) or formula (ii) or a salt or a mixture thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
More preferably, the compounds of formula (i) or formula (ii) may contain basic functional groups and are thus capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Specifically, suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids, and representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, para-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, tannic acid, salts of acetic acid, salts of propionic acid, salts of valeric acid, salts of maleic acid, hydroxybenzoic acid, salts of p-maleic acid, salts of acrylic acid, salts of propionic acid, salts of benzoic acid, salts of propionic acid, salts of benzoic acid, salts of acids, salts, Formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, propionate laureate (estolate), methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, sulfanilate, p-toluenesulfonate (toluenesulfonate), naphthalene-2-sulfonate and the like.
Preferably, the tumor or cancer is lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor, or myeloma.
More preferably, the tumor or cancer is lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, or mesothelioma.
More preferably, the lung cancer is small cell lung cancer or non-small cell lung cancer.
More preferably, the leukemia is chronic myeloleukemia, acute myeloleukemia or mixed cell line leukemia.
More preferably, the lymphoma is non-hodgkin's lymphoma, diffuse large B-cell lymphoma or follicular lymphoma.
Compared with the prior art, the invention has the following advantages and effects:
the EZH2 covalent irreversible inhibitor provided by the invention has good specificity and strong drug effect, has high selectivity on histone methyltransferase EZH2, and can be used for preparing drugs for inhibiting EZH2 and drugs for preventing and/or treating tumors or cancers.
Drawings
Figure 1 is a cell proliferation inhibition assay for compounds 34, 37 and EZP 6438;
FIG. 2 is the IC of EZH2 inhibition at the molecular level of compounds 34 and 37 at different SAM concentrations50。
Detailed Description
The present invention will be further explained with reference to the following examples and drawings, but the examples are not intended to limit the present invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the present invention are commercially available.
Example 1
5-acrylamido-N- ((((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (1)
Figure BDA0003027517040000061
Step 1.3-bromo-2-methyl-5-nitrobenzoic acid methyl ester (1b)
N-bromosuccinimide (27.0g,151.7mmol) was added in portions to a concentrated sulfuric acid solution of methyl 2-methyl-5-nitrobenzoate (25.0g,128.2mmol), and heated and stirred at 60 ℃ for 2 hours. After the reaction, the reaction solution was slowly poured into ice water, stirred for 15 minutes, and filtered by suction to obtain 30.0g of a white solid with a yield of 85.7%.1H NMR(400MHz,DMSO-d6)δ8.58(d,J＝2.4Hz,1H),8.47(d,J＝2.4Hz,1H),3.90(s,3H),2.63(s,3H).EI-MS:m/z(M+H+):293.96.
Step 2.2-methyl-5-nitro-3- ((tetrahydro-2H-pyran-4-yl) amino) benzoic acid methyl ester (1c)
Compound 1b (2.73g,10.0mmol), tetrahydro-2H-pyran-4-amine (1.52g,20.0mmol), tris (dibenzylideneacetone) dipalladium (915.7mg,1.0mmol), bis- (diphenylphosphino) -1, 1' -binaphthyl (1.25g,2.0mmol), and cesium carbonate (6.5g,20mmol) were dissolved in 100mL of anhydrous 1.4-dioxane and reacted with stirring at 110 ℃ under nitrogen for 8 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filter cake was washed with ethyl acetate, the organic phases were combined, the filtrate was concentrated under reduced pressure, and column chromatography purification was performed to obtain 588mg of a yellow solid, which was 21.1% in yield.1H NMR(500MHz,CDCl3)δ7.98(d,J＝2.2Hz,1H),7.51(d,J＝2.2Hz,1H),4.04(dt,J＝11.9,3.3Hz,2H),3.93(s,3H),3.89(d,J＝7.2Hz,1H),3.69–3.63(m,1H),3.59(td,J＝11.7,1.9Hz,2H),2.39(s,3H),2.10(dd,J＝12.8,1.2Hz,2H),1.57(m,J＝23.9,11.0,4.3Hz,2H).m/z(M+H+):295.12.
Step 3.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid methyl ester (1d)
Compound 1c (700mg,2.55mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, and acetaldehyde (448mg,10.2mmol) and acetic acid (765mg,12.8mmol) were added thereto and stirred for reaction for 1 hour, and sodium triacetoxyborohydride (1.62g,7.5mmol) was added thereto and stirred for reaction for 12 hours at room temperature. After the reaction is finished, the reaction solution is decompressed and concentrated, ethyl acetate and saturated sodium bicarbonate solution are added for layering, the water phase is extracted by ethyl acetate, the organic phases are combined and washed by saturated sodium chloride solutionWashing, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain brown yellow solid 1d 580mg with yield of 71.0%.1H NMR(500MHz,CDCl3)δ8.44(d,J＝2.2Hz,1H),8.08(d,J＝2.2Hz,1H),4.01–3.97(m,2H),3.96(s,3H),3.39–3.29(m,2H),3.15(q,J＝7.0Hz,2H),3.05–2.96(m,1H),2.61(s,3H),1.74–1.67(m,4H),0.90(t,J＝7.1Hz,3H).m/z(M+H+):323.15.
Step 4.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid (1e)
Compound 1d (580mg,1.80mmol) was dissolved in 10mL of methanol and 4mL of tetrahydrofuran, and 5mL of 2M sodium hydroxide solution was added and reacted at room temperature for 3 hours. After the reaction is finished, the pH is adjusted to 5-6 by using diluted hydrochloric acid (2N)) under the ice bath condition, ethyl acetate and water are used for extraction, organic phases are combined, anhydrous sodium sulfate is dried, filtration is carried out, the filtrate is decompressed and concentrated, and light yellow solid 1e 530mg with the yield of 95.3% is obtained.1H NMR(500MHz,DMSO-d6)δ13.52(s,1H),8.24(s,1H),8.04(s,1H),3.82(d,J＝10.6Hz,2H),3.26(t,J＝11.4Hz,2H),3.12(q,J＝6.7Hz,2H),3.04(t,J＝10.7Hz,1H),2.54(s,3H),1.64(d,J＝11.9Hz,2H),1.54(dd,J＝20.3,11.0Hz,2H),0.82(t,J＝6.8Hz,3H).m/z(M+H+):309.14.
Step 5.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzamide (1f)
Compound 1e (2.2g,7.12mmol) was dissolved in 20mL of dichloromethane, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (3.25g,8.54mmol), N, N-diisopropylethylamine (2.75g,21.36mmol) were added, stirring was carried out for 1 hour, 3-aminomethyl-4, 6-dimethylpyridin-2 (1H) -one (1.30g,8.54mmol) was added, and stirring was carried out overnight at room temperature. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 1f 2.9g of a yellow solid, the yield of which was 90.6%.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),8.44(t,J＝4.8Hz,1H),7.91(d,J＝2.1Hz,1H),7.75(d,J＝2.1Hz,1H),5.88(s,1H),4.30(d,J＝4.9Hz,2H),3.83(d,J＝10.7Hz,2H),3.26(t,J＝10.8Hz,2H),3.11(q,J＝6.9Hz,2H),3.03(td,J＝10.8,5.4Hz,1H),2.31(s,3H),2.22(s,3H),2.12(s,3H),1.63(d,J＝10.8Hz,2H),1.55(ddd,J＝15.8,12.0,4.2Hz,2H),0.82(t,J＝7.0Hz,3H).m/z(M+H+):443.22.
Step 6.5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (1g)
Compound 1g (2.9g,6.56mmol) was dissolved in 20mL of ethanol, and iron powder (1.92g,34.35mmol), ammonium chloride (2.23g,41.22mmol) and 5mL of water were added, followed by reaction at 78 ℃ for 4 hours under reflux. After the reaction is finished, the reaction solution is concentrated under reduced pressure, ethyl acetate and water are added for separation, the water phase is extracted by ethyl acetate, organic phases are combined, saturated sodium chloride solution is used for washing, anhydrous sodium sulfate is used for drying, filtering is carried out, the filtrate is concentrated under reduced pressure, and column chromatography purification is carried out to obtain a white solid 1h 1.5g, wherein the yield is 55%.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),7.81(t,J＝4.9Hz,1H),6.44(d,J＝1.9Hz,1H),6.26(d,J＝2.0Hz,1H),5.86(s,1H),4.91(s,2H),4.25(d,J＝5.0Hz,2H),3.82(d,J＝10.4Hz,2H),3.22(t,J＝11.0Hz,2H),2.92(q,J＝6.9Hz,2H),2.85(dd,J＝12.6,9.2Hz,1H),2.19(s,3H),2.11(s,3H),2.03(s,3H),1.62(d,J＝11.4Hz,2H),1.51–1.43(m,2H),0.79(t,J＝6.9Hz,3H).m/z(M+H+):413.25.
Step 7.5-acrylamido-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (1)
Compound 1g (100mg,0.24mmol) was dissolved in anhydrous dichloromethane, and acryloyl chloride (75.0mg,0.58mmol) and triethylamine (72mg,0.72mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50mg of a white solid, the yield of which was 44.6%.1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.15(s,1H),8.13(t,J＝4.8Hz,1H),7.65(s,1H),7.33(s,1H),6.45(dd,J＝16.9,10.0Hz,1H),6.29(d,J＝16.9Hz,1H),5.93(s,1H),5.79(d,J＝11.8Hz,1H),4.33(d,J＝4.8Hz,2H),3.89(d,J＝10.4Hz,2H),3.29(t,J＝11.1Hz,2H),3.05(dd,J＝13.7,6.8Hz,2H),3.00–2.93(m,1H),2.26(s,3H),2.21(s,3H),2.17(s,3H),1.69(d,J＝11.1Hz,2H),1.61–1.53(m,2H),0.87(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C26H34N4O4(M+H+):467.2653；found:467.2651.
Example 2
5- (2-butenyl) -N- (((4, 6-dimethyl-2-oxo-1, 2, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (2)
Figure BDA0003027517040000071
The compound (1g, 100mg,0.24mmol) was dissolved in methylene chloride, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), crotonic acid (25.0mg,0.29mmol) and the mixture were added and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50mg of a white solid, the yield of which was 43.4%.1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),9.87(s,1H),8.02(t,J＝4.9Hz,1H),7.56(s,1H),7.25(s,1H),6.76(q,J＝13.9,6.9Hz,1H),6.07(d,J＝15.2Hz,1H),5.86(s,1H),4.27(d,J＝4.9Hz,2H),3.82(d,J＝10.5Hz,2H),3.23(t,J＝11.2Hz,2H),2.98(q,J＝6.7Hz,2H),2.90(t,J＝10.9Hz,1H),2.19(s,3H),2.14(s,3H),2.11(s,3H),1.85(d,J＝6.2Hz,3H),1.63(d,J＝11.5Hz,2H),1.50(dd,J＝21.5,9.5Hz,2H),0.80(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C27H36N4O4(M+H+):481.2809；found:481.2804.
Example 3
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -5-methacrylamido-2-methylbenzamide (3)
Figure BDA0003027517040000072
Conversion of acryloyl chloride to methylAcryloyl chloride, the remaining desired starting materials, reagents and preparation were the same as in example 1, step 7, affording a white solid.1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),9.69(s,1H),8.00(t,J＝5.0Hz,1H),7.60(d,J＝1.9Hz,1H),7.34(d,J＝2.0Hz,1H),5.87(s,1H),5.79(s,1H),5.49(s,1H),4.27(d,J＝5.0Hz,2H),3.83(d,J＝10.2Hz,2H),3.23(t,J＝10.9Hz,2H),2.99(q,J＝6.9Hz,2H),2.94–2.86(m,1H),2.20(s,3H),2.15(s,3H),2.11(s,3H),1.93(s,3H),1.64(d,J＝10.8Hz,2H),1.50(qd,J＝11.8,4.2Hz,2H),0.81(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C27H36N4O4(M+H+):481.2809；found:481.2805.
Example 4
O- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (4- (dimethylamino) but-2-enyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (4)
Figure BDA0003027517040000073
Crotonic acid was replaced with 4- (dimethylamino) but-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in example 2 to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.46(s,1H),10.01(s,1H),8.05(t,J＝5.0Hz,1H),7.59(s,1H),7.23(d,J＝1.6Hz,1H),6.70(dt,J＝15.4,6.0Hz,1H),6.21(d,J＝15.4Hz,1H),5.86(s,1H),4.26(d,J＝4.9Hz,2H),3.82(d,J＝9.8Hz,2H),3.23(t,J＝11.0Hz,2H),3.06(d,J＝5.7Hz,2H),2.98(q,J＝6.8Hz,2H),2.90(dd,J＝12.7,9.1Hz,1H),2.19(s,3H),2.17(s,6H),2.13(s,3H),2.11(s,3H),1.62(m,J＝11.0Hz,2H),1.50(m,J＝24.2,12.0,4.2Hz,2H),0.80(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C29H41N5O4(M+H+):524.3230；found:524.3231.
Example 5
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (4-morpholinobut-2-enamide) benzamide (5)
Figure BDA0003027517040000074
Crotonic acid was replaced with 4-morpholinobut-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in example 2 to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),9.99(s,1H),8.03(t,J＝4.9Hz,1H),7.57(s,1H),7.25(s,1H),6.70(dt,J＝15.3,5.9Hz,1H),6.23(d,J＝15.4Hz,1H),5.86(s,1H),4.27(d,J＝4.9Hz,2H),3.83(d,J＝10.6Hz,2H),3.65–3.55(m,4H),3.23(t,J＝11.1Hz,2H),3.11(d,J＝5.7Hz,2H),2.98(q,J＝6.8Hz,2H),2.90(t,J＝10.8Hz,1H),2.39(s,4H),2.19(s,3H),2.14(s,3H),2.11(s,3H),1.63(d,J＝10.8Hz,2H),1.50(dt,J＝11.5,7.8Hz,2H),0.80(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C26H34N4O4(M+H+):566.3337；found:566.3339.
Example 6
5- (but-2-amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (6)
Figure BDA0003027517040000081
The crotonic acid was replaced by 2-butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 2, step one, to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),10.48(s,1H),8.04(t,J＝4.9Hz,1H),7.45(d,J＝1.7Hz,1H),7.23(d,J＝1.8Hz,1H),5.86(s,1H),4.26(d,J＝4.9Hz,2H),3.82(d,J＝10.4Hz,2H),3.23(t,J＝10.9Hz,2H),2.95(dt,J＝9.3,5.3Hz,2H),2.92–2.84(m,1H),2.18(d,J＝9.9Hz,3H),2.13(s,3H),2.11(s,3H),2.03(s,3H),1.61(d,J＝10.9Hz,2H),1.55–1.44(m,2H),0.79(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C27H34N4O4(M+H+):479.2653；found:479.2651.
Example 7
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (vinylsulfonamido) benzamide (7)
Figure BDA0003027517040000082
Pyridine (55.8mg,0.71mmol) was added dropwise to a solution of chloroformylsulfonyl chloride (45.5mg,0.31mmol) in anhydrous dichloromethane, stirred at-78 ℃ for 30 minutes, and then returned to room temperature and stirred for 1 hour. Under ice-bath conditions, 1g (100mg,0.24mmol) of the compound and triethylamine (72.7mg,0.72mmol) were added to the reaction, followed by stirring for 1 hour. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50.0mg of a white solid with a yield of 41.7%.1H NMR(400MHz,DMSO-d6)δ11.48(s,1H),9.85(s,1H),8.07(t,J＝4.7Hz,1H),7.00(d,J＝1.8Hz,1H),6.88–6.59(m,2H),6.03(d,J＝25.3Hz,2H),5.86(s,1H),4.25(d,J＝4.7Hz,2H),3.82(d,J＝10.4Hz,2H),3.22(t,J＝10.8Hz,2H),2.96(dd,J＝13.9,6.9Hz,2H),2.92–2.84(m,1H),2.18(s,3H),2.11(s,6H),1.58(d,J＝10.9Hz,2H),1.48(dt,J＝11.2,7.5Hz,2H),0.77(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C25H34N4O5S(M+H+):503.2323；found:503.2322.
Example 8
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (8)
Figure BDA0003027517040000083
Step 1.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (methylamino) benzamide (8a)
1g (2.25g,5.45mmol) of the compound, paraformaldehyde (490mg,5.45mmol) and sodium methoxide (1.17g,21.80mmol) were dissolved in 40mL of anhydrous methanol and reacted at 45 ℃ under nitrogen protectionOvernight. Sodium borohydride (414.4mg,10.9mmol) was added under ice-bath conditions, the ice-bath was removed and stirred at room temperature for 2 hours. After the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to separate the aqueous phase from the ethyl acetate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain a white solid 8a 2.0g, with a yield of 85.8%.1H NMR(500MHz,DMSO-d6)δ11.45(s,1H),7.84(s,1H),6.38(s,1H),6.19(s,1H),5.85(s,1H),5.41(d,J＝4.9Hz,1H),4.24(d,J＝4.4Hz,2H),3.82(d,J＝10.7Hz,2H),3.22(t,J＝11.4Hz,2H),2.95(q,J＝6.5Hz,2H),2.87(t,J＝10.5Hz,1H),2.62(d,J＝4.7Hz,3H),2.19(s,3H),2.10(s,3H),2.04(s,3H),1.62(d,J＝12.2Hz,2H),1.47(dd,J＝20.6,11.0Hz,2H),0.80(t,J＝6.7Hz,3H).m/z(M+H+):427.27.
Step 2.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (8)
Compound 8a (103mg,0.24mmol) was dissolved in anhydrous dichloromethane, and acryloyl chloride (22.7mg,0.25mmol) and triethylamine (72mg,0.72mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 45mg of a white solid, the yield of which was 39.1%.1H NMR(500MHz,DMSO-d6)δ11.48(s,1H),7.01(s,1H),6.87(s,1H),6.11(t,J＝14.7Hz,2H),5.87(s,1H),5.52(d,J＝9.5Hz,1H),4.27(s,2H),3.83(d,J＝10.4Hz,2H),3.29–3.12(m,5H),3.00(dt,J＝19.4,8.5Hz,3H),2.21(s,3H),2.20(s,3H),2.11(s,3H),1.61(d,J＝11.9Hz,2H),1.51(dd,J＝20.5,10.9Hz,2H),0.80(t,J＝6.6Hz,3H).HRMS(ESI)calcd for C27H36N4O4(M+H+):481.2809；found:481.2808.
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- (N-methylbut-2-enylamino) benzamide (9)
Figure BDA0003027517040000091
Compound 8a (100mg,0.23mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), crotonic acid (25.0mg,0.29mmol) and stirred at room temperature overnight. After the reaction was completed, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a white solid 75mg with a yield of 67.7%.1H NMR(500MHz,CDCl3)δ12.07(s,1H),7.07(s,1H),6.90(s,1H),6.89–6.78(m,2H),5.95(s,1H),5.71(d,J＝14.6Hz,1H),4.54(s,2H),3.94(d,J＝10.9Hz,2H),3.30(s,2H),3.25(s,3H),3.01(d,J＝6.5Hz,2H),2.95(s,1H),2.39(s,3H),2.30(s,3H),2.22(s,3H),1.68(d,J＝6.4Hz,4H),1.64(s,3H),0.83(t,J＝5.7Hz,3H).HRMS(ESI)calcd for C28H35N4O4(M+H+):495.2966；found:495.2963.
Example 10
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (4- (dimethylamino) -N-methylbutan-2-amino) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (10)
Figure BDA0003027517040000092
Crotonic acid was changed to 4- (dimethylamino) but-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in example 9 to obtain a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.50(s,1H),8.19(t, J ═ 4.9Hz,1H),6.99(d, J ═ 2.0Hz,1H),6.89(d, J ═ 2.1Hz,1H),6.62(dt, J ═ 15.2,6.2Hz,1H),5.87(s,1H),4.27(d, J ═ 5.0Hz,2H),3.83(d, J ═ 10.2Hz,2H), 3.28-3.23 (m,2H),3.20(s,3H), 3.05-2.91 (m,3H),2.83(d, J ═ 5.9Hz,2H),2.22(s,3H),2.20(s,3H), 2.11.11 (s,3H), 2.56 (s,6H), 1H (m, 1H), 1.46 (d, 10H), 5H, 5 (H), 1H, 6.9H, 1H, 6, 1H, 6H, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6H, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 1H, 6, 130H43N5O4(M+H+):538.3388；found:538.3389.
Example 11
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methyl-4-morpholinobut-2-enamide) benzamide (11)
Figure BDA0003027517040000093
Crotonic acid was replaced with 4-morpholinobut-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in example 9 to obtain a white solid.1H NMR(500MHz,CDCl3)δ11.54(s,1H),7.27(s,1H),6.87(d,J＝10.4Hz,3H),5.95(s,2H),4.53(s,2H),3.96(d,J＝10.8Hz,2H),3.70(s,4H),3.33(d,J＝10.0Hz,2H),3.27(d,J＝12.4Hz,3H),3.09(d,J＝45.3Hz,2H),3.03(d,J＝6.5Hz,2H),2.97(s,1H),2.48(s,4H),2.38(s,3H),2.32(s,3H),2.26(s,3H),1.66(s,4H),0.85(t,J＝6.0Hz,3H).HRMS(ESI)calcd for C32H45N5O5(M+H+):580.3493；found:580.34996.
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- (N-methylethenesulfonamido) benzamide (12)
Figure BDA0003027517040000094
The compound 1g was replaced with the compound 8a, and the remaining required starting materials, reagents and preparation were the same as in example 7 to give a white solid.1H NMR(400MHz,CDCl3)δ12.06(s,1H),7.13(d,J＝2.0Hz,1H),7.06(t,J＝5.6Hz,1H),6.98(d,J＝2.0Hz,1H),6.41(dd,J＝16.6,9.9Hz,1H),6.15(d,J＝16.6Hz,1H),5.99(d,J＝9.9Hz,1H),5.96(s,1H),4.54(d,J＝5.7Hz,2H),3.94(d,J＝11.3Hz,2H),3.31(td,J＝11.5,4.3Hz,2H),3.17(s,3H),3.03(q,J＝7.0Hz,2H),2.96(dd,J＝9.2,4.6Hz,1H),2.40(s,3H),2.28(s,3H),2.23(s,3H),1.72–1.61(m,4H),0.85(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C27H36N4O5S(M+H+):517.2479；found:517.2480.
Example 13
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methylbutan-2-amino) benzamide (13)
Figure BDA0003027517040000095
Crotonic acid was replaced by 2-butynoic acid and the remaining required raw materials, reagents and preparation were the same as in example 9 to give a white solid.1H NMR(500MHz,DMSO)δ11.47(s,1H),8.16(s,1H),7.14(s,1H),6.96(s,1H),5.86(s,1H),4.27(d,J＝3.3Hz,2H),3.83(d,J＝10.3Hz,2H),3.24(t,J＝11.2Hz,2H),3.19(d,J＝28.0Hz,3H),3.00(dd,J＝15.0,8.9Hz,3H),2.21(d,J＝9.0Hz,6H),2.11(s,3H),1.80–1.65(m,3H),1.64(d,J＝11.5Hz,2H),1.50(dd,J＝20.5,10.3Hz,2H),0.81(t,J＝6.2Hz,3H).HRMS(ESI)calcd for C28H36N4O4(M+H+):483.2809；found:483.2810.
Example 14
5- (2-chloro-N-methylacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (14)
Figure BDA0003027517040000101
The acryloyl chloride was replaced with chloroacetyl chloride, and the remaining required starting materials, reagents and preparation were the same as in example 8, step 2, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.49(s,1H),8.19(s,1H),7.21(s,1H),6.96(s,1H),5.87(s,1H),4.28(d,J＝3.4Hz,2H),4.02(s,2H),3.83(d,J＝10.3Hz,2H),3.25(t,J＝11.3Hz,2H),3.16(s,3H),3.03(d,J＝6.5Hz,2H),2.98(s,1H),2.21(s,6H),2.11(s,3H),1.63(d,J＝11.9Hz,2H),1.56–1.45(m,2H),0.80(t,J＝6.4Hz,3H).HRMS(ESI)calcd for C26H35N4O4Cl(M+H+):503.2420；found:503.2417.
Example 15
5- (2-bromo-N-methylpropionamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (15)
Figure BDA0003027517040000102
The acryloyl chloride was replaced with 2-bromopropionyl chloride, and the remaining required starting materials, reagents and preparation were the same as in example 8, step 2, to give a white solid.1H NMR(500MHz,CDCl3)δ11.70(s,1H),7.08(d,J＝5.3Hz,2H),6.94(s,1H),5.95(s,1H),4.53(d,J＝3.5Hz,2H),4.22(d,J＝6.3Hz,1H),3.95(d,J＝10.9Hz,2H),3.31(s,2H),3.21(s,3H),3.05(d,J＝6.6Hz,2H),2.98(s,1H),2.40(s,3H),2.32(s,3H),2.23(s,3H),1.71(d,J＝26.2Hz,4H),1.67–1.61(m,3H),0.86(t,J＝6.0Hz,3H).HRMS(ESI)calcd for C27H37N4O4Br(M+H+):561.2071；found:561.2068.
Example 16
5- (2-cyano-N-methylacetamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino 0-2-methylbenzamide (16)
Figure BDA0003027517040000103
Crotonic acid was replaced by cyanoacetic acid and the remaining required raw materials, reagents and preparation method were the same as in example 9 to obtain a white solid.1H NMR(500MHz,DMSO)δ11.49(s,1H),8.14(s,1H),7.20(s,1H),6.96(s,1H),5.88(s,1H),4.28(d,J＝3.9Hz,2H),3.83(d,J＝10.4Hz,2H),3.58(s,2H),3.26(d,J＝11.4Hz,2H),3.14(s,3H),3.03(d,J＝6.7Hz,2H),2.96(s,1H),2.21(s,6H),2.12(s,3H),1.63(d,J＝11.8Hz,2H),1.51(dd,J＝20.5,10.7Hz,2H),0.80(t,J＝6.5Hz,3H).HRMS(ESI)calcd for C27H35N5O4(M+H+):494.2762；found:494.2765.
Example 17
5- (1-cyano-N-methylcyclopropane-1-carboxamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (17)
Figure BDA0003027517040000104
Crotonic acid was replaced with 1-cyano-2-cyclopropylcarboxylic acid, and the remaining required raw materials, reagents and preparation methods were the same as in example 9 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.49(s,1H),7.99(s,1H),7.27(s,1H),7.04(s,1H),5.87(s,1H),4.28(d,J＝4.4Hz,2H),3.82(d,J＝10.6Hz,2H),3.23(d,J＝17.1Hz,5H),3.03(q,J＝6.4Hz,2H),2.95(t,J＝10.7Hz,1H),2.24(s,3H),2.21(s,3H),2.11(s,3H),1.67(d,J＝14.4Hz,4H),1.51(dd,J＝20.1,11.2Hz,2H),1.41(s,2H),0.82(t,J＝6.7Hz,3H).HRMS(ESI)calcd for C29H37N5O4(M+H+):520.2918；found:520.2918.
Example 18
5- (2-cyano-N, 4-dimethylpent-2-amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (18)
Compound 16(200mg,0.405mmol) was dissolved in anhydrous ethanol, and isobutyraldehyde (184mg,2.55mmol), piperidine (4mg,0.05mmol) and acetic acid (1 mL) were added thereto, followed by stirring at 80 ℃ overnight. After the reaction is finished, the reaction solution is decompressed and concentrated, dichloromethane and water are added for extraction, organic phases are combined, saturated sodium chloride solution is used for washing, anhydrous sodium sulfate is used for drying, filtration is carried out, the filtrate is decompressed and concentrated, and column chromatography purification is carried out to obtain 58.0mg of white solid, wherein the yield is 26.1%.1H NMR(400MHz,CDCl3)δ12.01(s,1H),7.11(d,J＝10.4Hz,1H),6.91(d,J＝18.0Hz,3H),5.94(s,1H),4.52(d,J＝5.4Hz,2H),3.94(d,J＝11.1Hz,2H),3.39–3.22(m,5H),3.02(dd,J＝13.5,6.5Hz,2H),2.94(dd,J＝14.8,8.2Hz,1H),2.82–2.61(m,1H),2.39(s,3H),2.32(s,3H),2.24(s,3H),1.67(s,4H),1.00(d,J＝6.5Hz,6H),0.86(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C31H41N5O4(M+H+):548.3231；found:548.3235.
Example 19
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (19)
Figure BDA0003027517040000111
Step 1.3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid methyl ester (19a)
The acetaldehyde was replaced with formaldehyde and the remaining required starting materials, reagents and preparation were the same as in example 1, step three to give a white solid.1H NMR(500MHz,CDCl3)δ8.40(s,1H),8.04(s,1H),4.00(d,J＝10.8Hz,2H),3.95(s,3H),3.36(t,J＝11.6Hz,2H),3.06–3.00(m,1H),2.72(s,3H),2.59(s,3H),1.83–1.75(m,2H),1.66(d,J＝8.4Hz,2H).m/z(M+H+):309.14.
Step 2.3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid (19b)
Compound 1d was replaced with compound 19a, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(500MHz,CDCl3)δ8.56(d,J＝2.3Hz,1H),8.09(d,J＝2.3Hz,1H),4.10–3.96(m,2H),3.38(dd,J＝11.6,10.2Hz,2H),3.04(ddd,J＝14.9,7.6,3.8Hz,1H),2.74(s,3H),2.66(s,3H),1.81(ddd,J＝15.9,12.1,4.4Hz,2H),1.68(d,J＝12.7Hz,2H).m/z(M+H+):295.12.
Step 3.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzamide (19c)
Compound 1e was replaced with compound 19b, and the remaining required starting materials, reagents and preparation were the same as in example 1, step five, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),8.43(t,J＝4.9Hz,1H),7.86(d,J＝2.3Hz,1H),7.72(d,J＝2.3Hz,1H),5.88(s,1H),4.29(d,J＝5.0Hz,2H),3.86(d,J＝11.0Hz,2H),3.28(dd,J＝11.4,10.2Hz,2H),3.06(tt,J＝11.0,3.8Hz,1H),2.65(s,3H),2.30(s,3H),2.21(s,3H),2.12(s,3H),1.66(qd,J＝12.0,4.3Hz,2H),1.56(d,J＝10.7Hz,2H).m/z(M+H+):429.21.
Step 4.5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (19d)
Compound 1f was replaced with compound 19c, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),7.78(t,J＝4.8Hz,1H),6.39(d,J＝1.9Hz,1H),6.21(d,J＝1.9Hz,1H),5.85(s,1H),4.88(s,2H),4.24(d,J＝4.9Hz,2H),3.84(d,J＝11.0Hz,2H),3.24(td,J＝11.2,4.5Hz,2H),2.86(t,J＝9.8Hz,1H),2.18(s,3H),2.11(s,3H),2.01(s,3H),1.56(s,4H).m/z(M+H+):399.21.
Step 5.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (methylamino) benzamide (19e)
The compound 1g was replaced with the compound 19d, and the remaining required starting materials, reagents and preparation were the same as in the first step of example 9 to give a white solid.1H NMR(400MHz,CDCl3)δ12.66(s,1H),7.01(t,J＝5.1Hz,1H),6.33(d,J＝16.1Hz,2H),5.92(s,1H),4.51(d,J＝5.5Hz,2H),3.93(d,J＝11.0Hz,2H),3.30(t,J＝10.8Hz,2H),2.97–2.88(m,1H),2.73(s,3H),2.56(s,3H),2.37(s,3H),2.18(s,3H),2.15(s,3H),1.73–1.59(m,4H).m/z(M+H+):413.25.
Step 6.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (methyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (19)
The compound 8a was replaced with the compound 19e, and the remaining required starting materials, reagents and preparation methods were the same as in the second step of example 8, to give a white solid.1H NMR(500MHz,CDCl3)δ12.02(s,1H),7.09(s,1H),6.86(s,2H),6.32(d,J＝16.8Hz,1H),6.14–6.00(m,1H),5.96(s,1H),5.47(d,J＝10.0Hz,1H),4.54(d,J＝4.8Hz,2H),3.98(d,J＝10.9Hz,2H),3.33(t,J＝11.5Hz,2H),3.28(s,3H),2.98(t,J＝9.7Hz,1H),2.60(s,3H),2.39(s,3H),2.31(s,3H),2.23(s,3H),1.78–1.69(m,2H),1.61(d,J＝12.2Hz,2H).HRMS(ESI)calcd for C26H34N4O4(M+H+):467.2653；found:467.2655.
Example 20
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (isobutyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (20)
Figure BDA0003027517040000121
Step 1.3- (isobutyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid (20a)
The acetaldehyde was replaced with isobutyraldehyde, and the remaining required raw materials, reagents and preparation methods were the same as in example 1, to obtain a white solid. Then, 2M NaOH solution was added dropwise to a mixed solvent of methanol and tetrahydrofuran as a white solid, and the mixture was reacted at room temperature for 3 hours. After the reaction is finished, neutralizing the reaction solution by using dilute hydrochloric acid (2N) under an ice bath condition until the pH value is 5-6, extracting by using ethyl acetate and water, combining organic phases, drying by using anhydrous sodium sulfate, and spin-drying the solvent to obtain a white solid.1H NMR(500MHz,CD3OD)δ8.24(d,J＝2.4Hz,1H),8.03(d,J＝2.5Hz,1H),3.86(dd,J＝11.6,4.5Hz,2H),3.25(d,J＝12.3Hz,2H),2.84(p,J＝3.8Hz,1H),2.54(s,3H),1.79–1.68(m,2H),1.61(s,2H),1.34(dt,J＝13.4,6.7Hz,1H),0.78(s,3H),0.76(s,3H).m/z(M+H+):337.17.
Step 2.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (isobutyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzamide (20b)
The compound 1e was replaced with the compound 20a, and the remaining required starting materials, reagents and preparation methods were the same as those in the fifth step of example 1, to obtain a white solid。1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),8.45(t,J＝5.0Hz,1H),7.91(d,J＝2.4Hz,1H),7.71(d,J＝2.3Hz,1H),5.88(s,1H),4.30(d,J＝5.1Hz,2H),3.90–3.82(m,2H),3.27–3.17(m,2H),2.95–2.83(m,2H),2.33(s,3H),2.22(s,3H),2.12(s,3H),1.76–1.65(m,2H),1.59(s,2H),1.41–1.32(m,1H),0.81(s,3H),0.79(s,3H).m/z(M+H+):471.25.
Step 3.5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (isobutyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (20c)
Compound 1f was replaced with compound 20b, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(500MHz,CDCl3)δ12.57(s,1H),7.01(t,J＝5.9Hz,1H),6.50(d,J＝2.4Hz,1H),6.39(d,J＝2.3Hz,1H),5.95(s,1H),4.52(d,J＝5.8Hz,2H),3.95(dd,J＝11.7,4.3Hz,2H),3.25(d,J＝11.9Hz,2H),2.81(ddd,J＝11.5,7.5,4.0Hz,1H),2.39(s,3H),2.22(s,3H),2.20(s,3H),1.71(s,2H),1.64(s,2H),1.44(dt,J＝13.4,6.7Hz,1H),0.80(s,3H),0.78(s,3H).m/z(M+H+):441.28.
Step 4.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (isobutyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (methylamino) benzamide (20d)
The compound 1g was replaced with the compound 20c, and the remaining required starting materials, reagents and preparation were the same as in the first step of example 9 to give a white solid.1H NMR(500MHz,CDCl3)δ12.86(s,1H),7.03(t,J＝5.9Hz,1H),6.42(d,J＝2.4Hz,1H),6.31(d,J＝2.4Hz,1H),5.94(s,1H),4.53(d,J＝5.8Hz,2H),3.94(dd,J＝11.5,4.3Hz,2H),3.25(t,J＝11.2Hz,2H),2.81(dq,J＝11.4,3.8Hz,1H),2.74(s,3H),2.39(s,3H),2.20(s,3H),2.19(s,3H),1.80–1.67(m,2H),1.68–1.59(m,2H),1.45(dp,J＝13.4,6.7Hz,1H),0.80(s,3H),0.78(s,3H).m/z(M+H+):455.29.
Step 5N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (isobutyl (tetrahydro-2 Hpyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (20)
Replacing compound 8a withCompound 20d, the remaining required starting materials, reagents and preparation were the same as in example 8, step two, affording a white solid.1H NMR(500MHz,CDCl3)δ11.84(s,1H),7.08(s,1H),6.86(d,J＝5.6Hz,2H),6.30(d,J＝16.8Hz,1H),6.02(s,1H),5.95(s,1H),5.45(d,J＝10.1Hz,1H),4.53(s,2H),3.97(d,J＝10.4Hz,2H),3.27(s,5H),2.85(t,J＝10.2Hz,3H),2.39(s,3H),2.31(s,3H),2.22(s,3H),1.75(s,2H),1.60(s,2H),1.40–1.31(m,1H),0.79(d,J＝5.4Hz,6H).HRMS(ESI)calcd for C29H40N4O4(M+H+):509.3050；found:509.3050.
Example 21
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (21)
Figure BDA0003027517040000122
Step 1.3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid methyl ester (21a)
The acetaldehyde was replaced with propionaldehyde, and the remaining required starting materials, reagents and preparation were the same as in example 1, step three, to give a white solid.1H NMR(500MHz,CDCl3)δ8.42(d,J＝2.4Hz,1H),8.08(d,J＝2.4Hz,1H),4.01–3.98(m,2H),3.96(s,3H),3.35–3.29(m,2H),3.06(t,J＝7.1Hz,2H),2.97–2.92(m,1H),2.61(s,3H),1.78–1.74(m,2H),1.69(dt,J＝10.8,2.5Hz,2H),1.31–1.26(m,2H),0.82(t,J＝7.3Hz,3H).m/z(M+H+):337.17.
Step 2.3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid (21b)
Compound 1d was replaced with Compound 21a, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(500MHz,CD3OD)δ8.38(d,J＝2.4Hz,1H),8.15(d,J＝2.4Hz,1H),4.93(s,2H),3.96(dt,J＝11.6,3.2Hz,2H),3.37(td,J＝11.5,10.8,4.9Hz,2H),3.14(t,J＝7.2Hz,2H),3.09–3.02(m,1H),2.64(s,3H),1.74(dd,J＝8.0,3.4Hz,4H),1.32(q,J＝7.3Hz,2H),0.85(t,J＝7.4Hz,3H).m/z(M+H+):323.15.
Step 3.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzamide (21c)
The compound 1e was replaced with the compound 21b, and the remaining required starting materials, reagents and preparation were the same as in example 1, step five, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),8.45(t,J＝5.0Hz,1H),7.91(d,J＝2.4Hz,1H),7.73(d,J＝2.1Hz,1H),5.88(s,1H),4.30(d,J＝5.0Hz,2H),3.85(dt,J＝11.2,3.3Hz,2H),3.24(td,J＝11.1,5.3Hz,2H),3.04(t,J＝6.9Hz,2H),2.97(ddd,J＝15.1,9.7,6.0Hz,1H),2.32(s,3H),2.22(s,3H),2.12(s,3H),1.61(td,J＝9.3,8.1,3.8Hz,4H),1.25–1.20(m,2H),0.77(t,J＝7.3Hz,3H).m/z(M+H+):457.24.
Step 4.5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (21d)
Compound 1f was replaced with compound 21c, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(500MHz,CDCl3)δ12.28(s,1H),6.99(t,J＝6.9Hz,1H),6.50(s,1H),6.41(s,1H),5.94(s,1H),4.52(s,2H),3.94(d,J＝9.9Hz,2H),3.29(q,J＝9.0,8.3Hz,2H),2.88(q,J＝7.6Hz,3H),2.39(s,3H),2.22(s,3H),2.18(s,3H),1.66(s,4H),1.26(p,J＝7.5,6.9Hz,2H),0.77(t,J＝7.4Hz,3H).m/z(M+H+):427.26.
Step 5.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (methylamino) benzamide (21f)
The compound 1g was replaced with 21d, and the remaining required starting materials, reagents and preparation were the same as in example 9, step one to give a white solid.1H NMR(500MHz,CDCl3)δ12.44(s,1H),6.99(t,J＝5.9Hz,1H),6.42(d,J＝2.4Hz,1H),6.35(d,J＝2.4Hz,1H),5.94(s,1H),4.53(d,J＝5.9Hz,2H),3.94(dt,J＝11.4,3.4Hz,2H),3.32–3.23(m,2H),2.91(d,J＝7.1Hz,2H),2.89–2.82(m,1H),2.75(s,3H),2.39(s,3H),2.21(s,3H),2.18(s,3H),1.67(dt,J＝6.6,3.5Hz,4H),1.26(q,J＝7.3Hz,2H),0.77(t,J＝7.3Hz,3H).m/z(M+H+):441.28.
Step 6.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (N-methacrylamido) benzamide (21)
The compound 8a was replaced with the compound 21f, and the remaining required starting materials, reagents and preparation methods were the same as in the second step of example 8, to give a white solid.1H NMR(500MHz,CDCl3)δ11.69(s,1H),7.07(s,1H),6.87(s,2H),6.31(d,J＝16.9Hz,1H),6.09–5.98(m,1H),5.95(s,1H),5.46(d,J＝9.9Hz,1H),4.54(s,2H),3.96(d,J＝10.9Hz,2H),3.30(d,J＝11.8Hz,2H),3.27(s,3H),2.92(s,3H),2.39(s,3H),2.30(s,3H),2.22(s,3H),1.71(s,2H),1.62(d,J＝11.9Hz,2H),1.26–1.20(m,2H),0.78(t,J＝6.2Hz,3H).HRMS(ESI)calcd for C28H38N4O4(M+H+):495.2966；found:495.2962.
Example 22
3- ((cyclobutylmethyl) (tetrahydro-2H-pyran-4-yl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) benzamide (22)
Figure BDA0003027517040000131
Step 1.3- ((cyclobutylmethyl) (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5-nitrobenzoic acid (22a)
The acetaldehyde was replaced with cyclobutanecarboxaldehyde and the remaining required starting materials, reagents and preparation were the same as in example 1, step four to give a white solid. Then, 2M NaOH solution was added dropwise to a mixed solvent of methanol and tetrahydrofuran as a white solid, and the mixture was reacted at room temperature for 3 hours. After the reaction, the reaction solution was neutralized with diluted hydrochloric acid (2N) under ice bath conditions to PH5-6, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a white solid.1H NMR(400MHz,CD3OD)δ8.37(d,J＝2.4Hz,1H),8.14(d,J＝2.5Hz,1H),3.95(dt,J＝11.5,3.3Hz,2H),3.40–3.33(m,2H),3.17(d,J＝7.4Hz,2H),2.96(m,J＝8.8,6.7Hz,1H),2.59(s,3H),2.19(q,J＝7.7Hz,1H),1.91–1.77(m,4H),1.76–1.69(m,4H),1.63(m,J＝8.2,1.7Hz,2H).m/z(M+H+):349.17.
Step 2.3- ((cyclobutylmethyl) (tetrahydro-2H-pyran-4-yl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5-nitrobenzamide (22b)
Compound 1e was replaced with compound 22a, and the remaining required starting materials, reagents and preparation were the same as in example 1, step five, to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.46(t,J＝5.0Hz,1H),7.93(d,J＝2.4Hz,1H),7.74(d,J＝2.3Hz,1H),5.88(d,J＝1.0Hz,1H),4.29(d,J＝5.0Hz,2H),3.85(dt,J＝11.3,3.2Hz,2H),3.28–3.19(m,2H),3.10(d,J＝7.5Hz,2H),2.89(t,J＝7.7Hz,1H),2.28(s,3H),2.22(s,3H),2.12(s,3H),2.08(d,J＝7.5Hz,1H),1.81–1.69(m,4H),1.60(dd,J＝7.9,3.8Hz,4H),1.59–1.52(m,2H).m/z(M+H+):483.25.
Step 3.5-amino-3- ((cyclobutylmethyl) (tetrahydro-2H-pyran-4-yl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (22c)
Compound 1f was replaced with compound 22b, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.48(s,1H),7.80(t,J＝5.1Hz,1H),6.45(d,J＝2.3Hz,1H),6.23(d,J＝2.2Hz,1H),5.86(s,1H),4.85(s,2H),4.24(d,J＝5.1Hz,2H),3.87–3.82(m,2H),3.23–3.16(m,2H),2.91(d,J＝7.4Hz,2H),2.73(tt,J＝11.1,4.0Hz,1H),2.19(s,3H),2.11(s,3H),2.08(d,J＝7.6Hz,1H),1.99(s,3H),1.84–1.77(m,2H),1.74(td,J＝9.8,8.4,5.7Hz,2H),1.62–1.58(m,2H),1.54(dd,J＝7.4,2.0Hz,2H).m/z(M+H+):453.28.
Step 4.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (propyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (methylamino) benzamide (22d)
Changing 1g of compound into compound22c, the remaining required starting materials, reagents and preparation were the same as in example 9, giving a white solid.1H NMR(500MHz,CDCl3)δ12.71(s,1H),7.00(t,J＝5.9Hz,1H),6.42(d,J＝2.5Hz,1H),6.35(d,J＝2.4Hz,1H),5.95(s,1H),4.53(d,J＝5.9Hz,2H),3.94(dt,J＝11.4,3.3Hz,2H),3.31–3.24(m,2H),2.95(d,J＝7.5Hz,2H),2.83–2.78(m,1H),2.74(s,3H),2.39(s,3H),2.21(s,3H),2.19–2.12(m,5H),1.86–1.80(m,2H),1.76–1.71(m,2H),1.67(d,J＝3.4Hz,2H),1.57–1.50(m,2H).m/z(M+H+):467.29.
Step 5.3- ((cyclobutylmethyl) (tetrahydro-2H-pyran-4-yl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) benzamide (22)
The compound 8a was replaced with the compound 22d, and the remaining required starting materials, reagents and preparation were the same as in example 8, step two, to give a white solid.1H NMR(500MHz,CDCl3)δ12.04(s,1H),7.08(s,1H),6.89(s,2H),6.31(d,J＝16.8Hz,1H),6.09–5.99(m,1H),5.97(s,1H),5.47(d,J＝10.1Hz,1H),4.54(d,J＝5.0Hz,2H),3.97(d,J＝10.9Hz,2H),3.29(d,J＝16.5Hz,5H),2.98(d,J＝6.7Hz,2H),2.85(t,J＝10.5Hz,1H),2.40(s,3H),2.28(s,3H),2.23(s,3H),2.11(dt,J＝15.2,7.6Hz,1H),1.84(s,2H),1.79–1.74(m,2H),1.73–1.66(m,2H),1.63(d,J＝11.8Hz,2H),1.55(dd,J＝17.5,8.5Hz,2H).HRMS(ESI)calcd for C30H40N4O4(M+H+):521.3122；found:521.3119.
Example 23
5- (N-Cyclobutylacrylamide) -N- (((4, 6-dimethyl-2-oxo-1, 2, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (23)
Figure BDA0003027517040000141
Step 1.5- (Cyclobutylamino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (23a)
Compound 1g (412.3mg,1mmol), cyclobutanone (210.0mg,3mmol) was dissolved in anhydrous methanol, and the mixture was sealed at 70 ℃ overnight, followed by addition of sodium borohydride (190mg, 5mmol) under ice-bath conditions and reaction at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, dichloromethane and water were added for extraction, the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain 149.0mg of a white solid with a yield of 32.0%.1H NMR(400MHz,CDCl3)δ12.52(s,1H),6.97(q,J＝7.0,5.9Hz,1H),6.34(d,J＝2.4Hz,1H),6.29(d,J＝2.4Hz,1H),5.93(s,1H),4.52(d,J＝5.9Hz,2H),3.91(dt,J＝11.6,3.3Hz,2H),3.82(p,J＝6.5Hz,1H),3.74–3.58(m,1H),3.28(td,J＝11.3,2.8Hz,2H),2.97(q,J＝7.0Hz,2H),2.94–2.86(m,1H),2.38(s,3H),2.20(s,3H),2.16(s,3H),1.80–1.70(m,4H),1.69–1.57(m,4H),0.83(t,J＝7.0Hz,3H).m/z(M+H+):467.29.
Step 2.5- (N-Cyclobutylacrylamide) -N- (((4, 6-dimethyl-2-oxo-1, 2, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (23)
The compound 8a was replaced with the compound 23a, and the remaining required starting materials, reagents and preparation methods were the same as in the second step of example 8, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.50(s,1H),8.32(s,1H),8.26(d,J＝5.1Hz,1H),6.87(s,1H),6.73(s,1H),6.09(d,J＝16.4Hz,1H),5.87(s,2H),5.47(d,J＝10.4Hz,1H),4.93(p,J＝8.6Hz,1H),4.28(d,J＝4.2Hz,2H),3.83(d,J＝10.0Hz,2H),3.26(d,J＝11.5Hz,2H),3.04–3.01(m,2H),2.98(d,J＝15.4Hz,1H),2.24(s,3H),2.20(s,3H),2.11(s,3H),1.76–1.44(m,10H),0.79(t,J＝6.6Hz,3H).HRMS(ESI)calcd for C30H40N4O4(M+H+):521.3122；found:521.3117.
Example 24
Tert-butyl (4- ((3- ((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methyl-5- (N-methacrylamido) phenyl) (ethyl) amino) cyclohexyl) carbamate (24)
Figure BDA0003027517040000142
Step 1.3- ((4- ((tert-butoxycarbonyl) amino) cyclohexyl) amino) -2-methyl-5-nitrobenzoic acid methyl ester (24a)
The tetrahydro-2H-pyran-4-amine was replaced with tert-butyl (4-aminocyclohexyl) carbamate and the remaining required starting materials, reagents and preparation were the same as in example 1 to give a brown solid.1H NMR(400MHz,CDCl3)δ7.96(d,J＝2.3Hz,1H),7.48(d,J＝2.3Hz,1H),4.61(s,1H),3.93(s,3H),3.69(d,J＝7.1Hz,1H),3.65–3.58(m,1H),2.38(s,3H),1.93–1.78(m,4H),1.73–1.57(m,4H),1.46(s,9H).m/z(M+H+):408.21.
Step 2.3- ((4- ((tert-butoxycarbonyl) amino) cyclohexyl) (ethyl) amino) -2-methyl-5-nitrobenzoic acid (24b)
Compound 1c was replaced with compound 24a, and the remaining required starting materials, reagents and preparation were the same as in step three of example 1 to give a white solid.1H NMR(400MHz,CD3CN-d6)δ8.41(d,J＝2.5Hz,1H),8.12(d,J＝2.5Hz,1H),3.72–3.50(m,1H),3.39–2.95(m,3H),2.67(s,3H),1.93–1.81(m,2H),1.73(ddd,J＝12.8,6.4,3.3Hz,2H),1.69–1.60(m,2H),1.56(td,J＝9.7,3.8Hz,2H),1.40(s,9H),0.92(t,J＝7.0Hz,3H).m/z(M+H+):422.22.
Step 3. tert-butyl (4- ((3- ((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methyl-5-nitrophenyl) (ethyl) amino) cyclohexyl) carbamate (24c)
Compound 1d was replaced with compound 24b, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),8.44(t,J＝5.3Hz,1H),7.86(s,1H),7.72(s,1H),6.94(s,1H),5.88(s,1H),4.30(d,J＝5.0Hz,2H),3.45(tt,J＝8.1,5.7Hz,1H),3.11(q,J＝7.1Hz,2H),3.00(s,1H),2.32(s,3H),2.22(s,3H),2.12(s,3H),1.78(q,J＝10.6,10.2Hz,2H),1.54(q,J＝7.7,6.7Hz,2H),1.46(d,J＝9.3Hz,2H),1.39(d,J＝1.7Hz,9H),1.26(q,J＝7.1Hz,2H),0.86–0.78(m,3H).m/z(M+H+):556.31.
Step 4. tert-butyl (4- ((5-amino-3- ((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methylphenyl) (ethyl) amino) cyclohexyl) carbamate (24d)
Compound 1e was replaced with Compound 24c, and the remaining required starting materials, reagents and preparation were the same as in example 1, step five, affording a white solid.1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),7.77(t,J＝5.3Hz,1H),6.41(d,J＝2.3Hz,1H),6.21(d,J＝2.2Hz,1H),5.85(s,1H),4.82(s,2H),4.24(d,J＝5.1Hz,2H),3.40(s,1H),2.93(q,J＝6.9Hz,2H),2.84(s,1H),2.19(s,3H),2.11(s,3H),2.04(s,3H),1.77–1.69(m,2H),1.60–1.51(m,2H),1.37(d,J＝7.8Hz,13H),0.79(t,J＝6.2Hz,3H).m/z(M+H+):526.33.
Step 5 tert-butyl (4- ((3- ((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methyl-5- (methylamino) phenyl) (ethyl) amino) cyclohexyl) carbamate (24e)
Compound 1f was replaced with compound 24d, and the remaining required starting materials, reagents and preparation were the same as in step 1 of example 8 to give a white solid.1H NMR(500MHz,CDCl3)δ11.91(s,1H),6.97(s,1H),6.40(s,1H),6.36(s,1H),5.93(s,1H),4.66–4.54(m,1H),4.52(d,J＝5.9Hz,2H),3.64–3.56(m,1H),2.97(q,J＝7.2Hz,2H),2.76(s,3H),2.39(s,3H),2.21(s,3H),2.18(s,3H),1.70(s,2H),1.64–1.56(m,4H),1.49(s,2H),1.45(s,9H),0.84(t,J＝7.1Hz,3H).m/z(M+H+):540.35.
Step 6. tert-butyl (4- ((3- ((((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) carbamoyl) -2-methyl-5- (N-methacrylamido) phenyl) ethyl) amino) cyclohexyl) carbamate (24)
The compound 1g was replaced with the compound 24e, and the remaining required starting materials, reagents and preparation were the same as in example 8, step two, to give a white solid.1H NMR(400MHz,CDCl3)δ12.00(s,1H),7.10(s,1H),6.90(s,1H),6.87(s,1H),6.31(dd,J＝16.8,2.0Hz,1H),6.04(dd,J＝16.8,10.3Hz,1H),5.96(s,1H),5.51–5.44(m,1H),4.54(d,J＝5.8Hz,2H),3.67–3.52(m,1H),3.28(s,3H),3.01(d,J＝7.1Hz,2H),2.98–2.92(m,1H),2.39(s,3H),2.31(s,3H),2.23(s,3H),1.71–1.50(m,8H),1.45(s,9H),0.83(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C33H47N5O5(M+H+):594.3650；found:594.3648.
Example 25
3- ((4-Acylaminocyclohexyl) ethyl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) benzamide (25)
Figure BDA0003027517040000151
Step 1.3- ((4-aminocyclohexyl) (ethyl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5-nitrobenzamide (25a)
2mL of trifluoroacetic acid was slowly added dropwise to a solution of Compound 24d in dichloromethane, and stirred at room temperature for 2 hours. After the reaction is finished, adjusting the pH value to be neutral by using a saturated sodium bicarbonate solution, extracting and separating liquid, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by using column chromatography to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ8.43(t,J＝5.0Hz,1H),7.88(d,J＝2.4Hz,1H),7.73(d,J＝2.3Hz,1H),5.88(s,1H),4.30(d,J＝5.0Hz,2H),3.09(d,J＝7.5Hz,3H),3.01(s,1H),2.70(s,2H),2.34(s,3H),2.22(s,3H),2.12(s,3H),1.90–1.38(m,8H),0.83(t,J＝6.9Hz,3H).m/z(M+H+):456.25.
Step 2.3- ((4-Acylaminocyclohexyl) (ethyl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5-nitrobenzamide (25b)
Compound 25a (455.6mg,1mmol) was dissolved in anhydrous dichloromethane, and acetyl chloride (79.0mg,1mmol) and triethylamine (303.6mg,3mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction is finished, washing the mixture by using water and a saturated sodium chloride solution, drying the mixture by using anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by using column chromatography to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.43(t,J＝5.0Hz,1H),7.88(d,J＝2.4Hz,1H),7.77(d,J＝7.7Hz,1H),7.73(d,J＝2.3Hz,1H),5.88(s,1H),4.30(d,J＝5.0Hz,2H),3.73(s,1H),3.12(q,J＝6.9Hz,2H),3.01(dq,J＝8.6,4.0Hz,1H),2.34(s,3H),2.22(s,3H),2.12(s,3H),1.82(s,3H),1.74(t,J＝10.2Hz,2H),1.52(s,4H),1.44–1.37(m,2H),0.84(t,J＝7.0Hz,3H).m/z(M+H+):498.60.
Step 3.3- ((4-Acylaminocyclohexyl) (ethyl) amino) -5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (25c)
Compound 1f was replaced with compound 25b, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),7.79(t,J＝5.1Hz,1H),7.72(d,J＝7.5Hz,1H),6.42(d,J＝2.3Hz,1H),6.22(d,J＝2.2Hz,1H),5.86(s,1H),4.83(s,2H),4.25(d,J＝5.1Hz,2H),3.69(s,1H),2.95(q,J＝6.9Hz,2H),2.87(s,1H),2.19(s,3H),2.11(s,3H),2.06(s,3H),1.81(s,3H),1.75–1.67(m,2H),1.55(d,J＝7.2Hz,2H),1.47(d,J＝10.4Hz,2H),1.37(t,J＝6.4Hz,2H),0.81(t,J＝6.9Hz,3H).m/z(M+H+):468.29.
Step 4.3- ((4-Acylaminocyclohexyl) (ethyl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (methylamino) benzamide (25d)
The compound 1g was replaced with the compound 25c, and the remaining required starting materials, reagents and preparation were the same as in example 8, step 1, to give a white solid.1H NMR(500MHz,CDCl3)δ11.29(s,1H),7.03–6.91(m,1H),6.40(s,1H),6.37(s,1H),5.93(s,1H),4.52(d,J＝5.6Hz,2H),3.93–3.84(m,1H),3.12–3.02(m,1H),3.02–2.90(m,2H),2.76(s,3H),2.40(s,3H),2.22(s,3H),2.20(s,3H),1.96(s,3H),1.59(d,J＝12.2Hz,8H),0.85(t,J＝7.2Hz,3H).m/z(M+H+):482.31.
Step 5.3- ((4-Acylaminocyclohexyl) (ethyl) amino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) benzamide (25)
Changing the compound 8a to the compound 25d, and the rest of the required raw materials and reagentsAnd the preparation method is the same as the second step in example 8, and a white solid is obtained.1H NMR(400MHz,CDCl3)δ12.12(s,1H),7.16(t,J＝5.8Hz,1H),6.90(s,1H),6.87(s,1H),6.30(dd,J＝16.8,2.0Hz,1H),6.03(dd,J＝16.7,10.5Hz,1H),5.97(s,1H),5.69(d,J＝7.7Hz,1H),5.47(d,J＝9.2Hz,1H),4.54(d,J＝5.8Hz,2H),3.90(tt,J＝5.7,2.5Hz,1H),3.28(s,3H),3.06(s,1H),3.00(q,J＝7.0Hz,2H),2.40(s,3H),2.34(s,3H),2.23(s,3H),1.97(s,3H),1.67–1.52(m,8H),0.83(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C30H41N5O5(M+H+):536.3231；found:536.3234.
Example 26
5- (Acrylamidomethyl) -N- (((4, 6-dimethyl-2-oxo-1, 2 dihydropyridin-3-yl) methyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (26)
Figure BDA0003027517040000161
Step 1.5-bromo-2-methyl-3- ((tetrahydro-2H-pyran-4-yl) amino) benzoic acid methyl ester (26b)
Methyl 3-amino-5-bromo-2-methylbenzoate (24.4g, 100mmol), tetrahydro-2H-pyran-4-one (14.7g,150mmol), and acetic acid (30g,500mmol) were dissolved in 200mL of dichloromethane, stirred at room temperature for 3 hours, and sodium triacetoxyborohydride (63.6g,300mmol) was added under ice bath conditions, and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by recrystallization from ethyl acetate to obtain 25g of a white solid with a yield of 76.7%.1H NMR(400MHz,CDCl3)δ7.24(d,J＝1.8Hz,1H),6.85(d,J＝1.7Hz,1H),4.02(dt,J＝11.8,3.5Hz,2H),3.88(s,3H),3.67(d,J＝6.0Hz,1H),3.58–3.52(m,2H),2.24(s,3H),2.09–2.02(m,2H),1.52(qd,J＝10.8,4.2Hz,2H).m/z(M+H+):328.05.
Step 2.5-bromo-3- ((tetrahydro-2H-pyran-4-ylethyl) amino) -2-methylbenzoic acid methyl ester (26c)
Compound 26b (25g,76.7mmol), acetaldehyde (6.7g,153.4mmol), EtOHThe acid (23.0g,383.5mmol) was dissolved in 200mL of dichloromethane, stirred at room temperature for 3 hours, and then sodium triacetoxyborohydride (48.8g, 230.1mmol) was added thereto under ice-bath conditions, and stirred at room temperature overnight. After the reaction is finished, washing the reaction product by using water and a saturated sodium chloride solution, drying the reaction product by using anhydrous sodium sulfate, filtering the reaction product, concentrating the filtrate under reduced pressure, and purifying the filtrate by using column chromatography to obtain 18g of white solid, wherein the yield is 66%.1H NMR(400MHz,CDCl3)δ7.72(d,J＝2.0Hz,1H),7.38(d,J＝2.0Hz,1H),3.97(d,J＝11.3Hz,2H),3.90(s,3H),3.33(td,J＝11.4,2.7Hz,2H),3.10–3.00(m,2H),2.95(td,J＝10.5,5.1Hz,1H),2.46(s,3H),1.73–1.69(m,2H),1.66–1.57(m,2H),0.88(t,J＝7.1Hz,3H).m/z(M+H+):356.08.
Step 3.5-cyano-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzoic acid methyl ester (26d)
Compound 26c (18g,50.7mmol), cuprous cyanide (13.7g,152.1mmol) was dissolved in 40mL of anhydrous DMF and stirred overnight at 150 ℃ under nitrogen. After the reaction is finished, adding 500mL of ammonia water to quench cuprous cyanide, adding ethyl acetate for layering, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and recrystallizing and purifying with ethanol to obtain 10.0g of white solid with the yield of 65.4%.1H NMR(400MHz,CDCl3)δ7.87(d,J＝1.3Hz,1H),7.50(d,J＝1.2Hz,1H),3.97(dd,J＝8.6,5.6Hz,2H),3.93(s,3H),3.37–3.29(m,2H),3.09(q,J＝7.0Hz,2H),3.01–2.91(m,1H),2.57(s,3H),1.68(dt,J＝9.3,4.5Hz,4H),0.87(t,J＝7.0Hz,3H).m/z(M+H+):303.16.
Step 4.5-cyano-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzoic acid (26e)
Compound 1d was replaced with compound 26d, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(400MHz,CDCl3)δ8.04(d,J＝1.2Hz,1H),7.55(d,J＝1.1Hz,1H),4.02(d,J＝11.4Hz,2H),3.37(td,J＝11.8,7.1Hz,2H),3.11(q,J＝7.0Hz,2H),2.99(dt,J＝14.9,7.6Hz,1H),2.65(s,3H),1.69(dt,J＝13.0,4.1Hz,4H),0.89(t,J＝7.0Hz,3H).m/z(M+H+):289.15.
Step 5.5-cyano-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (26f)
The compound 1e was replaced with the compound 26e, and the remaining required starting materials, reagents and preparation were the same as in example 1, step five, to give a white solid.1H NMR(400MHz,CDCl3)δ12.16(s,1H),7.36(d,J＝1.5Hz,1H),7.32(d,J＝1.4Hz,1H),7.31(s,1H),5.99(s,1H),4.53(d,J＝5.8Hz,2H),4.03–3.91(m,2H),3.31(td,J＝11.5,4.0Hz,2H),3.06(q,J＝7.0Hz,2H),2.99–2.90(m,1H),2.39(s,3H),2.37(s,3H),2.25(s,3H),1.71–1.63(m,4H),0.85(t,J＝7.0Hz,3H).m/z(M+H+):424.22.
Step 6.5- (aminomethyl) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (26g)
Compound 26f (1.5g,3.52mmol), Raney nickel (500mg), 2mL of aqueous ammonia were dissolved in 20mL of methanol and stirred overnight at room temperature under hydrogen gas. After the reaction is finished, the Raney nickel is removed by filtration, the filtrate is concentrated under reduced pressure, and the white solid is obtained by column chromatography purification, wherein the yield is 80 percent and 1.2 g.1H NMR(400MHz,CDCl3)δ5.95(s,1H),4.54(d,J＝5.8Hz,2H),3.93(d,J＝11.3Hz,2H),3.77(s,2H),3.30(td,J＝11.2,3.3Hz,2H),3.04(q,J＝7.0Hz,2H),2.96(td,J＝9.8,4.7Hz,1H),2.40(s,3H),2.29(s,3H),2.21(s,3H),1.68–1.59(m,4H),0.83(t,J＝7.0Hz,3H).m/z(M+H+):428.25.
Step 7.5- (Acrylamidomethyl) -N- (((4, 6-dimethyl-2-oxo-1, 2, dihydropyridin-3-yl) methyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (26)
26g (103mg,0.24mmol) of the compound was dissolved in anhydrous dichloromethane, and acryloyl chloride (75.0mg,0.58mmol) and triethylamine (72mg,0.72mmol) were added thereto with stirring in an ice bath, and the mixture was stirred at room temperature overnight. After the reaction is finished, washing the reaction product by using water and a saturated sodium chloride solution, drying the reaction product by using anhydrous sodium sulfate, filtering the reaction product, concentrating the filtrate under reduced pressure, and purifying the filtrate by using column chromatography to obtain a white solid 60mg, wherein the yield is 52.2%.1H NMR(400MHz,CDCl3)δ11.91(s,1H),7.05(s,2H),6.97(s,1H),6.27(d,J＝17.0Hz,2H),6.11(dd,J＝17.0,10.2Hz,1H),5.94(s,1H),5.62(d,J＝10.2Hz,1H),4.50(d,J＝5.8Hz,2H),4.37(d,J＝5.6Hz,2H),3.92(d,J＝11.3Hz,2H),3.29(td,J＝11.3,3.7Hz,2H),3.02(q,J＝7.0Hz,2H),2.93(td,J＝9.5,4.7Hz,1H),2.38(s,3H),2.27(s,3H),2.21(s,3H),1.68–1.59(m,4H),0.81(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C27H36N4O4(M+H+):481.2809；found:481.2803.
Example 27
5- (but-2-Enylaminomethyl) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (27)
Figure BDA0003027517040000171
26g (100mg,0.23mmol) of the compound was dissolved in methylene chloride, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), crotonic acid (24.9mg,0.29mmol) and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50mg of a white solid with a yield of 44.0%.1H NMR(400MHz,CDCl3)δ12.05(s,1H),7.05(d,J＝8.7Hz,2H),6.97(s,1H),6.83(dd,J＝15.1,7.0Hz,1H),5.99(s,1H),5.94(s,1H),5.81(dd,J＝15.2,1.3Hz,1H),4.51(d,J＝5.7Hz,2H),4.36(d,J＝5.6Hz,2H),3.92(d,J＝11.2Hz,2H),3.29(td,J＝11.3,3.6Hz,2H),3.01(q,J＝6.9Hz,2H),2.96–2.88(m,1H),2.38(s,3H),2.27(s,3H),2.20(s,3H),1.87–1.79(m,3H),1.62(d,J＝10.5Hz,4H),0.81(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C28H38N4O4(M+H+):495.2966；found:495.2965.
Example 28
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((4- (dimethylamino) but-2-amino) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (28)
Figure BDA0003027517040000172
Crotonic acid was replaced with 4- (dimethylamino) but-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in the first step of example 29 to obtain a white solid.1H NMR(500MHz,CDCl3)δ11.82(s,1H),7.20(s,1H),7.04(s,1H),6.96(s,1H),6.86–6.78(m,1H),6.31(s,1H),6.01(d,J＝15.5Hz,1H),5.93(s,1H),4.48(d,J＝5.7Hz,2H),4.38(d,J＝5.4Hz,2H),3.93(d,J＝11.1Hz,2H),3.29(dd,J＝14.9,7.1Hz,2H),3.09(d,J＝6.1Hz,2H),3.02(dd,J＝13.9,6.9Hz,2H),2.96–2.90(m,1H),2.38(s,3H),2.29(s,3H),2.28(s,6H),2.21(s,3H),1.64(s,4H),0.82(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C30H43N5O4(M+H+):538.3388；found:538.3389.
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- ((4-morpholinobut-2-enamino) methyl) benzamide (29)
Figure BDA0003027517040000173
Crotonic acid was replaced with 4-morpholinobut-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in the first step of example 29 to obtain a white solid.1H NMR(400MHz,CDCl3)δ11.55(s,1H),7.18–7.12(m,1H),7.05(s,1H),6.99(s,1H),6.86–6.72(m,1H),6.54(t,J＝5.0Hz,1H),6.07(d,J＝15.3Hz,1H),5.97(s,1H),4.49(d,J＝5.3Hz,2H),4.37(d,J＝5.4Hz,2H),3.92(d,J＝10.9Hz,2H),3.71(s,4H),3.30(t,J＝10.7Hz,2H),3.18(d,J＝5.9Hz,2H),3.02(dd,J＝13.2,6.3Hz,2H),2.97–2.92(m,1H),2.55(s,4H),2.39(s,3H),2.29(s,3H),2.22(s,3H),1.64(s,2H),1.59(d,J＝12.2Hz,2H),0.82(t,J＝6.8Hz,3H).HRMS(ESI)calcd for C32H45N5O5(M+H+):580.3421；found:580.3420.
Example 30
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-5- (vinylsulfonamidomethyl) benzamide (30)
Figure BDA0003027517040000174
The compound 1g was replaced with the compound 26g, and the remaining required starting materials, reagents and preparation were the same as in example 7 to give a white solid.1H NMR(400MHz,CDCl3)δ11.50(s,1H),7.14(t,J＝5.7Hz,1H),7.06(s,2H),6.44(dd,J＝16.5,9.9Hz,1H),6.17(d,J＝16.5Hz,1H),5.95(s,1H),5.84(d,J＝9.9Hz,2H),4.48(d,J＝5.8Hz,2H),4.09(d,J＝5.8Hz,2H),3.92(d,J＝11.3Hz,2H),3.29(td,J＝11.4,4.2Hz,2H),3.02(q,J＝6.9Hz,2H),2.94(d,J＝5.2Hz,1H),2.39(s,3H),2.29(s,3H),2.22(s,3H),1.63(t,J＝10.7Hz,4H),0.81(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C26H36N4O5S(M+H+):517.2479；found:517.2474.
Example 31
5- (But-2-aminomethyl) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methylbenzamide (31)
Figure BDA0003027517040000181
Crotonic acid was replaced with 2-butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in step one of example 28 to give a white solid.1H NMR(500MHz,CDCl3)δ11.94,7.10,7.04,6.97,6.15,5.95,4.53,4.52,4.35,4.34,3.94,3.92,3.32,3.32,3.30,3.30,3.28,3.27,3.05,3.03,3.02,3.00,2.95,2.94,2.94,2.93,2.92,2.39,2.27,2.21,1.92,1.65,1.64,1.62,1.61,1.59,0.84,0.82,0.81.HRMS(ESI)calcd for C28H36N4O4(M+H+):493.2809；found:493.2805.
Example 32
5- (Acrylamidomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) benzamide (32)
Figure BDA0003027517040000182
Step 1.5-cyano-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) benzamide (32a)
The compound 1d was changed to the compound 26e, 3-aminomethyl-4, 6-dimethylpyridin-2 (1H) -one to 3-aminomethyl-4-propyl-6-methylpyridin-2 (1H) -one and the remaining required starting materials, reagents and preparation were the same as in example 1, step five to give a white solid.1H NMR(500MHz,CDCl3)δ12.50(s,1H),7.36(s,1H),7.32(s,1H),6.00(s,1H),4.55(d,J＝5.6Hz,2H),3.96(d,J＝11.5Hz,2H),3.31(t,J＝10.7Hz,2H),3.06(q,J＝6.9Hz,2H),2.95(td,J＝9.8,4.8Hz,1H),2.70–2.64(m,2H),2.37(s,3H),2.26(s,3H),1.72–1.66(m,2H),1.65(d,J＝3.5Hz,2H),1.63–1.59(m,2H),1.01(t,J＝7.3Hz,3H),0.85(t,J＝6.9Hz,3H).m/z(M+H+):451.26.
Step 2.5- (aminomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) benzamide (32b)
Compound 26f was replaced with compound 32a, and the remaining desired starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(500MHz,CDCl3)δ7.16(t,J＝5.2Hz,1H),7.08(s,1H),7.02(s,1H),5.96(s,1H),4.54(d,J＝5.7Hz,2H),3.93(d,J＝11.3Hz,2H),3.78(s,2H),3.29(dd,J＝16.7,5.8Hz,2H),3.04(q,J＝6.9Hz,2H),2.94(dt,J＝9.5,5.1Hz,1H),2.71–2.66(m,2H),2.30(s,3H),2.22(s,3H),1.66(s,2H),1.63(d,J＝7.6Hz,2H),1.60(d,J＝7.6Hz,2H),1.00(t,J＝7.3Hz,3H),0.83(t,J＝7.0Hz,3H).m/z(M+H+):455.29.
Step 3.5- (Acrylamidomethyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-2-oxo-4-propyl-1, 2-dihydropyridin-3-yl) methyl) benzamide (32)
The same procedures used in example 28 were repeated except for changing 26g of compound to 32b and the remaining required starting materials, reagents and preparation were the same as those in example 28 to give a white solid.1H NMR(400MHz,CDCl3)δ11.84(s,1H),7.14(s,1H),7.07(s,1H),6.97(s,1H),6.32(s,1H),6.24(s,1H),6.11(dd,J＝17.0,10.1Hz,1H),5.95(s,1H),5.60(d,J＝10.2Hz,1H),4.51(d,J＝5.4Hz,2H),4.37(d,J＝5.5Hz,2H),3.91(d,J＝11.1Hz,2H),3.28(t,J＝10.0Hz,2H),3.04(d,J＝6.9Hz,2H),2.96(s,1H),2.71–2.63(m,2H),2.28(s,3H),2.21(s,3H),1.68–1.57(m,6H),0.99(t,J＝7.3Hz,3H),0.82(t,J＝6.8Hz,3H).HRMS(ESI)calcd for C29H40N4O4(M+H+):509.3122；found:509.3121.
Example 33
5- (Acrylamidomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -N- ((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (33)
Figure BDA0003027517040000183
Step 1.5-cyano-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -N- ((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (33a)
The compound 1d was changed to the compound 26e, 3-aminomethyl-4, 6-dimethylpyridin-2 (1H) -one to 3-aminomethyl-4-methoxy-6-methylpyridin-2 (1H) -one and the remaining required starting materials, reagents and preparation were the same as in example 1, step five to give a white solid.1H NMR(400MHz,CDCl3)δ12.96(s,1H),7.53(s,1H),7.36(s,2H),5.98(s,1H),4.57(d,J＝4.7Hz,2H),3.96(d,J＝11.1Hz,2H),3.91(s,3H),3.31(t,J＝8.6Hz,2H),3.07(dd,J＝13.4,6.5Hz,2H),3.00–2.93(m,1H),2.40(s,3H),2.31(s,3H),1.88(s,2H),1.66–1.60(m,2H),0.85(t,J＝6.7Hz,3H).m/z(M+H+):439.23.
Step 2.5- (aminomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -N- ((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (35b)
Compound 26f was replaced with compound 33a, and the remaining desired starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(500MHz,CDCl3)δ7.13(s,1H),7.07(s,1H),7.06(s,1H),5.94(s,1H),4.57(d,J＝5.0Hz,2H),3.94(d,J＝10.9Hz,2H),3.89(s,3H),3.78(s,2H),3.31(t,J＝11.2Hz,2H),3.05(dd,J＝13.7,6.7Hz,2H),2.96(dd,J＝9.5,4.8Hz,1H),2.32(s,3H),2.27(s,3H),1.69–1.61(m,4H),0.84(t,J＝6.9Hz,3H).m/z(M+H+):443.26.
Step 3.5- (Acrylamidomethyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -N- ((4-methoxy-6-methyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methylbenzamide (33)
The same procedures used in example 28 were repeated except for changing 26g of compound to 33b and the remaining required starting materials, reagents and preparation were the same as those in example 28 to give a white solid.1H NMR(400MHz,CDCl3)δ12.53(s,1H),7.17(s,1H),7.05(s,1H),7.00(s,1H),6.69(s,1H),6.26(d,J＝16.6Hz,1H),6.15(dd,J＝16.9,10.0Hz,1H),5.92(s,1H),5.59(d,J＝10.0Hz,1H),4.51(s,2H),4.37(d,J＝5.1Hz,2H),3.91(d,J＝11.0Hz,2H),3.86(s,3H),3.29(t,J＝10.1Hz,2H),3.02(dd,J＝13.6,6.6Hz,2H),2.96–2.89(m,1H),2.30(s,3H),2.24(s,3H),1.64(s,2H),1.60(s,2H),0.81(t,J＝6.8Hz,3H).；HRMS(ESI)calcd for C27H36N4O5(M+H+):497.2858；found:497.2856.
Example 34
5- (Acrylamidomethyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (34)
Figure BDA0003027517040000191
Step 1.3- (bis (methylthio) methylene) pentane-2, 4-dione (34b)
Acetylacetone (10g,100mmol), potassium carbonate (41.4g,300mmol) was dissolved in anhydrous N' N-dimethyl-methaneIn amide, the mixture was stirred at room temperature for 1 hour under nitrogen protection, then carbon disulfide (7.6g, 100mmol) was injected into the reaction solution under ice bath conditions, after reaction for 1 hour, methyl iodide (28.6g,200mmol) was slowly dropped into the reaction solution under ice bath conditions, and the mixture was stirred at room temperature overnight. After the reaction, the reaction solution was poured into water, stirred well, and filtered to obtain 17g of pale yellow solid with a yield of 83.3%.1H NMR(400MHz,DMSO-d6)δ2.37(s,6H),2.40(s,6H).m/z(M+H+):205.03.
Step 2.4, 4-bis (methylthio) -3-buten-2-one (34c)
Compound 34b (17g,83.3mmol) was dissolved in dichloromethane and 10mL of concentrated sulfuric acid was slowly added dropwise and stirred overnight. After the reaction, the reaction solution was neutralized with dilute hydrochloric acid (2N) under ice bath conditions to weak acidity, extracted with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.0g of a yellow solid with a yield of 74.3%.1H NMR(400MHz,CDCl3)δ6.05(s,1H),2.46(s,3H),2.46(s,3H),2.19(s,3H).m/z(M+H+):163.02.
Step 3.6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridine-3-carbonitrile (34d)
Compound 34c (10g,61.6mmol), cyanoacetamide (5.2g,61.6mmol), and potassium tert-butoxide (13.8g,112.2mmol) were dissolved in 250mL of tert-butanol and reacted at 85 ℃ overnight. After the reaction is finished, water is added into the reaction liquid until the reaction liquid is clear, diluted hydrochloric acid (2N) is used for neutralizing the reaction liquid until the reaction liquid is acidic, the reaction liquid is stirred uniformly, and light yellow solid 10.2g is obtained through filtration, wherein the yield is 91.9%.1H NMR(400MHz,DMSO)δ6.28(s,1H),2.57(s,3H),2.26(s,3H).m/z(M+H+):181.04.
Step 4.3-aminomethyl-4-methylsulfanyl-6-methylpyridin-2 (1H) -one (34e)
Compound 34d (2g,11.1mmol) was dissolved in 10mL of anhydrous tetrahydrofuran, and a solution of lithium aluminum hydride in tetrahydrofuran was added dropwise under protection of nitrogen in an ice bath and stirred at room temperature overnight. After the reaction is finished, ice water is dripped to quench the reaction, the reaction solution is decompressed and concentrated, ethyl acetate and water are added to separate the reaction solution, the water phase is extracted by ethyl acetate, the organic phase is combined and washed by saturated sodium chloride solution, the filtrate is decompressed and concentrated to obtain 1.9g of white solid,the yield was 93.1%.1H NMR(400MHz,DMSO-d6)δ6.02(s,1H),3.50(s,2H),2.43(s,3H),2.15(s,3H).m/z(M+H+):185.07.
Step 5.5-cyano-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (34f)
Compound 26e (1.9g,6.6mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (3.0g,7.9mmol), N, N-diisopropylethylamine (2.5g,19.8mmol), compound 34e (1.8g,9.9mmol) and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 3.9g of a white solid with a yield of 85.5%.1H NMR(400MHz,CDCl3)δ12.73(s,1H),7.36(s,2H),7.18(s,1H),6.06(s,1H),4.63(d,J＝4.9Hz,2H),3.96(d,J＝11.2Hz,2H),3.31(t,J＝8.6Hz,2H),3.07(dd,J＝13.8,6.8Hz,2H),2.95(dd,J＝11.2,6.4Hz,1H),1.68(d,J＝12.9Hz,2H),1.66–1.61(m,2H),0.85(t,J＝6.9Hz,3H).m/z(M+H+):455.20.
Step 6.5- (aminomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (34g)
Compound 26f was changed to compound 34f, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(500MHz,CDCl3)δ7.08(s,2H),7.00(s,1H),6.00(s,1H),4.60(d,J＝4.9Hz,2H),3.92(d,J＝10.8Hz,2H),3.79(s,2H),3.29(t,J＝10.5Hz,2H),3.03(dd,J＝13.5,6.6Hz,2H),2.97–2.92(m,1H),2.47(s,3H),2.33(s,3H),2.26(s,3H),1.65(s,2H),1.62(d,J＝8.6Hz,2H).m/z(M+H+):459.24.
Step 7.5- (Acrylamidomethyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (34)
34g (100mg,0.23mmol) of the compound was dissolved in anhydrous dichloromethane, and propylene was added thereto under stirring in ice bathAcid chloride (21.6mg,0.24mmol), triethylamine (70.3mg,0.69mmol), and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 70mg of a white solid with a yield of 59.4%.1H NMR(400MHz,CDCl3)δ12.40(s,1H),7.06(s,1H),7.03(d,J＝3.7Hz,1H),7.02(s,1H),6.76(s,1H),6.26(d,J＝16.9Hz,1H),6.16(dd,J＝17.0,9.8Hz,1H),5.96(s,1H),5.58(d,J＝9.9Hz,1H),4.55(d,J＝4.5Hz,2H),4.38(d,J＝5.5Hz,2H),3.91(d,J＝11.1Hz,2H),3.28(t,J＝10.1Hz,2H),3.02(dd,J＝13.3,6.4Hz,2H),2.97–2.91(m,1H),2.44(s,3H),2.32(s,3H),2.21(s,3H),1.64(s,2H),1.60(s,2H),0.81(t,J＝6.8Hz,3H).HRMS(ESI)calcd for C27H36N4O4S(M+H+):513.2530；found:513.2531.
Example 35
6- (but-2-Enylaminomethyl) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (35)
Figure BDA0003027517040000201
34g (100mg,0.22mmol) of the compound was dissolved in methylene chloride, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (102.7mg,0.27mmol), N, N-diisopropylethylamine (85.0mg,0.66mmol), crotonic acid (24.9mg,0.29mmol) and the mixture was stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 70mg of a white solid with a yield of 61.9%.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.34(s,1H),7.89(s,1H),7.06(s,1H),6.88(s,1H),6.63(dd,J＝14.5,7.0Hz,1H),6.07(s,1H),5.94(d,J＝15.2Hz,1H),4.30(s,2H),4.25(d,J＝4.7Hz,2H),3.82(d,J＝9.8Hz,2H),3.22(t,J＝11.1Hz,2H),2.99(d,J＝6.3Hz,2H),2.91(s,1H),2.44(s,3H),2.19(s,3H),2.16(s,3H),1.79(d,J＝6.1Hz,3H),1.61(d,J＝11.4Hz,2H),1.48(d,J＝10.2Hz,2H),0.78(t,J＝5.5Hz,3H).HRMS(ESI)calcd for C28H38N4O4S(M+H)+:527.2687；found:527.2689.
Example 36
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -5- (methacrylaminomethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (36)
Figure BDA0003027517040000202
The acryloyl chloride was replaced with methacryloyl chloride and the remaining required starting materials, reagents and preparation were the same as in example 36, step seven to provide a white solid.1H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.46(t,J＝6.0Hz,1H),7.89(t,J＝4.3Hz,1H),7.07(s,1H),6.89(s,1H),6.08(s,1H),5.66(s,1H),5.38–5.31(m,1H),4.30(d,J＝4.3Hz,2H),4.25(d,J＝6.0Hz,2H),3.82(d,J＝10.3Hz,2H),3.22(t,J＝10.9Hz,2H),2.99(q,J＝6.8Hz,2H),2.92(dd,J＝12.6,9.1Hz,1H),2.45(s,3H),2.19(s,3H),2.16(s,3H),1.86(s,3H),1.61(d,J＝11.0Hz,2H),1.53–1.43(m,2H),0.78(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C28H38N4O4S(M+H+):527.2687；found:527.2687.
Example 37
5- ((4- (dimethylamino) but-2-enylamino) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (37)
Figure BDA0003027517040000203
Crotonic acid was replaced with 4- (dimethylamino) but-2-enoic acid and the remaining required raw materials, reagents and preparation method were the same as in example 35 to give a white solid.1H NMR(500MHz,CDCl3)δ12.03(s,1H),7.20(s,1H),7.05(s,1H),7.02(s,1H),6.87(s,1H),6.80–6.73(m,1H),6.03(d,J＝15.7Hz,1H),6.00(s,1H),4.55(s,2H),4.35(d,J＝4.6Hz,2H),3.91(d,J＝10.1Hz,2H),3.28(t,J＝10.7Hz,2H),3.05(d,J＝5.8Hz,2H),3.01(d,J＝6.9Hz,2H),2.93(s,1H),2.46(s,3H),2.30(s,3H),2.22(s,8H),1.63(s,2H),1.60(d,J＝12.5Hz,2H),0.80(t,J＝6.6Hz,3H).HRMS(ESI)calcd for C30H43N5O4S(M+H)+:570.3109；found:570.3106.
Example 38
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((4-morpholinobut-2-enylamino) methyl) benzamide (38)
Figure BDA0003027517040000204
Crotonic acid was replaced with 4-morpholinobut-2-enoic acid and the remaining required raw materials, reagents and preparation methods were the same as in example 35 to obtain a white solid.1H NMR(500MHz,DMSO)δ11.52(s,1H),8.48(s,1H),7.90(s,1H),7.06(s,1H),6.89(s,1H),6.64–6.48(m,1H),6.09(d,J＝17.0Hz,2H),4.30(s,2H),4.26(d,J＝4.0Hz,2H),3.82(d,J＝9.6Hz,2H),3.57(s,4H),3.22(t,J＝11.1Hz,2H),3.06(s,2H),2.99(d,J＝5.9Hz,2H),2.91(s,1H),2.45(s,3H),2.35(s,4H),2.19(s,3H),2.16(s,3H),1.61(d,J＝11.5Hz,2H),1.48(d,J＝10.7Hz,2H),0.77(s,3H).HRMS(ESI)calcd for C32H45N5O5S(M+H+):612.3214；found:612.3208.
Example 39
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (vinylsulfonamidomethyl) benzamide (39)
Figure BDA0003027517040000211
The compound 1g was replaced with 34g, and the remaining required starting materials, reagents and preparation methods were the same as in example 7 to give a white solid.1H NMR(500MHz,CDCl3)δ11.98(s,1H),7.11(s,1H),7.06(s,1H),7.05(s,1H),6.42(dd,J＝16.6,9.9Hz,1H),6.15(d,J＝16.6Hz,1H),5.99(s,1H),5.83(d,J＝9.9Hz,1H),4.54(d,J＝4.7Hz,2H),4.09(d,J＝5.8Hz,2H),3.91(d,J＝11.3Hz,2H),3.29(t,J＝9.8Hz,2H),3.05–3.00(m,2H),2.97–2.90(m,1H),2.45(s,3H),2.33(s,3H),2.23(s,3H),1.64(s,2H),1.60(s,2H),0.81(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C26H36N4O5S2(M+H+):549.2200；found:549.2203.
Example 40
5- (but-2-aminomethyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (40)
Figure BDA0003027517040000212
Crotonic acid was replaced with 2-butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 35 to give a white solid.1H NMR(500MHz,CDCl3)δ12.47(s,1H),7.04(s,1H),7.02(s,1H),6.93(s,1H),6.39(d,J＝20.2Hz,1H),6.01(s,1H),4.62(d,J＝4.7Hz,2H),4.35(d,J＝5.6Hz,2H),3.92(d,J＝11.1Hz,2H),3.30(t,J＝11.1Hz,2H),3.05–3.01(m,2H),2.97–2.92(m,1H),2.47(s,3H),2.32(s,3H),2.25(s,3H),1.91(d,J＝1.5Hz,3H),1.65(s,2H),1.61(s,2H),0.82(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C28H36N4O4S(M+H+):525.2530；found:525.2526.
EXAMPLE 41
5- ((2-Chloroacetamido) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (41)
Figure BDA0003027517040000213
The acryloyl chloride was replaced with chloroacetyl chloride, and the remaining required starting materials, reagents and preparation were the same as in example 36, step seven, affording a white solid.1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.71(t,J＝5.9Hz,1H),7.90(t,J＝4.4Hz,1H),7.08(s,1H),6.90(s,1H),6.08(s,1H),4.31(d,J＝4.3Hz,2H),4.23(d,J＝5.9Hz,2H),4.08(s,2H),3.82(d,J＝10.2Hz,2H),3.22(t,J＝10.9Hz,2H),3.00(q,J＝6.9Hz,2H),2.95–2.88(m,1H),2.45(s,3H),2.20(s,3H),2.16(s,3H),1.62(d,J＝10.8Hz,2H),1.49(dd,J＝11.7,3.4Hz,2H),0.78(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C26H35N4O4SCl(M+H+):535.2140；found:535.2137.
Example 42
5- ((2-Cyanoacetamido) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (42)
Figure BDA0003027517040000214
Crotonic acid was replaced by cyanoacetic acid and the remaining required raw materials, reagents and preparation method were the same as in example 35 to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),10.27(s,1H),7.96(s,1H),7.44(s,1H),7.15(s,1H),6.08(s,1H),4.31(s,2H),3.88–3.76(m,4H),3.34(s,2H),3.23(t,J＝9.8Hz,2H),2.99(s,2H),2.90(s,1H),2.45(s,3H),2.17(s,6H),1.62(d,J＝8.8Hz,2H),1.50(d,J＝9.1Hz,2H),0.80(s,3H).HRMS(ESI)calcd for C27H35N5O4S(M+H+):526.2483；found:526.2483.
Example 43
5- ((1-cyanocyclopropane-1-carboxamido) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (43)
Figure BDA0003027517040000215
The crotonic acid is replaced by 1-cyano-2-cyclopropyl carboxylic acid, and other required raw materials, reagents and preparation methods are the same as those of the raw materialsExample 35, a white solid was obtained.1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),8.72(s,1H),7.91(s,1H),7.07(s,1H),6.89(s,1H),6.08(s,1H),4.31(s,2H),4.21(d,J＝4.8Hz,2H),3.82(d,J＝10.0Hz,2H),3.23(t,J＝11.3Hz,2H),3.00(d,J＝6.5Hz,2H),2.93(d,J＝9.7Hz,1H),2.46(s,3H),2.19(s,3H),2.17(s,3H),1.64–1.54(m,4H),1.53–1.44(m,4H),0.78(t,J＝6.0Hz,3H).HRMS(ESI)calcd for C29H37N5O4S(M+H+):552.2639；found:552.2641.
Example 44
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((N-methylpropionamido) methyl) benzamide (44)
Figure BDA0003027517040000221
Step 1.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -5-formyl-2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (44a)
Compound 34f (1.5g,3.32mmol) was dissolved in anhydrous dichloromethane and diisobutylaluminum hydride was added slowly with stirring at-78 deg.C under nitrogen for 1 hour. After the reaction, ice water was added to quench the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added to conduct extraction, the organic phases were combined, washed with a saturated sodium chloride solution, and the filtrate was concentrated under reduced pressure to obtain 500mg of a white solid with a yield of 33.0%.1H NMR(400MHz,CDCl3)δ12.71(s,1H),9.88(s,1H),7.62(d,J＝1.2Hz,1H),7.57(d,J＝1.2Hz,1H),7.10(t,J＝5.1Hz,1H),6.02(s,1H),4.64(d,J＝5.3Hz,2H),3.93(d,J＝11.3Hz,2H),3.33–3.26(m,2H),3.09(q,J＝7.0Hz,2H),3.01–2.95(m,1H),2.48(s,3H),2.43(s,3H),2.24(s,4H),1.66(td,J＝8.1,3.0Hz,4H),0.84(t,J＝7.0Hz,3H).m/z(M+H+):458.20.
Step 2.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((methylamino) methyl) benzamide (44b)
Compound 44a (457mg,1mmol), 3mL of methylamine solution were dissolved in 10mL of methanol and stirred at room temperature overnight. Sodium borohydride (76mmol,2mmol) was added under ice-bath conditions and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and water were added for extraction, the organic phases were combined, washed with saturated sodium chloride solution, and the filtrate was concentrated under reduced pressure to give 440mg of a white solid with a yield of 93.2%.1H NMR(500MHz,CDCl3)δ7.08(s,1H),7.07(s,1H),6.96(t,J＝4.7Hz,1H),6.01(s,1H),4.62(d,J＝5.1Hz,2H),3.93(d,J＝11.1Hz,2H),3.67(s,2H),3.30(t,J＝10.1Hz,2H),3.04(dd,J＝13.7,6.7Hz,2H),2.98–2.93(m,1H),2.48(s,3H),2.39(s,3H),2.34(s,3H),2.27(s,3H),1.68–1.61(m,4H),0.83(t,J＝6.9Hz,3H).m/z(M+H+):573.25.
Step 3.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((N-methacrylamido) methyl) benzamide (44)
Compound 44b (100mg,0.21mmol) was dissolved in anhydrous dichloromethane, and acryloyl chloride (19.8mg,0.22mmol) and triethylamine (63.6mg,0.63mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50mg of a white solid, the yield of which was 43.2%.1H NMR(500MHz,DMSO-d6)δ11.05(s,1H),7.47(s,1H),7.01(s,1H),6.91(s,1H),6.69(dd,J＝16.7,10.5Hz,1H),6.08(d,J＝16.8Hz,1H),6.02(s,1H),5.60(d,J＝10.5Hz,1H),4.52(s,2H),4.37(s,2H),3.81(d,J＝11.1Hz,2H),3.24(td,J＝11.5,2.2Hz,2H),3.01(d,J＝7.0Hz,2H),2.98(d,J＝9.5Hz,1H),2.91(s,3H),2.44(s,3H),2.24(s,3H),2.18(s,3H),1.67–1.60(m,2H),1.46(qd,J＝11.8,4.4Hz,2H),0.81(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C28H38N4O4S(M+H+):527.2686；found:527.2687.
Example 45
5- ((4- (dimethylamino) -N-methylbutane-2- -2-amino) methyl) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (45)
Figure BDA0003027517040000222
Compound 44b (100mg,0.22mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (100.4mg,0.26mmol), N, N-diisopropylethylamine (85.0mg,0.66mmol), 4- (dimethylamino) but-2-enoic acid hydrochloride (43.0mg,0.26mmol) and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 60mg of a white solid with a yield of 46.8%.1H NMR(500MHz,DMSO-d6)δ7.53(s,1H),7.00(s,1H),6.90(s,1H),6.62(dt,J＝15.3,6.1Hz,1H),6.52(d,J＝15.3Hz,1H),6.03(s,1H),4.52(s,2H),4.37(s,2H),3.81(d,J＝11.1Hz,2H),3.23(d,J＝11.4Hz,2H),3.09(d,J＝6.2Hz,2H),3.00(d,J＝7.0Hz,2H),2.98(s,1H),2.90(s,3H),2.45(s,3H),2.23(s,3H),2.20(s,6H),2.18(s,3H),1.63(d,J＝12.7Hz,2H),1.47(td,J＝11.8,4.4Hz,2H),0.81(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C31H45N5O4S(M+H+):584.3192；found:584.3190.
Example 46
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((N-methylbut-2-amino) methyl) benzamide (46)
Figure BDA0003027517040000223
The 4- (dimethylamino) but-2-enoic acid hydrochloride was replaced with 2-butynoic acid and the remaining required starting materials, reagents and preparation were the same as in example 45 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),7.55(s,1H),7.05(s,1H),6.93(s,1H),6.03(s,1H),4.55(d,J＝106.1Hz,2H),4.37(s,2H),3.82(d,J＝10.8Hz,2H),3.25(t,J＝11.4Hz,2H),3.04–3.01(m,2H),3.00(s,1H),2.90(s,3H),2.45(s,3H),2.24(s,3H),2.17(s,3H),1.98(d,J＝7.0Hz,3H),1.64(d,J＝12.8Hz,2H),1.48(tt,J＝11.8,5.9Hz,2H),0.82(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C29H38N4O4S(M+H+):539.2686；found:539.2687.
Example 47
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- ((N-methylvinylsulfonamido) methyl) benzamide (47)
Figure BDA0003027517040000231
The compound 1g was replaced with the compound 44b, and the remaining required starting materials, reagents and preparation were the same as in example 7 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.37(s,1H),7.82(t,J＝4.8Hz,1H),7.13(s,1H),6.96(s,1H),6.77(ddd,J＝16.4,10.0,1.6Hz,1H),6.15–6.08(m,2H),6.06(s,1H),4.34(d,J＝4.5Hz,2H),4.15(s,2H),3.85–3.79(m,2H),3.24(t,J＝11.4Hz,2H),3.02(d,J＝7.0Hz,2H),2.96(d,J＝11.0Hz,1H),2.61(s,3H),2.45(s,3H),2.23(s,3H),2.17(s,3H),1.63(d,J＝12.6Hz,2H),1.48(td,J＝11.9,4.1Hz,2H).HRMS(ESI)calcd for C27H38N4O5S2(M+H+):563.2356；found:563.2352.
Example 48
5-acrylamido-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (48)
Figure BDA0003027517040000232
Step 1.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5-nitrobenzamide (48a)
By exchanging 3-aminomethyl-4, 6-dimethylpyridin-2 (1H) -oneTo form compound 34e, the remaining required starting materials, reagents and preparation were the same as in example 1, step five, affording a white solid.1H NMR(500MHz,CDCl3)δ12.67(s,1H),7.93(d,J＝2.4Hz,2H),7.23(t,J＝4.8Hz,1H),6.03(s,1H),4.64(d,J＝5.1Hz,2H),3.95(d,J＝11.4Hz,2H),3.30(td,J＝11.4,2.8Hz,2H),3.11(q,J＝7.0Hz,2H),2.99(ddd,J＝14.6,9.8,4.8Hz,1H),2.49(s,3H),2.44(s,3H),2.27(s,3H),1.74–1.68(m,2H),1.67(s,2H),0.87(t,J＝7.0Hz,3H).m/z(M+H+):475.19.
Step 2.5-amino-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (48b)
Compound 1e was replaced with compound 48a, and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(500MHz,CDCl3)δ12.79(s,1H),6.86(t,J＝4.5Hz,1H),6.47(s,2H),5.96(s,1H),4.60(d,J＝5.0Hz,2H),3.91(d,J＝10.9Hz,2H),3.29(t,J＝10.8Hz,2H),2.97(dd,J＝13.8,6.8Hz,2H),2.90(t,J＝10.6Hz,1H),2.43(s,3H),2.23(s,3H),2.21(s,3H),1.66(t,J＝10.6Hz,3H),1.64–1.55(m,2H),0.83(t,J＝6.9Hz,3H).m/z(M+H+):445.22.
Step 3.5-acrylamido-3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (48)
Compound 48b (106.7mg,0.24mmol) was dissolved in anhydrous dichloromethane, and acryloyl chloride (22.7mg,0.25mmol) and triethylamine (72mg,0.72mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a white solid 40mg, with a yield of 33.5%.1H NMR(500MHz,CDCl3)δ10.10(s,1H),7.94(s,1H),7.60(s,1H),7.27(s,1H),6.40(dd,J＝16.7,10.2Hz,1H),6.23(d,J＝16.9Hz,1H),6.08(s,1H),5.72(d,J＝10.0Hz,1H),4.31(s,2H),3.83(d,J＝9.7Hz,2H),3.23(t,J＝11.1Hz,2H),2.99(d,J＝6.4Hz,2H),2.91(s,1H),2.46(s,3H),2.17(d,J＝4.2Hz,6H),1.63(d,J＝11.0Hz,2H),1.51(d,J＝10.3Hz,2H),0.81(d,J＝6.0Hz,3H).HRMS(ESI)calcd for C26H34N4O4S(M+H+):499.2374；found:499.2373.
Example 49
5- (but-2-amino) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (49)
Figure BDA0003027517040000233
Compound 48b (106.7mg,0.24mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), 2-butynoic acid (24.4mg,0.29mmol) and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 70mg of a white solid, the yield of which was 57.4%.1H NMR(500MHz,DMSO-d6)δ11.52(s,1H),10.49(s,1H),7.92(s,1H),7.44(s,1H),7.24(s,1H),6.07(s,1H),4.30(s,2H),3.82(d,J＝9.9Hz,2H),3.22(t,J＝11.0Hz,2H),2.96(d,J＝6.0Hz,2H),2.88(s,1H),2.45(s,3H),2.16(s,6H),2.02(s,3H),1.61(d,J＝11.0Hz,2H),1.49(d,J＝10.9Hz,2H),0.79(s,3H).HRMS(ESI)calcd for C27H34N4O4S(M+H+):511.2374；found:511.2372.
Example 50
5- (4- (dimethylamino) but-2-ylamino) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio)) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (50)
Figure BDA0003027517040000234
Example 49 was repeated except for the starting materials, reagents and preparation method used in example 49 to replace 2-butynoic acid with 4- (dimethylamino) but-2-enoic acid to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.04(s,1H),7.92(t,J＝4.2Hz,1H),7.61(s,1H),7.24(s,1H),6.70(dt,J＝15.2,6.0Hz,1H),6.24(d,J＝15.3Hz,1H),6.08(s,1H),4.31(d,J＝4.2Hz,2H),3.83(d,J＝10.8Hz,2H),3.23(t,J＝11.3Hz,2H),3.14(d,J＝5.8Hz,2H),2.98(q,J＝6.8Hz,2H),2.90(t,J＝10.9Hz,1H),2.46(s,3H),2.23(s,6H),2.17(s,6H),1.63(d,J＝11.6Hz,2H),1.51(tt,J＝11.5,5.9Hz,2H),0.80(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C29H41N5O4S(M+H+):556.2952；found:556.2953.
Example 51
5- (2-Cyanoacetamido) -3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (51)
Figure BDA0003027517040000241
The 2-butynoic acid was replaced with cyanoacetic acid and the remaining required starting materials, reagents and preparation were the same as in example 49 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),10.27(s,1H),7.96(s,1H),7.44(s,1H),7.15(s,1H),6.08(s,1H),4.31(s,2H),3.88–3.76(m,4H),3.34(s,2H),3.23(t,J＝9.8Hz,2H),2.99(s,2H),2.90(s,1H),2.45(s,3H),2.17(s,6H),1.62(d,J＝8.8Hz,2H),1.50(d,J＝9.1Hz,2H),0.80(s,3H).HRMS(ESI)calcd for C26H33N5O4S(M+H+):512.2326；found:512.2328.
Example 52
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (N-methacrylamido) benzamide (52)
Step 1.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (methylamino) benzamide (52a)
Changing 1g of the compound into 48b, and the other required raw materials, reagents and preparation methods are the same as those of the compoundStep one in example 9, a white solid was obtained.1H NMR(500MHz,CDCl3)δ12.86(s,1H),6.85(s,1H),6.42(d,J＝3.3Hz,2H),5.98(s,1H),4.63(d,J＝3.1Hz,2H),3.93(d,J＝10.4Hz,2H),3.30(t,J＝11.1Hz,2H),3.00(dd,J＝12.9,6.5Hz,2H),2.95–2.89(m,1H),2.76(s,3H),2.45(s,3H),2.24(s,3H),2.22(s,3H),1.69(d,J＝11.0Hz,3H),1.63(d,J＝10.5Hz,2H),0.85(t,J＝6.0Hz,3H).m/z(M+H+):459.24.
Step 2.3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (N-methacrylamido) benzamide (52)
Compound 52a (110.0mg,0.24mmol) was dissolved in anhydrous dichloromethane, and acryloyl chloride (22.7mg,0.25mmol) and triethylamine (72mg,0.72mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction, the reaction product was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 50mg of a white solid with a yield of 40.6%.1H NMR(500MHz,CDCl3)δ12.69(s,1H),6.91(d,J＝2.0Hz,1H),6.85(d,J＝8.5Hz,1H),6.28(d,J＝18.6Hz,1H),6.08–5.96(m,2H),5.44(d,J＝10.1Hz,1H),4.61(d,J＝5.2Hz,2H),3.92(d,J＝11.3Hz,2H),3.34–3.16(m,5H),3.00(dd,J＝13.9,6.9Hz,2H),2.97–2.89(m,1H),2.46(s,3H),2.33(s,3H),2.26(s,3H),1.69–1.56(m,4H),0.81(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C27H36N4O4S(M+H+):513.2530；found:513.2529.
Example 53
5- (4- (dimethylamino) -N-methylbutan-2-amino) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (53)
Figure BDA0003027517040000242
Reacting 3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (methylamino) benzeneFormamide (110.7mg,0.24mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N-diisopropylethylamine (75.0mg,0.58mmol), 4- (dimethylamino) but-2-enoic acid (48.0mg,0.29mmol) and stirred at room temperature overnight. After the reaction, the reaction mixture was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 70mg of a white solid, the yield of which was 57.4%.1H NMR(500MHz,DMSO-d6)δ12.51(s,1H),10.04(s,1H),7.92(t,J＝4.2Hz,1H),6.99(s,1H),6.85(s,1H),6.70(dt,J＝15.2,6.0Hz,1H),6.24(d,J＝15.3Hz,1H),6.08(s,1H),4.31(d,J＝4.2Hz,2H),3.83(d,J＝10.8Hz,2H),3.23(t,J＝11.3Hz,2H),3.14(d,J＝5.8Hz,2H),2.76(s,3H),2.98(q,J＝6.8Hz,2H),2.90(t,J＝10.9Hz,1H),2.46(s,3H),2.23(s,6H),2.17(s,6H),1.63(d,J＝11.6Hz,2H),1.51(tt,J＝11.5,5.9Hz,2H),0.80(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C30H43N5O4S(M+H+):569.3036；found:569.3030.
Example 54
3- (Ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (N-methylbutan-2-amino) benzamide (54)
Figure BDA0003027517040000243
Example 53 was repeated except for the starting materials, reagents and preparation method used in example 53 to replace 4- (dimethylamino) but-2-enoic acid with 2-butynoic acid to give a white solid.1H NMR(500MHz,CDCl3)δ12.47(s,1H),7.03(s,1H),6.98(s,1H),6.86(t,J＝4.2Hz,1H),6.03(s,1H),4.64(d,J＝5.0Hz,2H),3.93(d,J＝11.0Hz,2H),3.31(t,J＝12.3Hz,2H),3.22(s,3H),3.03(dd,J＝14.0,6.9Hz,2H),3.00–2.91(m,1H),2.48(s,3H),2.36(s,3H),2.29(s,3H),1.71(d,J＝0.8Hz,3H),1.69–1.62(m,4H),0.85(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C28H36N4O4S(M+H+):525.2530；found:525.2539.
Example 55
5- (2-cyano-N-methylacetamido) -3- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -2-methyl-N- (((6-methyl-4- (methylthio) -2-) oxy-1, 2-dihydropyridin-3-yl) methyl) benzamide (55)
Figure BDA0003027517040000251
The 4- (dimethylamino) but-2-enoic acid was replaced with cyanoacetic acid, and the remaining required starting materials, reagents and preparation methods were the same as in example 53 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.55(s,1H),7.98(s,1H),7.19(s,1H),6.94(s,1H),6.09(s,1H),4.32(s,2H),3.83(d,J＝9.9Hz,2H),3.57(s,2H),3.24(t,J＝11.0Hz,2H),3.14(s,3H),3.03(d,J＝6.2Hz,2H),2.99–2.92(m,1H),2.45(s,3H),2.25(s,3H),2.17(s,3H),1.63(d,J＝11.3Hz,2H),1.51(d,J＝10.1Hz,2H),0.80(s,3H).HRMS(ESI)calcd for C27H35N5O4S(M+H+):526.2483；found:526.2483.
Example 56
5- (2-Cyanoacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (56)
Step 1.2-methyl-5-nitro-1H-indole-3-carbaldehyde (56b)
Under the protection of nitrogen, phosphorus oxychloride (1.10g,96mmol) is slowly injected into 30mL of anhydrous N, N-dimethylformamide, stirred for 30 minutes under the condition of ice bath, and then a solution of 2-methyl-5-nitro-1H-indole (14.0g, 80mmol) in anhydrous N, N-dimethylformamide is added, and the reaction is carried out at room temperature overnight. After the reaction, the reaction solution was slowly poured into ice water, the pH was adjusted to acidity with sodium hydroxide solution (2N), stirred for 30 minutes, and filtered under suction to obtain 15.0g of a tan solid, with a yield of 92.0%.1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.86(d,J＝1.3Hz,1H),8.05(dd,J＝8.8,1.6Hz,1H),7.55(d,J＝8.9Hz,1H),2.73(s,3H).m/z(M+H+):205.05.
Step 2.2-methyl-5-nitro-1- (pentyl-3-yl) -1H-indole-3-carbaldehyde (56c)
Compound 56b (2.04g,10mmol), 3-bromopentane (4.54g,30mmol), and cesium carbonate (8.14g,30mmol) were dissolved in 10mL of N, N-dimethylformamide and reacted at 80 ℃ overnight. After the reaction is finished, ethyl acetate and water are added for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is decompressed and concentrated, column chromatography purification is carried out, and brown yellow solid 56c 904.2mg is obtained, and the yield is 33.0%.1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.01(s,1H),8.05(d,J＝8.7Hz,1H),7.92(d,J＝9.0Hz,1H),4.38(s,1H),2.77(s,3H),2.15(d,J＝7.2Hz,2H),1.99(dd,J＝13.1,6.6Hz,2H),0.68(t,J＝7.0Hz,6H).m/z(M+H+):275.13.
Step 3.2-methyl-5-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid (56d)
An aqueous solution of potassium permanganate (4.74g,30mmol) was added to a solution of compound 56c (2.74g,10mmol) in acetone and reacted at room temperature for 4 hours. After the reaction is finished, 30% hydrogen peroxide solution is dripped into the reaction solution until no obvious bubbles are generated, the solution is filtered, the filtrate is neutralized by dilute hydrochloric acid until the pH value is 5-6, and white solid 56d 2.17g is obtained by suction filtration, and the yield is 75.0%.1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),10.19(s,1H),9.03–8.89(m,1H),8.02(dd,J＝23.3,8.7Hz,1H),7.87(t,J＝12.1Hz,1H),4.45–4.27(m,1H),2.78(d,J＝10.4Hz,3H),2.23–2.06(m,2H),1.96(td,J＝13.5,6.8Hz,3H),0.65(t,J＝7.2Hz,7H).m/z(M+H+):291.13.
Step 4.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxamide (56e)
To a dichloromethane solution of compound 56d were added 2- (7-azabenzotriazole) -N, N' -tetramethylurea hexafluorophosphate (4.56g,12.0mmol) and N, N-diisopropylethylamine (4.65g,36mmol), and the mixture was stirred for 1 hour, and then 3-aminomethyl-4, 6-dimethylpyridin-2 (1H) -one (1.84g,12mmol) was added and the mixture was stirred at room temperature overnight. After the reaction, the reaction product was washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a yellow solid 3.0g, with a yield of 70.6%.1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.64(s,1H),8.01(t,J＝4.9Hz,1H),7.95(d,J＝9.3Hz,1H),7.79(d,J＝9.2Hz,1H),5.89(s,1H),4.34(d,J＝5.0Hz,2H),4.27(s,1H),2.69(s,3H),2.58(s,3H),2.28(s,3H),2.13(s,5H),1.99–1.90(m,2H),0.65(t,J＝7.2Hz,6H).m/z(M+H+):425.21.
Step 5.5-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (56f)
Compound 1d was changed to 56e and the remaining required starting materials, reagents and preparation were the same as in step six of example 1 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.53(s,1H),7.32–7.18(m,2H),6.93(s,1H),6.44(d,J＝8.4Hz,1H),5.89(s,1H),4.55(s,2H),4.31(d,J＝5.3Hz,2H),4.06(s,1H),2.57(d,J＝63.5Hz,3H),2.27(s,3H),2.16–1.96(m,5H),1.82(dd,J＝13.0,6.4Hz,2H),0.61(t,J＝7.0Hz,6H).m/z(M+H+):395.24.
Step 6.5- (2-Cyanoacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (56)
Compound 56f (100mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), cyanoacetic acid (21.3mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.20(s,1H),7.88(s,1H),7.52(dd,J＝11.3,6.9Hz,2H),7.29(d,J＝8.6Hz,1H),5.89(s,1H),4.32(d,J＝5.0Hz,2H),4.14(s,1H),3.87(s,2H),2.52(s,3H),2.27(s,3H),2.12(s,5H),1.92–1.82(m,2H),0.62(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C26H31N5O3(M+H+):462.2500；found:462.2500.
Example 57
5-acrylamido-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (57)
Figure BDA0003027517040000261
Cyanoacetic acid was replaced with acrylic acid, and the remaining required raw materials, reagents and preparation method were the same as in step 6 of example 56, to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.03(s,1H),8.02(s,1H),7.54–7.42(m,3H),6.47(dd,J＝16.9,10.1Hz,1H),6.25(d,J＝16.9Hz,1H),5.88(s,1H),5.71(d,J＝10.1Hz,1H),4.34(d,J＝4.7Hz,2H),4.13(s,1H),2.53(s,3H),2.28(s,3H),2.11(s,5H),1.87(dd,J＝12.9,6.4Hz,2H),0.64(d,J＝6.5Hz,6H).HRMS(ESI)calcd for C26H32N4O43(M+H+):449.2547；found:449.2548.
Example 58
5- (2-Butylamino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (58)
Figure BDA0003027517040000262
Cyanoacetic acid was replaced with butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in step 6 of example 56 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),10.42(s,1H),7.98(s,1H),7.48(dd,J＝12.8,7.0Hz,2H),7.25(d,J＝8.7Hz,1H),5.89(s,1H),4.31(d,J＝5.1Hz,2H),4.20–4.05(m,1H),2.51(s,3H),2.27(s,3H),2.11(s,5H),2.04(s,3H),1.85(tt,J＝13.5,6.8Hz,2H),0.61(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C27H32N4O3(M+H+):461.2548；found:461.2547.
Example 59
5- (2-butenyl) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (59)
Figure BDA0003027517040000263
The cyanoacetic acid was replaced with crotonic acid, and the remaining required raw materials, reagents and preparation method were the same as in step 6 of example 56 to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),9.82(s,1H),7.98(s,1H),7.52–7.45(m,2H),7.41(d,J＝8.8Hz,1H),6.76(dq,J＝13.9,6.8Hz,1H),6.14(d,J＝15.2Hz,1H),5.88(s,1H),4.32(d,J＝5.2Hz,2H),4.13(d,J＝4.7Hz,1H),2.52(s,3H),2.28(s,3H),2.11(s,5H),1.90–1.82(m,5H),0.62(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C27H34N4O3(M+H+):463.2704；found:463.2706.
Example 60
(E) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (4- (dimethylamino) but-2-enyl) -2-methyl-1- (pent-3-yl) -1H-indole-3-carboxamide (60)
Figure BDA0003027517040000264
Cyanoacetic acid was replaced with 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 6 of example 56 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),9.95(s,1H),8.00(s,1H),7.48(d,J＝7.8Hz,2H),7.40(d,J＝8.6Hz,1H),6.70(dt,J＝15.1,5.9Hz,1H),6.30(s,1H),5.88(s,1H),4.32(d,J＝4.8Hz,2H),4.13(s,1H),3.06(d,J＝5.7Hz,2H),2.52(s,3H),2.28(s,3H),2.19(s,6H),2.11(s,5H),1.92–1.81(m,2H).HRMS(ESI)calcd for C29H39N5O3(M+H+):506.3126；found:506.3126.
Example 61
5- (2-Chloroacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2, dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (61)
Figure BDA0003027517040000265
Compound 56f (100mg,0.25 mmo)l) was dissolved in anhydrous dichloromethane, chloroacetyl chloride (31.5mg,0.28mmol) and triethylamine (75.8mg, 0.75mmol) were added with stirring in an ice bath, and stirred at room temperature overnight. After the reaction is finished, washing the mixture by using water and a saturated sodium chloride solution, drying the mixture by using anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by using column chromatography to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.49(s,1H),10.17(s,1H),7.92(s,1H),7.53–7.48(m,2H),7.33(d,J＝8.7Hz,1H),5.89(s,1H),4.33(d,J＝5.2Hz,2H),4.24(s,2H),4.20–4.09(m,1H),2.53(s,3H),2.28(s,4H),2.12(s,6H),1.95–1.80(m,3H),0.63(t,J＝7.1Hz,7H).HRMS(ESI)calcd for C25H31N4O3Cl(M+H+):471.2157；found:471.2160.
Example 62
5- (1-cyanocyclopropane-1-carboxamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (62)
Figure BDA0003027517040000271
Cyanoacetic acid was replaced with 1-cyanocyclopropane-1-carboxylic acid, and the remaining required starting materials, reagents and preparation were the same as in step 6 of example 56 to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),9.90(s,1H),7.88(s,1H),7.55–7.43(m,2H),7.23(d,J＝8.6Hz,1H),5.88(s,1H),4.32(d,J＝5.1Hz,2H),4.14(s,1H),2.52(s,3H),2.27(s,3H),2.11(s,5H),1.91–1.82(m,2H),1.65(s,4H),0.62(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C28H33N5O3(M+H+):488.2656；found:488.2656.
Example 63
7- (2-cyano-2-methylpropionamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (63)
Figure BDA0003027517040000272
Cyanoacetic acid was replaced with 2-cyano-2-methylpropanoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 56, step 6, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.48(s,1H),9.89(s,1H),7.92(s,1H),7.50(d,J＝8.5Hz,2H),7.30(d,J＝8.7Hz,1H),5.88(s,1H),4.32(d,J＝5.2Hz,2H),4.14(s,1H),2.52(s,3H),2.27(s,3H),2.11(s,5H),1.87(tt,J＝13.7,6.9Hz,2H),1.66(s,6H),0.63(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C28H35N5O3(M+H+):490.2813；found:490.2812.
Example 64
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (64)
Figure BDA0003027517040000273
Step 1.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (methylamino) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (64a)
Compound 56f (2.15g,5.45mmol), paraformaldehyde (490mg,5.45mmol), and sodium methoxide (1.17g,21.80mmol) were dissolved in 40mL of anhydrous methanol and reacted overnight at 45 ℃ under nitrogen protection. The reaction was returned to room temperature, and sodium borohydride (414.4mg,10.9mmol) was added under ice-cooling, followed by stirring at room temperature for 2 hours. After the reaction is finished, concentrating the reaction solution under reduced pressure, adding ethyl acetate and a water layer, extracting a water phase by using ethyl acetate, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by using column chromatography to obtain a white solid.1H NMR(500MHz,CDCl3)δ13.12(s,1H),7.60(d,J＝8.5Hz,1H),7.33(t,J＝5.7Hz,1H),6.60(s,1H),6.38(dd,J＝8.5,1.8Hz,1H),5.92(s,1H),4.61(d,J＝6.0Hz,2H),4.12–3.97(m,1H),2.81(s,3H),2.66(s,3H),2.43(s,3H),2.26–2.14(m,5H),1.84(tt,J＝14.1,7.2Hz,2H),0.71(t,J＝7.3Hz,6H).m/z(M+H+):409.25.
Step 2.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (64)
Compound 64a (102.0mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), acrylic acid (21.3mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(500MHz,CDCl3)δ12.55(s,1H),7.71(s,1H),7.42(d,J＝8.3Hz,1H),7.32(s,1H),6.85(d,J＝8.1Hz,1H),6.25(d,J＝16.7Hz,1H),6.04(dd,J＝16.3,10.5Hz,1H),5.91(s,1H),5.37(d,J＝10.1Hz,1H),4.59(d,J＝4.5Hz,2H),4.24–4.02(m,1H),3.31(s,3H),2.69(s,3H),2.40(s,3H),2.25–2.16(m,2H),2.15(s,3H),1.92(dt,J＝19.6,6.6Hz,2H),0.73(t,J＝6.4Hz,6H).HRMS(ESI)calcd for C27H34N4O3(M+H+):463.2704；found:463.2703.
Example 65
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methylbut-2-amino) -1- (pent-3-yl) -1H-indole-3-carboxamide (65)
Figure BDA0003027517040000281
The acrylic acid was replaced with butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 64, step 2, to give a white solid.1H NMR(400MHz,CDCl3)δ12.33(s,1H),7.77(s,1H),7.42(d,J＝8.7Hz,1H),7.31(t,J＝5.4Hz,1H),6.97(d,J＝8.6Hz,1H),5.93(s,1H),4.61(d,J＝5.8Hz,2H),4.23–4.00(m,1H),3.28(s,2H),2.42(s,3H),2.19(s,5H),2.07(s,1H),1.90(dd,J＝16.4,9.4Hz,3H),1.59(s,2H),0.85–0.66(m,6H).m/z(M+H+):475.27；HRMS(ESI)calcd for C28H34N4O3(M+H+):475.2704；found:475.2705.
Example 66
5- (2-cyano-N-methylacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (66)
Figure BDA0003027517040000282
Acrylic acid was replaced with cyanoacetic acid, and the remaining required starting materials, reagents and preparation were the same as in example 64, step 2, to give a white solid.1H NMR(400MHz,CDCl3)δ12.03(s,1H),7.81(d,J＝1.4Hz,1H),7.51(dd,J＝15.9,7.1Hz,2H),6.95(d,J＝8.7Hz,1H),5.96(s,1H),4.63(d,J＝5.6Hz,2H),4.15(ddd,J＝15.3,10.0,4.9Hz,1H),3.28(s,3H),2.73(s,3H),2.39(s,3H),2.24(s,3H),2.22–2.12(m,2H),1.95(dt,J＝21.3,7.1Hz,2H),0.74(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C27H33N5O3(M+H+):476.2656；found:476.2657.
Example 67
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (4- (dimethylamino) -N-methylbutan-2-amino) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (67)
Figure BDA0003027517040000283
The acrylic acid was changed to 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in example 64, step 2, to give a white solid.1H NMR(400MHz,CDCl3)δ12.19(s,1H),7.72(s,1H),7.52(s,1H),7.43(d,J＝8.6Hz,1H),6.95–6.82(m,2H),6.07(d,J＝15.1Hz,1H),5.89(s,1H),4.53(d,J＝4.0Hz,2H),4.22–4.02(m,1H),3.32(s,3H),2.69(s,3H),2.34(s,3H),2.24(s,6H),2.18(s,5H),1.99–1.89(m,2H),0.76(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C30H41N5O3(M+H+):520.3282；found:520.3279.
Example 68
8-acrylamido-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (68)
Figure BDA0003027517040000284
Step 1.2-methyl-6-nitro-1H-indole-3-carbaldehyde (68b)
Compound 56a was replaced with compound 68a, and the remaining required starting materials, reagents and preparation were the same as in step 1 of example 56 to give a brown solid.1H NMR(500MHz,DMSO-d6)δ10.12(s,1H),8.25(s,1H),8.18(d,J＝8.7Hz,1H),8.05(d,J＝8.7Hz,1H),2.77(s,3H).m/z(M+H+):205.05.
Step 2.2-methyl-6-nitro-1- (pentyl-3-yl) -1H-indole-3-carbaldehyde (68c)
The compound 56b was replaced with the compound 68a, and the remaining required starting materials, reagents and preparation were the same as in example 56, step 2, to give a tan solid.1H NMR(500MHz,CDCl3)δ10.25(s,1H),8.46(s,1H),8.41(d,J＝8.6Hz,1H),8.15(d,J＝8.7Hz,1H),4.28(qd,J＝8.4,3.6Hz,1H),2.80(s,3H),2.37–2.19(m,2H),2.14–1.99(m,2H),0.81(t,J＝6.9Hz,6H).m/z(M+H+):275.13.
Step 3.2-methyl-6-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid (68d)
Compound 56c was replaced with compound 68c and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 56 to give a white solid.1H NMR(500MHz,CDCl3)δ8.46(s,1H),8.38(d,J＝8.9Hz,1H),8.15(dd,J＝8.9,1.9Hz,1H),4.31(tt,J＝10.2,5.0Hz,1H),2.90(s,3H),2.34–2.24(m,2H),2.11–2.04(m,2H),0.79(t,J＝7.3Hz,6H).m/z(M+H+):291.13.
Step 4.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxamide (68e)
The other required raw materials, reagents and preparation methods of the compound 56d are changed into the compound 68dStep 4 in example 56 gave a yellow solid.1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.36(s,1H),8.02(s,1H),7.97–7.80(m,2H),5.89(s,1H),4.31(d,J＝5.1Hz,3H),2.62(s,3H),2.27(s,3H),2.12(s,5H),2.01–1.92(m,2H),0.66(t,J＝7.2Hz,6H).m/z(M+H+):425.21.
Step 5.6-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (68f)
Compound 56e was replaced with compound 68e, and the remaining required starting materials, reagents and preparation were the same as in example 56, step 5 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),7.41(dd,J＝11.4,6.9Hz,2H),6.75(s,1H),6.43(d,J＝8.4Hz,1H),5.89(s,1H),4.80(s,2H),4.29(d,J＝5.5Hz,2H),4.07(dd,J＝10.1,5.2Hz,1H),2.52(s,3H),2.26(s,3H),2.18–1.99(m,5H),1.87–1.75(m,2H),0.63(t,J＝7.2Hz,6H).m/z(M+H+):395.24.
Step 6.6-acrylamido-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (68)
Compound 68f (100mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), acrylic acid (20.9mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.73–11.50(m,1H),10.13(s,1H),8.27(s,1H),7.71–7.59(m,2H),7.26–7.17(m,1H),6.46(dd,J＝16.9,10.1Hz,1H),6.26(dd,J＝16.9,2.1Hz,1H),5.89(s,1H),5.74(dd,J＝10.0,2.1Hz,1H),4.32(d,J＝5.4Hz,2H),4.18(td,J＝10.0,4.8Hz,1H),2.58(s,3H),2.28(s,3H),2.13(s,5H),1.94–1.84(m,2H),0.64(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C26H32N4O3(M+H+):449.2547；found:449.2546.
Example 69
6- (but-2-enylamino) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (69)
Figure BDA0003027517040000291
The acrylic acid was replaced with crotonic acid, and the remaining required raw materials, reagents and preparation method were the same as in step 6 of example 68 to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),9.95(s,1H),8.24(s,1H),7.67–7.61(m,2H),7.18(d,J＝8.6Hz,1H),6.78(dq,J＝13.8,6.8Hz,1H),6.13(d,J＝15.2Hz,1H),5.91(s,1H),4.31(d,J＝5.4Hz,2H),4.21–4.12(m,1H),2.56(s,3H),2.27(s,3H),2.17–2.07(m,5H),1.92–1.82(m,5H),0.63(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C27H34N4O3(M+H+):463.2704；found:463.2702.
Example 70
6- (but-2-Enylamide) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (70)
Figure BDA0003027517040000292
The acrylic acid was replaced with butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 68, step 6, to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.52(s,1H),8.08(s,1H),7.71–7.61(m,2H),7.22(d,J＝8.6Hz,1H),5.89(s,1H),4.30(d,J＝5.4Hz,2H),4.22–4.10(m,1H),2.57(s,3H),2.26(s,3H),2.16–1.97(m,8H),1.93–1.80(m,2H),0.62(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C27H32N4O3(M+H+):461.2547；found:461.2547.
Example 71
6- (2-Chloroacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (71)
Figure BDA0003027517040000293
Example 61 was repeated except for the required starting materials, reagents and preparation method by replacing compound 56f with compound 68f to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.26(s,1H),8.11(s,1H),7.70–7.62(m,2H),7.17(d,J＝8.6Hz,1H),5.89(s,1H),4.31(d,J＝5.3Hz,2H),4.26(s,2H),4.22–4.13(m,1H),2.57(s,3H),2.27(s,3H),2.17–2.06(m,5H),1.95–1.84(m,2H),0.63(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C25H31N4O3Cl(M+H+):471.2157；found:471,2159.
Example 72
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (5- (dimethylamino) pent-3-enylamino) -2-methyl-1- (pentan-3-yl) -1H-indole-3-carboxamide (72)
Figure BDA0003027517040000294
Acrylic acid was replaced with 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 6 of example 68 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),10.03(s,1H),8.28(s,1H),7.65(dd,J＝13.0,7.0Hz,2H),7.18(d,J＝8.6Hz,1H),6.72(dt,J＝15.3,5.9Hz,1H),6.27(d,J＝15.4Hz,1H),5.89(s,1H),4.31(d,J＝5.4Hz,2H),4.25–4.10(m,1H),3.06(d,J＝5.7Hz,2H),2.57(s,3H),2.27(s,3H),2.18(s,6H),2.15–2.06(m,5H),1.93–1.83(m,2H),0.63(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C29H39N5O3(M+H+):506.3126；found:506.3122.
Example 73
6- (2-Cyanoacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (73)
Figure BDA0003027517040000301
The acrylic acid was replaced with cyanoacetic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 6 of example 68 to obtain a white solid.1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.26(s,1H),8.07(s,1H),7.67(t,J＝8.1Hz,2H),7.11(d,J＝8.7Hz,1H),5.90(s,1H),4.31(d,J＝5.3Hz,2H),4.24–4.11(m,1H),3.89(s,2H),2.57(s,3H),2.27(s,3H),2.18–2.03(m,5H),1.94–1.83(m,2H),0.63(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C26H31N5O3(M+H+):462.2500；found:462.2500.
Example 74
6- (1-cyanocyclopropane-1-carboxamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (74)
Figure BDA0003027517040000302
Acrylic acid was replaced with 1-cyanocyclopropane-1-carboxylic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 6 of example 68, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),9.93(d,J＝5.8Hz,1H),7.94(d,J＝3.8Hz,1H),7.67(s,2H),7.31(d,J＝6.4Hz,1H),5.90(d,J＝5.6Hz,1H),4.32(s,2H),4.17(d,J＝4.5Hz,1H),3.36(s,3H),2.58(d,J＝5.4Hz,3H),2.28(d,J＝6.1Hz,3H),2.13(d,J＝5.9Hz,5H),1.88(dd,J＝12.5,6.3Hz,2H),1.73–1.63(m,4H),0.63(d,J＝6.5Hz,6H).HRMS(ESI)calcd for C28H33N5O3(M+H+):488.2656；found:488.2657.
Example 75
6- (2-cyano-2-methylpropionamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (75)
Figure BDA0003027517040000303
Acrylic acid was replaced with 2-cyano-2-methylpropanoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 6 of example 68, to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.61(s,1H),9.90(s,1H),8.01(s,1H),7.71–7.61(m,2H),7.33(d,J＝8.6Hz,1H),5.90(s,1H),4.32(d,J＝5.0Hz,2H),4.17(d,J＝4.8Hz,1H),2.57(s,3H),2.27(s,3H),2.12(s,5H),1.94–1.84(m,3H),1.67(s,6H),0.64(t,J＝7.1Hz,6H).HRMS(ESI)calcd for C28H35N5O3(M+H+):490.2813；found:490.2813.
Example 76
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (76)
Figure BDA0003027517040000304
Step 1.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6- (methylamino) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (76a)
Compound 68f (2.15g,5.45mmol), paraformaldehyde (490mg,5.45mmol), and sodium methoxide (1.17g,21.80mmol) were dissolved in 40mL of anhydrous methanol and reacted overnight at 45 ℃ under nitrogen protection. The reaction was returned to room temperature, sodium borohydride (414.4mg,10.9mmol) was added under ice-bath conditions, the ice-bath was removed and the reaction was stirred at room temperature for 2 hours. After the reaction is finished, concentrating the reaction solution under reduced pressure, adding ethyl acetate and a water layer, extracting a water phase by using ethyl acetate, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by using column chromatography to obtain a white solid.1H NMR(500MHz,CDCl3)δ13.12(s,1H),7.60(d,J＝8.5Hz,1H),7.33(t,J＝5.7Hz,1H),6.60(s,1H),6.38(dd,J＝8.5,1.8Hz,1H),5.92(s,1H),4.61(d,J＝6.0Hz,2H),4.12–3.97(m,1H),2.81(s,3H),2.66(s,3H),2.43(s,3H),2.26–2.14(m,5H),1.84(tt,J＝14.1,7.2Hz,2H),0.71(t,J＝7.3Hz,6H).m/z(M+H+):409.25.
Step 2.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (76)
Compound 76a (102.0mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), acrylic acid (20.9mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(500MHz,CDCl3)δ12.67(s,1H),7.86(d,J＝8.4Hz,1H),7.39(s,1H),7.21(s,1H),6.86(d,J＝8.1Hz,1H),6.32(dd,J＝16.9,1.7Hz,1H),6.05–5.97(m,1H),5.95(s,1H),5.43(d,J＝10.5Hz,1H),4.62(d,J＝5.5Hz,2H),4.19–4.06(m,1H),3.37(s,3H),2.71(s,3H),2.45(s,3H),2.20(s,3H),2.14–2.04(m,2H),1.90(dd,J＝13.0,6.6Hz,2H),0.72(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C27H34N4O3(M+H+):463.2704；found:463.2709.
Example 77
6- (2-cyano-N-methylacetamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (77)
Figure BDA0003027517040000311
The acrylic acid was replaced with cyanoacetic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 2 of example 76 to obtain a white solid.1H NMR(500MHz,CDCl3)δ12.31(s,1H),7.93(d,J＝8.4Hz,1H),7.33(dd,J＝12.8,7.1Hz,2H),6.90–6.82(m,1H),5.97(s,1H),4.62(d,J＝5.9Hz,2H),4.19–4.09(m,1H),3.32(s,3H),3.17(s,2H),2.71(s,3H),2.45(s,3H),2.22(s,3H),2.19–2.06(m,2H),1.95(dd,J＝13.3,6.7Hz,2H),0.73(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C27H33N5O3(M+H+):476.2656；found:476.2659.
Example 78
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6- (N-methylbut-2-amino) -1- (pent-3-yl) -1H-indole-3-carboxamide (78)
Figure BDA0003027517040000312
The acrylic acid was replaced with butynoic acid, and the remaining required starting materials, reagents and preparation were the same as in example 76, step 2 to give a white solid.1H NMR(400MHz,CDCl3)δ12.33(s,1H),7.77(s,1H),7.42(d,J＝8.7Hz,1H),7.31(t,J＝5.4Hz,1H),6.97(d,J＝8.6Hz,1H),5.93(s,1H),4.61(d,J＝5.8Hz,2H),4.23–4.00(m,1H),3.28(s,3H),2.42(s,3H),2.19(m,5H),2.07(s,1H),1.90(m,J＝16.4,9.4Hz,2H),1.59(s,3H),0.85–0.66(m,6H).HRMS(ESI)calcd for C28H34N4O3(M+H+):475.2704；found:475.2701.
Example 79
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (4- (dimethylamino) -N-methylbut-2-enylamino) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (79)
Figure BDA0003027517040000313
The acrylic acid was changed to 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in example 76, step 2, to give a white solid.1H NMR(500MHz,CDCl3)δ12.34(s,1H),7.88(d,J＝8.4Hz,1H),7.40(s,1H),7.22(s,1H),6.88(dd,J＝16.7,7.5Hz,2H),5.96(s,1H),5.87(d,J＝15.1Hz,1H),4.63(d,J＝5.8Hz,2H),4.19–4.08(m,1H),3.38(s,3H),2.92(d,J＝6.2Hz,2H),2.72(s,3H),2.45(s,3H),2.22(s,3H),2.17(s,6H),2.09(dd,J＝14.3,9.0Hz,2H),1.94–1.86(m,2H),0.73(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C27H35N5O4S(M+H+):526.2483；found:526.2483.
Example 80
6-acrylamido-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1-isopropyl-2-methyl-1H-indole-3-carboxamide (80)
Figure BDA0003027517040000314
Step 1.2-methyl-6-nitro-1- (propyl-3-yl) -1H-indole-3-carbaldehyde (80a)
Compound 68b (2.04g,10mmol), 2-bromopropane (3.66g,30mmol), cesium carbonate (8.14g,30mmol) was dissolved in 10mL of N, N-dimethylformamide and reacted overnight at 70 ℃ with tube sealing. After the reaction is finished, ethyl acetate and water are added for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration is carried out, filtrate is decompressed and concentrated, column chromatography purification is carried out, and brown yellow solid 80a 984.4mg is obtained, and the yield is 40.0%.1H NMR(400MHz,CDCl3)δ10.22(s,1H),8.47(d,J＝1.8Hz,1H),8.37(d,J＝8.8Hz,1H),8.15(dd,J＝8.8,2.0Hz,1H),4.85(dt,J＝14.1,7.1Hz,1H),2.81(s,3H),1.75(s,3H),1.73(s,3H).m/z(M+H+):247.10.
Step 2.2-methyl-6-nitro-1- (propyl-3-yl) -1H-indole-3-carboxylic acid (80b)
Compound 68c was replaced with compound 80a, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 56 to give a white solid.1H NMR(400MHz,DMSO)δ12.54(s,1H),8.51(s,1H),8.19(d,J＝8.8Hz,1H),8.04(d,J＝7.8Hz,1H),5.12–4.94(m,1H),2.87(s,3H),1.63(s,3H),1.61(s,3H).m/z(M+H+):263.10.
Step 3.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6-nitro-1- (propyl-3-yl) -1H-indole-3-carboxamide (80c)
Compound 68d was replaced with the remaining required starting materials, reagents and preparation procedures for compound 80b as in step 4 of example 56 to give a yellow solid.1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),8.48(d,J＝1.9Hz,1H),7.93(dd,J＝8.8,2.0Hz,2H),7.87(d,J＝8.9Hz,1H),5.89(s,1H),4.95(dt,J＝13.8,6.8Hz,1H),4.32(d,J＝5.2Hz,2H),2.66(s,3H),2.26(s,3H),2.12(s,3H),1.59(d,J＝7.0Hz,6H).m/z(M+H+):397.18.
Step 4.6-amino-N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (propyl-3-yl) -1H-indole-3-carboxamide (80d)
Compound 68e was replaced with compound 80c, and the remaining desired starting materials, reagents and preparation were the same as in example 56, step 5, to give a white solid.1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),7.41–7.35(m,2H),6.79(d,J＝1.2Hz,1H),6.43(dd,J＝8.5,1.8Hz,1H),5.89(s,1H),4.80(s,2H),4.62(hept,J＝6.9Hz,1H),4.30(d,J＝5.6Hz,2H),2.55(s,3H),2.26(s,3H),2.12(s,3H),1.50(d,J＝7.0Hz,6H).m/z(M+H+):367.21.
Step 5.6- (2-Cyanoacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (80)
Compound 80d (91.8mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), cyanoacetic acid (21.3mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.12(s,1H),8.30(s,1H),7.65(d,J＝8.6Hz,1H),7.59(t,J＝5.3Hz,1H),7.21(dd,J＝8.6,1.3Hz,1H),6.46(dd,J＝16.9,10.1Hz,1H),6.27(dd,J＝16.9,1.8Hz,1H),5.89(s,1H),5.75(dd,J＝10.1,1.8Hz,1H),4.73(dt,J＝13.9,6.9Hz,1H),4.31(d,J＝5.4Hz,2H),2.60(s,3H),2.27(s,3H),2.12(s,3H),1.54(t,J＝7.4Hz,6H).HRMS(ESI)calcd for C24H28N4O3(M+H+):421.2234；found:421.2234.
Example 81
6- (2-Cyanoacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1-isopropyl-2-methyl-1H-indole-3-carboxamide (81)
Figure BDA0003027517040000321
The acrylic acid was replaced with cyanoacetic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 5 of example 80 to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.27(s,1H),8.09(d,J＝1.2Hz,1H),7.66(d,J＝8.6Hz,1H),7.62(t,J＝5.4Hz,1H),7.11(dd,J＝8.6,1.6Hz,1H),5.89(s,1H),4.78–4.68(m,1H),4.31(d,J＝5.4Hz,2H),3.91(s,2H),2.60(s,3H),2.26(s,3H),2.12(s,3H),1.54(d,J＝7.0Hz,6H).HRMS(ESI)calcd for C24H27N5O3(M+H+):434.2187；found:434.2186.
Example 82
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (4- (dimethylamino) but-2-enylamino) -1-isopropyl-2-methyl-1H-indole-3-carboxamide (82)
Figure BDA0003027517040000322
Acrylic acid was replaced with 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 5 of example 80 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.62(s,1H),10.72(s,1H),8.37(s,1H),7.65(d,J＝8.7Hz,1H),7.61(t,J＝5.4Hz,1H),7.37–7.29(m,1H),6.88–6.79(m,1H),6.61(d,J＝15.3Hz,1H),5.89(s,1H),4.72(dt,J＝13.8,6.9Hz,1H),4.31(d,J＝5.3Hz,2H),3.88(d,J＝6.9Hz,2H),2.72(s,6H),2.60(s,3H),2.26(s,3H),2.13(s,3H),1.54(d,J＝6.9Hz,6H).HRMS(ESI)calcd for C27H35N5O3(M+H+):478.2813；found:478.2811.
Example 83
6- (2-Chloroacetamido) -N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1-isopropyl-2-methyl-1H-indole-3-carboxamide (83)
Figure BDA0003027517040000323
Compound 56f was replaced with compound 80d, and the remaining desired starting materials, reagents and preparation were the same as in example 61 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),10.25(s,1H),8.13(s,1H),7.64(d,J＝8.6Hz,1H),7.58(t,J＝5.3Hz,1H),7.15(dd,J＝8.6,1.5Hz,1H),5.87(s,1H),4.71(dt,J＝14.0,6.9Hz,1H),4.29(d,J＝5.4Hz,2H),4.25(s,2H),2.58(s,3H),2.24(s,3H),2.10(s,3H),1.52(d,J＝6.9Hz,6H).HRMS(ESI)calcd for C23H27N4O3Cl(M+H+):443.1844；found:443.1845.
Example 84
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6- (N-methacrylamido) -1- (propyl-3-yl) -1H-indole-3-carboxamide (84)
Figure BDA0003027517040000324
Step 1.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-6- (methylamino) -1- (propyl-3-yl) -1H-indole-3-carboxamide (84a)
Compound 80d (2.0g,5.45mmol), paraformaldehyde (490mg,5.45mmol), and sodium methoxide (1.17g,21.80mmol) were dissolved in 40mL of anhydrous methanol and reacted overnight at 45 ℃ under nitrogen protection. The reaction was returned to room temperature, sodium borohydride (414.4mg,10.9mmol) was added under ice-bath conditions, the ice-bath was removed and the reaction was stirred at room temperature for 2 hours. After the reaction is finished, concentrating the reaction solution under reduced pressure, adding ethyl acetate and a water layer, extracting a water phase by using ethyl acetate, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by using column chromatography to obtain a white solid.1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),7.44(d,J＝8.6Hz,1H),7.40(t,J＝5.5Hz,1H),6.59(d,J＝1.5Hz,1H),6.44(dd,J＝8.6,1.9Hz,1H),5.89(s,1H),5.38(q,J＝5.0Hz,1H),4.68(dt,J＝13.9,6.9Hz,1H),4.30(d,J＝5.6Hz,2H),2.72(d,J＝5.1Hz,3H),2.57(s,3H),2.26(s,3H),2.12(s,3H),1.52(d,J＝7.0Hz,6H).m/z(M+H+):381.22.
Step 2.N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-5- (N-methacrylamido) -1- (propyl-3-yl) -1H-indole-3-carboxamide (84)
Compound 84a (95.0mg,0.25mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), acrylic acid (21.3mg,0.29mmol) and stirred at room temperature overnight. After the reaction is finished, washing the mixture with water and saturated sodium chloride solution, drying the mixture with anhydrous sodium sulfate, filtering the dried mixture, concentrating the filtrate under reduced pressure, and purifying the filtrate by column chromatography to obtain a white solid.1H NMR(500MHz,CDCl3)δ12.18(s,1H),7.84(d,J＝8.4Hz,1H),7.35(s,1H),7.25(s,1H),6.34(d,J＝16.7Hz,1H),6.04(dd,J＝16.7,10.4Hz,1H),5.94(s,1H),5.44(d,J＝10.4Hz,1H),4.71(dt,J＝13.8,6.9Hz,1H),4.61(d,J＝5.6Hz,2H),3.38(s,3H),2.74(s,3H),2.44(s,3H),2.20(s,3H),1.58(d,J＝7.0Hz,6H).HRMS(ESI)calcd for C25H30N4O3(M+H+):435.2391；found:435.2391.
Example 85
N- (((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -6- (4- (dimethylamino) -N-methylbutan-2-amino) -2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxamide (85)
Figure BDA0003027517040000331
Acrylic acid was replaced with 4- (dimethylamino) but-2-enoic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 2 of example 84 to give a white solid.1H NMR(500MHz,CDCl3)δ12.41(s,1H),7.84(d,J＝8.4Hz,1H),7.37(t,J＝5.3Hz,1H),7.25(s,1H),5.95(s,1H),5.87(d,J＝15.2Hz,1H),4.70(dd,J＝13.9,6.9Hz,1H),4.61(d,J＝5.6Hz,2H),3.37(s,3H),2.92(d,J＝6.0Hz,2H),2.74(s,3H),2.43(s,3H),2.21(s,3H),2.15(s,6H),1.57(d,J＝6.9Hz,6H).HRMS(ESI)calcd for C28H37N5O3(M+H+):492.2896；found:492.2899.
Example 86
6- (2-cyano-N-methylacetamido) -N- ((4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -2-methyl-1- (propyl-3-yl) -1H-indole-3-carboxamide (86)
Figure BDA0003027517040000332
The acrylic acid was replaced with cyanoacetic acid, and the remaining required raw materials, reagents and preparation methods were the same as in step 2 of example 84 to obtain a white solid.1H NMR(500MHz,CDCl3)δ12.56(s,1H),7.90(d,J＝8.4Hz,1H),7.39–7.30(m,2H),6.85(d,J＝8.3Hz,1H),5.98(s,1H),4.74(dt,J＝13.9,6.9Hz,1H),4.61(d,J＝5.6Hz,2H),3.33(s,3H),3.19(s,2H),2.74(s,3H),2.44(s,3H),1.61(d,J＝6.9Hz,6H).HRMS(ESI)calcd for C28H37N5O3(M+H+):448.2270；found:448.2273.
Example 87
5- (Acrylamidomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (87)
Figure BDA0003027517040000333
Step 1.2-methyl-5-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid methyl ester (87a)
Compound 56d (1.45g,5mmol) and potassium carbonate (1.04g,7.5mmol) were dissolved in 5mL of N, N-dimethylformamide, and methyl iodide (1.02g,7mmol) was added dropwise under ice-bath conditions, and the reaction was allowed to return to room temperature overnight. After the reaction, ethyl acetate and water were added to separate layers, and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 1.37g of a white solid with a yield of 90.0％。1H NMR(400MHz,CDCl3)δ9.05(d,J＝2.2Hz,1H),8.06(dd,J＝9.1,2.3Hz,1H),7.54(d,J＝9.1Hz,1H),4.26(tt,J＝10.3,5.0Hz,1H),3.99(s,3H),2.84(s,3H),2.22(ddd,J＝14.4,10.4,7.3Hz,2H),2.05–1.98(m,2H),0.75(t,J＝7.4Hz,6H).m/z(M+H+):305.14.
Step 2.5-amino-2-methyl-1- (pent-3-yl) -1H-indole-3-carboxylic acid methyl ester (87b)
Compound 87a (3.04g,10mmol), palladium on carbon (304.0mg, 10% wt) was dissolved in methanol, evacuated, charged with hydrogen and reacted at room temperature overnight. After the reaction is finished, filtering is carried out, the filtrate is decompressed and concentrated, and column chromatography purification is carried out to obtain 2.60g of white solid with the yield of 94.9%.1H NMR(500MHz,CDCl3)δ7.49(s,1H),7.26(d,J＝8.5Hz,1H),6.58(d,J＝8.4Hz,1H),4.11(tt,J＝9.7,4.8Hz,1H),3.91(s,3H),3.59(s,2H),2.74(s,3H),2.26–2.13(m,2H),1.93–1.83(m,2H),0.72(t,J＝7.3Hz,6H).m/z(M+H+):275.17.
Step 3.5-iodo-2-methyl-1- (pent-3-yl) -1H-indole-3-carboxylic acid methyl ester (87c)
An aqueous solution of sodium nitrite (138.0mg,2mmol) and 3mL of dilute hydrochloric acid (5M) were gradually added dropwise to a dichloromethane solution of the compound 87b (274mg,1mmol) in this order under an ice salt bath, and after a reaction at a low temperature for 30 minutes, an aqueous solution of cuprous iodide (340mg, 1.5mmol) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction is finished, the pH is adjusted to be alkalescent by using a saturated sodium bicarbonate solution under the ice bath condition, dichloromethane and water are used for extraction, organic phases are combined, anhydrous sodium sulfate is used for drying, filtration is carried out, the filtrate is decompressed and concentrated, column chromatography purification is carried out, and colorless oily liquid 87c 230.0mg is obtained, and the yield is 60.0%.1H NMR(400MHz,CDCl3)δ8.49(d,J＝1.4Hz,1H),7.40(dd,J＝8.7,1.5Hz,1H),7.24(d,J＝8.7Hz,1H),4.21–4.12(m,1H),3.93(s,3H),2.77(s,3H),2.25–2.11(m,2H),1.91(ddd,J＝14.1,7.2,5.2Hz,2H),0.71(t,J＝7.4Hz,6H).m/z(M+H+):386.05.
Step 4.5-cyano-2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid methyl ester (87d)
Compound 87c (2.87g,7.45mmol), cuprous cyanide (1.67g,18.64mmol) was dissolved in 10mL of anhydrous DMF and stirred overnight at 150 ℃ under nitrogen. Reaction ofAfter the reaction is finished, 50mL of ammonia water is added to quench cuprous cyanide, ethyl acetate is added to separate layers, organic phases are combined, anhydrous sodium sulfate is dried and filtered, filtrate is concentrated under reduced pressure, and ethanol is recrystallized and purified to obtain white solid 87d 1.80g, and the yield is 85.1%.1H NMR(400MHz,CDCl3)δ8.51(s,1H),7.54(d,J＝8.6Hz,1H),7.39(dd,J＝8.6,1.4Hz,1H),4.23(tt,J＝10.3,5.0Hz,1H),3.96(s,3H),2.82(s,3H),2.20(ddq,J＝14.6,10.4,7.3Hz,2H),2.02–1.94(m,2H),0.74(t,J＝7.4Hz,6H).m/z(M+H+):285.15.
Step 5.5-cyano-2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid (87e)
Compound 67d (2.0g,7.0mmol) was dissolved in 20mL of methanol and 10mL of tetrahydrofuran, and 8mL of 5M sodium hydroxide solution was added and refluxed for 5 hours. After the reaction was completed, the reaction mixture was neutralized to acidity with dilute hydrochloric acid (2N)) under ice bath conditions, extracted with ethyl acetate and water, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 1.35g of a white solid with a yield of 71.5%.1H NMR(500MHz,DMSO-d6)δ12.52(s,1H),8.41(s,1H),7.83(d,J＝8.6Hz,1H),7.48(d,J＝8.5Hz,1H),4.35(tt,J＝10.5,5.2Hz,1H),2.77(s,3H),2.14(dq,J＝16.6,8.1,7.6Hz,2H),1.94(dd,J＝13.6,6.8Hz,2H),0.63(t,J＝7.2Hz,6H).m/z(M+H+):270.14.
Step 6.5-cyano-2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (87f)
Compound 87e (1.35g,5mmol) was dissolved in dichloromethane, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (2.85g,7.5mmol), N, N-diisopropylethylamine (1.94g,15.0mmol), 3-aminomethyl-4-methylsulfanyl-6-methylpyridin-2 (1H) -one (1.64g, 9.0mmol) were added and stirred at room temperature overnight. After the reaction, washing with water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain white solid 1.5g with a yield of 68.8%.1H NMR(400MHz,CDCl3)δ13.33(s,1H),8.13(s,1H),7.41(d,J＝8.6Hz,1H),7.27–7.20(m,2H),5.95(s,1H),4.61(d,J＝5.0Hz,2H),4.06(tt,J＝10.7,5.4Hz,1H),2.61(s,3H),2.41(s,3H),2.10(s,3H),2.10–1.98(m,2H),1.88–1.80(m,2H),0.61(t,J＝7.3Hz,6H).m/z(M+H+):437.19.
Step 7.5- (aminomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (87g)
Compound 87f (872.0mg,2mmol), Raney nickel (500mg), 2mL of aqueous ammonia were dissolved in 20mL of methanol and stirred overnight at room temperature under hydrogen protection. After the reaction, raney nickel was removed by filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain a white solid 87g704.0mg, with a yield of 80.0%.1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.51(t,J＝5.6Hz,1H),7.39(d,J＝8.3Hz,1H),6.96(d,J＝8.5Hz,1H),5.98(s,1H),5.01(s,2H),4.71(d,J＝5.5Hz,2H),4.13(dtd,J＝10.9,7.4,4.3Hz,1H),3.85(s,2H),2.73(s,3H),2.47(s,3H),2.21(s,5H),1.91(td,J＝8.3,7.9,3.6Hz,2H),0.71(t,J＝7.3Hz,6H).m/z(M+H+):441.22.
Step 8.5- (Acrylamidomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (87)
87g (105.6mg,0.24mmol) of the compound was dissolved in anhydrous dichloromethane, and acryloyl chloride (75.0mg,0.58mmol) and triethylamine (72mg,0.72mmol) were added thereto with stirring in an ice bath, and the mixture was stirred at room temperature overnight. After the reaction, washing with water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain white solid 40.0mg with a yield of 33.7%.1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.50(t,J＝5.6Hz,1H),7.73(s,1H),7.59(t,J＝4.7Hz,1H),7.52(d,J＝8.5Hz,1H),7.01(d,J＝8.5Hz,1H),6.29(dd,J＝17.1,10.1Hz,1H),6.18–6.06(m,2H),5.60(dd,J＝10.0,2.4Hz,1H),4.40(d,J＝5.9Hz,4H),4.16(dt,J＝10.9,5.6Hz,1H),2.58(s,3H),2.48(s,3H),2.19(s,3H),2.19–2.06(m,2H),1.86(ddd,J＝19.4,9.5,5.7Hz,2H),0.61(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C27H34N4O3S(M+H+):495.2352；found:495.2350.
Example 88
5- (but-2-aminomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentan-3-yl) -1H-indole-3-carboxamide (88)
Figure BDA0003027517040000341
87g (101.2mg,0.23mmol) of the compound was dissolved in methylene chloride, and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol) and crotonic acid (24.9mg,0.29mmol) were added thereto, and the mixture was stirred at room temperature overnight. After the reaction, water and saturated sodium chloride solution were used for washing after the reaction was completed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography to obtain 52.8mg of a white solid with a yield of 54.0%.1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),8.94(t,J＝5.9Hz,1H),7.69(s,1H),7.60(s,1H),7.50(d,J＝8.6Hz,1H),6.98(d,J＝8.5Hz,1H),6.13(s,1H),4.41(d,J＝4.8Hz,2H),4.32(d,J＝6.0Hz,2H),4.15(tt,J＝10.5,4.7Hz,1H),2.56(s,3H),2.19(s,3H),2.18–2.05(m,2H),1.95(s,3H),1.86(dt,J＝13.9,6.6Hz,2H),0.61(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C28H34N4O3S(M+H+):507.2352；found:507.2350.
Example 89
5- ((2-Chloroacetamido) methyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentan-3-yl) -1H-indole-3-carboxamide (89)
Figure BDA0003027517040000351
The acryloyl chloride was replaced with chloroacetyl chloride, and the remaining required starting materials, reagents and preparation were the same as in example 87, step 8, affording a white solid.1H NMR(400MHz,CDCl3)δ11.90(s,1H),7.82(s,1H),7.42(t,J＝7.8Hz,2H),7.01(s,1H),6.95(s,1H),5.99(s,1H),4.70(d,J＝5.4Hz,2H),4.46(d,J＝5.3Hz,2H),4.18–4.07(m,1H),3.99(s,2H),2.71(s,3H),2.48(s,3H),2.21(s,5H),1.91(dd,J＝12.6,6.9Hz,2H),0.70(t,J＝7.3Hz,6H).m/z(M+H+):517.20；HRMS(ESI)calcd for C26H33N4O3SCl(M+H+):517.1962；found:517.1961.
Example 90
6- (Acrylamidomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (90)
Figure BDA0003027517040000352
Step 1.2-methyl-6-nitro-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid methyl ester (90a)
Compound 56d was replaced with compound 68d, and the remaining desired starting materials, reagents and preparation were the same as in example 87, step 1 to give a yellow solid.1H NMR(400MHz,CDCl3)δ8.49–8.40(m,1H),8.24(d,J＝8.9Hz,1H),8.12(dd,J＝8.9,2.0Hz,1H),4.29(tt,J＝10.0,5.1Hz,1H),3.98(s,3H),2.86(s,3H),2.28(ddt,J＝14.5,10.6,7.3Hz,2H),2.09–2.03(m,2H),0.78(t,J＝7.4Hz,6H).m/z(M+H+):305.14.
Step 2.6-amino-2-methyl-1- (pent-3-yl) -1H-indole-3-carboxylic acid methyl ester (90b)
The compound 87a was replaced with the compound 90a, and the remaining required starting materials, reagents and preparation were the same as in 2 of example 87 to give a brown oily liquid.1H NMR(500MHz,CDCl3)δ7.91(d,J＝8.4Hz,1H),6.79(s,1H),6.64(dd,J＝8.4,2.1Hz,1H),4.10(tt,J＝10.4,4.9Hz,1H),3.90(d,J＝1.6Hz,3H),3.50(s,2H),2.73(s,3H),2.30–2.09(m,2H),1.87(dq,J＝13.8,6.9Hz,2H),0.72(t,J＝7.3Hz,6H).m/z(M+H+):275.17.
Step 3.6-iodo-2-methyl-1- (pent-3-yl) -1H-indole-3-carboxylic acid methyl ester (90b)
The compound 87b was replaced with the compound 90b, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 87 to give a colorless oily liquid.1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.5Hz,1H),7.80(s,1H),7.48–7.45(m,1H),4.15(dt,J＝10.5,5.3Hz,1H),3.92(s,3H),2.76(s,3H),2.19(ddd,J＝14.3,10.5,7.2Hz,2H),1.93(td,J＝7.1,5.0Hz,2H),0.73(t,J＝7.3Hz,6H).m/z(M+H+):386.05.
Step 4.6-cyano-2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid methyl ester (90d)
The compound 87c was replaced with the compound 90c, and the remaining required starting materials, reagents and preparation were the same as in step 4 of example 87 to give a white solid.1H NMR(400MHz,CDCl3)δ8.22(d,J＝8.4Hz,1H),7.79(s,1H),7.43(dd,J＝8.4,1.3Hz,1H),4.23(dt,J＝10.7,5.5Hz,1H),3.94(d,J＝1.1Hz,3H),2.82(s,3H),2.27–2.13(m,2H),2.03–1.96(m,2H),0.74(t,J＝7.3Hz,6H).m/z(M+H+):285.15.
Step 5.6-cyano-2-methyl-1- (pentyl-3-yl) -1H-indole-3-carboxylic acid (90e)
Compound 87d was replaced with compound 90d, and the remaining required starting materials, reagents and preparation were the same as in example 87, step 5, to give a white solid.1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.4Hz,1H),7.82(s,1H),7.48(dd,J＝8.3,1.3Hz,1H),4.27(tt,J＝10.4,5.1Hz,1H),2.87(s,3H),2.21(ddt,J＝14.6,10.4,7.3Hz,2H),2.03(ddd,J＝14.4,7.4,2.3Hz,2H),0.77(t,J＝7.4Hz,6H).m/z(M+H+):270.14.
Step 6.6-cyano-2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (90f)
The compound 87e was replaced with the compound 90e, and the remaining required starting materials, reagents and preparation were the same as in step 6 of example 87 to give a white solid.1H NMR(400MHz,CDCl3)δ13.17(s,1H),7.90(d,J＝8.3Hz,1H),7.76(s,1H),7.40(d,J＝5.7Hz,1H),7.23(d,J＝8.3Hz,1H),6.03(s,1H),4.70(d,J＝5.4Hz,2H),4.22–4.10(m,1H),2.73(s,3H),2.49(s,3H),2.14(d,J＝12.8Hz,5H),2.00–1.92(m,2H),0.70(t,J＝7.4Hz,6H).m/z(M+H+):437.19.
Step 7.6- (aminomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (90g)
The compound 87f was replaced with the compound 90f, and the remaining required starting materials, reagents and preparation were the same as in step 7 of example 87 to give a white solid.1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.66(d,J＝8.0Hz,1H),7.57(s,1H),7.00(s,1H),5.99(s,1H),4.62(s,2H),4.09(s,2H),4.04(s,1H),2.66(s,3H),2.46(s,3H),2.32(s,3H),2.18(d,J＝19.7Hz,2H),1.89–1.80(m,2H),0.57(t,J＝7.4Hz,6H).m/z(M+H+):441.22.
Step 8.6- (Acrylamidomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentyl-3-yl) -1H-indole-3-carboxamide (90)
90g (105.6mg,0.24mmol) of the compound was dissolved in anhydrous dichloromethane, and acryloyl chloride (75.0mg,0.58mmol) and triethylamine (72mg,0.72mmol) were added thereto with stirring in an ice bath, and the mixture was stirred at room temperature overnight. After the reaction, washing with water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain white solid 40.0mg with a yield of 33.7%.1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.59(t,J＝6.0Hz,1H),7.80–7.62(m,2H),7.47(s,1H),6.98(d,J＝8.2Hz,1H),6.29(dd,J＝17.1,10.1Hz,1H),6.19–6.00(m,2H),5.61(dd,J＝10.1,2.4Hz,1H),4.43(d,J＝5.9Hz,2H),4.39(d,J＝4.8Hz,2H),4.17(dt,J＝9.5,5.4Hz,1H),2.59(s,3H),2.48(s,3H),2.19(s,3H),2.14(d,J＝10.3Hz,2H),1.94–1.83(m,2H),0.63(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C27H34N4O3S(M+H+):495.2352；found:495.2353.
Example 91
7- (but-2-aminomethyl) -2-methyl-N- (((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentan-3-yl) -1H-indole-3-carboxamide (91)
Figure BDA0003027517040000361
90g (101.2mg,0.23mmol) of the compound was dissolved in methylene chloride, and 2- (7-aza-amine) was addedBenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.5mg,0.29mmol), N, N-diisopropylethylamine (75.0mg,0.58mmol), crotonic acid (24.9mg,0.29mmol), and stirred at room temperature overnight. After the reaction, washing with water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by column chromatography to obtain white solid 42.8mg with a yield of 36.8%.1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.99(t,J＝6.1Hz,1H),7.82–7.63(m,2H),7.44(s,1H),6.94(d,J＝8.3Hz,1H),6.13(s,1H),4.39(d,J＝4.8Hz,2H),4.35(d,J＝6.1Hz,2H),4.18(dq,J＝11.0,5.7,5.3Hz,1H),2.59(s,3H),2.48(s,3H),2.19(s,5H),1.95(s,3H),1.88(dt,J＝13.3,6.4Hz,2H),0.63(t,J＝7.2Hz,6H).HRMS(ESI)calcd for C28H34N4O3S(M+H+):507.2352；found:507.2352.
Example 92
6- ((2-Chloroacetamido) methyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (pentan-3-yl) -1H-indole-3-carboxamide (92)
Figure BDA0003027517040000362
The acryloyl chloride was replaced with chloroacetyl chloride, and the remaining required starting materials, reagents and preparation were the same as in step 8 of example 90 to give a white solid.1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.75(t,J＝5.6Hz,1H),7.79–7.60(m,2H),7.47(s,1H),6.98(d,J＝9.0Hz,1H),6.13(s,1H),4.39(d,J＝5.3Hz,4H),4.19(dd,J＝10.0,4.6Hz,1H),4.10(s,2H),2.59(s,3H),2.48(s,3H),2.19(s,3H),2.19–2.08(m,2H),1.94–1.83(m,2H),0.63(t,J＝7.3Hz,6H).HRMS(ESI)calcd for C26H33N4O3SCl(M+H+):517.1962；found:517.1960.
Example 93
5- (Acrylamidomethyl) -3- (ethyl (1-2- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (93)
Figure BDA0003027517040000363
Step 1.4- ((5-bromo-3- (methoxycarbonyl) -2-methylphenyl) amino) piperidine-1-carboxylic acid tert-butyl ester (93a)
The compound tetrahydro-2H-pyran-4-one was replaced with the compound N-tert-butoxycarbonyl-piperidone, and the remaining required starting materials, reagents and preparation were the same as in the first step of example 26 to give a white solid.1H NMR(400MHz,CDCl3)δ7.23(d,J＝2.0Hz,1H),6.83(d,J＝2.0Hz,1H),4.05(s,2H),3.87(s,3H),3.63(s,1H),3.45(d,J＝10.3Hz,1H),2.96(t,J＝12.5Hz,2H),2.21(s,3H),2.07–2.01(m,2H),1.47(s,9H),1.40–1.34(m,2H).m/z(M+H+):427.12.
Step 2.4- ((5-bromo-3- (methoxycarbonyl) -2-methylphenyl) (ethyl) amino) piperidine-1-carboxylic acid tert-butyl ester (93b)
Compound 26b was changed to 93a and the remaining required starting materials, reagents and preparation were the same as in step two of example 26.1H NMR(400MHz,CDCl3)δ7.65(d,J＝2.0Hz,1H),7.30(d,J＝2.1Hz,1H),3.97(t,J＝11.6Hz,2H),3.82(s,3H),2.97(q,J＝7.0Hz,2H),2.84–2.77(m,1H),2.63(t,J＝12.4Hz,2H),2.38(s,3H),1.68(d,J＝12.7Hz,2H),1.52–1.41(m,2H),1.39(s,9H),0.80(t,J＝7.0Hz,3H).m/z(M+H+):455.12.
Step 3.4- ((5-cyano-3- (methoxycarbonyl) -2-methylphenyl) (ethyl) amino) piperidine-1-carboxylic acid tert-butyl ester (93c)
Compound 26c was changed to 93b and the remaining required starting materials, reagents and preparation were the same as in step three of example 26.1H NMR(400MHz,CDCl3)δ7.86(d,J＝1.7Hz,1H),7.48(d,J＝1.8Hz,1H),4.05(d,J＝11.1Hz,2H),3.93(s,3H),3.07(q,J＝7.1Hz,2H),2.88(ddd,J＝11.0,7.3,3.7Hz,1H),2.69(t,J＝13.0Hz,2H),2.56(s,3H),1.72(d,J＝11.3Hz,2H),1.56–1.49(m,2H),1.45(s,9H),0.87(t,J＝7.0Hz,3H).m/z(M+H+):402.23.
Step 4.5-cyano-3- (ethyl (piperidin-4-yl) amino) -2-methylbenzoic acid methyl ester (93d)
Dissolving 93c (100mg,0.33mmol) in 4mL dichloromethane, adding 1mL trifluoroacetic acid, reacting for 3h, adding saturated sodium bicarbonate solution under ice bath, quenching, extracting with dichloromethane, spin-drying the organic layer, and performing column chromatography to obtain 60mg white solid.1H NMR(400MHz,CDCl3)δ7.89(d,J＝1.6Hz,1H),7.49(d,J＝1.7Hz,1H),6.24(s,1H),3.93(s,3H),3.47(s,1H),3.40(d,J＝12.7Hz,2H),3.10(q,J＝7.0Hz,2H),3.02(h,J＝4.2Hz,1H),2.88–2.74(m,2H),2.56(s,3H),2.06–1.90(m,4H),0.88(t,J＝7.0Hz,3H).m/z(M+H+):302.18.
Step 5.5-cyano-3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methylbenzoic acid methyl ester (93e)
93d (150mg,0.5mmol), 2,2, 2-trifluoromethylsulfonate (174mg,0.75mmol) and cesium carbonate (488.7g,1.5mmol) were dissolved in 50mL of DMF, stirred at 90 ℃ for 3h, after the reaction was completed, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by recrystallization from ethyl acetate to obtain 80mg of a white solid.1H NMR(400MHz,CDCl3)δ7.84(d,J＝1.7Hz,1H),7.46(d,J＝1.8Hz,1H),3.92(s,3H),3.08(q,J＝7.0Hz,2H),2.98–2.89(m,4H),2.76–2.70(m,1H),2.54(s,3H),2.32(td,J＝10.8,4.3Hz,2H),1.70(td,J＝10.2,9.7,3.8Hz,4H),0.86(t,J＝7.0Hz,3H).m/z(M+H+):384.18.
Step 6.5-cyano-3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methylbenzoic acid (93f)
Compound 1d was replaced with compound 93e, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(500MHz,CDCl3)δ8.00(s,1H),7.53(s,1H),3.17(d,J＝11.9Hz,4H),3.10(t,J＝7.1Hz,2H),2.89(s,1H),2.63–2.60(m,3H),2.57(s,1H),1.86(s,4H),0.90–0.87(m,3H).m/z(M+H+):370.17.
Step 7.5-cyano-3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio-2) -oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (93g)
Changing the compound 26e to a compound 93f, and the rest of the required raw materials and reagentsAnd the preparation method was the same as that of step five in example 34 to obtain a white solid.1H NMR(400MHz,CD3OD)δ7.54(d,J＝1.7Hz,1H),7.39(d,J＝1.6Hz,1H),6.27(s,1H),4.53(s,2H),3.17–3.08(m,4H),3.06–2.99(m,2H),2.96(dd,J＝9.3,3.3Hz,2H),2.81(ddd,J＝14.8,9.6,5.7Hz,1H),2.53(s,3H),2.38(s,3H),2.36–2.31(m,2H),2.29(s,3H),1.74–1.67(m,4H),0.86(t,J＝7.0Hz,3H).m/z(M+H+):536.22.
Step 8.5- (aminomethyl) -3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (93h)
Compound 26f was replaced with 93g, and the remaining desired starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,CD3OD)δ7.31(s,1H),7.10(s,1H),6.28(s,1H),4.52(s,2H),3.93(s,2H),3.13–3.04(m,3H),2.97(dd,J＝21.9,11.1Hz,5H),2.80(dd,J＝9.5,5.4Hz,1H),2.53(s,3H),2.31(d,J＝7.8Hz,8H),1.75–1.63(m,4H),0.85(t,J＝6.9Hz,3H).m/z(M+H+):440.25.
Step 9.5- (Acrylamidomethyl) -3- (Ethyl (1-2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (93)
The compound 34g was replaced with 93h, and the remaining required starting materials, reagents and preparation were the same as in example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.19(d,J＝1.8Hz,1H),7.03(d,J＝1.7Hz,1H),6.30–6.21(m,3H),5.69(dd,J＝9.5,2.6Hz,1H),4.53(s,2H),4.40(s,2H),3.11–3.00(m,4H),2.99–2.91(m,3H),2.83–2.77(m,1H),2.31(s,6H),1.69(dtd,J＝35.3,12.5,12.1,3.7Hz,5H),0.85(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C29H38F3N5O3S(M+H+):594.2647；found:594.2650.
Example 94
5- (Acrylamidomethyl) -3- (Ethyl (1- (2,2, 2-trifluoroethylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyranePyridin-3-yl) methyl) benzamide (94)
Figure BDA0003027517040000371
Step 1.5-cyano-3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) carboxamide (94a)
Conversion of 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one to 3- (aminomethyl) -6-methyl-4- ((methyl-d)3) Thio) pyridin-2 (1H) -one, Compound 26e was replaced with Compound 56f, and the remaining required starting materials, reagents and preparation were the same as in example 34, step five, to provide a white solid.1H NMR(400MHz,CDCl3)δ12.61(s,1H),7.36–7.31(m,2H),7.14(t,J＝5.4Hz,1H),6.04(s,1H),4.62(d,J＝5.2Hz,2H),3.06(q,J＝7.0Hz,2H),2.93(dd,J＝11.1,7.3Hz,4H),2.72(q,J＝7.5Hz,1H),2.39(s,3H),2.34–2.19(m,6H),1.72–1.66(m,4H),0.84(t,J＝7.0Hz,3H).m/z(M+H+):539.24.
Step 2.5- (aminomethyl) -3- (ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (94b)
Compound 26f was changed to compound 94a, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,CD3OD)δ7.37(s,1H),7.16(d,1H),6.30(s,1H),4.54(s,2H),4.09(s,2H),3.19–3.10(m,3H),3.05–2.95(m,5H),2.86–2.80(m,1H),2.36–2.31(m,8H),1.72(ddd,J＝22.7,9.9,3.7Hz,4H),0.88(t,J＝7.0Hz,3H).m/z(M+H+):543.27.
Step 3.5- (Acrylamidomethyl) -3- (Ethyl (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (94)
Changing compound 34g to compound 94b, and the other required raw materials, reagents and preparation methods are the same asExample 34, a white solid was obtained.1H NMR(400MHz,CD3OD)δ7.19(d,J＝1.8Hz,1H),7.03(d,J＝1.7Hz,1H),6.30–6.21(m,3H),5.69(dd,J＝9.5,2.6Hz,1H),4.53(s,2H),4.40(s,2H),3.11–3.00(m,4H),2.99–2.91(m,3H),2.83–2.77(m,1H),2.31(s,6H),1.69(dtd,J＝35.3,12.5,12.1,3.7Hz,5H),0.85(t,J＝6.9Hz,3H).HRMS(ESI)calcd for C29H35D3F3N5O3S(M+H+):597.2836；found:597.2833.
Example 95
5- (Acrylamidomethyl) -3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (95)
Figure BDA0003027517040000381
Step 1.5-cyano-3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methylbenzoic acid methyl ester (95a)
93d (90mg,0.3mmol), 2-iodopropane (76.5mg,0.45mmol), potassium carbonate (207g,1.5mmol) were dissolved in 20mL of acetonitrile, stirred at 80 ℃ for 3h, after completion of the reaction, filtered, the filtrate was concentrated under reduced pressure, and column chromatography gave 74mg of a white solid in 72% yield.1H NMR(400MHz,CDCl3)δ7.85(d,J＝1.7Hz,1H),7.48(d,J＝1.7Hz,1H),3.11(q,J＝7.0Hz,2H),2.93–2.87(m,2H),2.77–2.69(m,2H),2.56(s,3H),2.12(td,J＝11.5,2.7Hz,3H),1.81–1.66(m,4H),1.04(d,J＝6.5Hz,6H),0.87(t,J＝7.0Hz,3H).m/z(M+H+):344.23.
Step 2.5-cyano-3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methylbenzoic acid (95b)
Compound 1d was replaced with Compound 95a, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(400MHz,CDCl3)δ7.55(d,J＝11.7Hz,2H),3.51(td,J＝17.1,15.2,8.5Hz,3H),3.18–3.01(m,5H),2.50(s,3H),2.12–1.97(m,4H),1.39(s,3H),1.37(s,3H),0.91(t,J＝7.0Hz,3H).m/z(M+H+):330.21.
Step 3.5-cyano-3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (95c)
Compound 26e was replaced with compound 95b, and the remaining desired starting materials, reagents and preparation were the same as in step five of example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.63(s,1H),7.44(s,1H),6.29(s,1H),4.52(s,2H),3.46–3.32(m,3H),3.18–3.05(m,3H),2.96(d,J＝11.9Hz,2H),2.54(s,3H),2.41(s,3H),2.30(s,3H),1.99(dd,J＝21.9,7.8Hz,4H),1.32(d,J＝6.6Hz,7H),0.88(t,J＝7.0Hz,4H).m/z(M+H+):496.27.
Step 4.5- (aminomethyl) -3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (95d)
Compound 26f was changed to compound 95c, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,CD3OD)δ7.48(s,1H),7.20(s,1H),6.29(s,1H),4.53(s,2H),4.10(s,2H),3.51–3.38(m,3H),3.18–2.98(m,5H),2.54(s,3H),2.36(s,3H),2.30(s,3H),2.11(d,J＝14.9Hz,2H),1.96(t,J＝8.1Hz,2H),1.36(d,J＝6.6Hz,6H),0.89(t,J＝7.0Hz,3H).m/z(M+H+):500.30.
Step 5.5- (Acrylamidomethyl) -3- (Ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (95)
The compound 34g was replaced with the compound 95d, and the remaining required starting materials, reagents and preparation methods were the same as in example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.27(s,1H),7.08(s,1H),6.35–6.22(m,3H),5.70(dd,J＝10.0,2.1Hz,1H),4.53(s,2H),4.41(s,2H),3.56–3.42(m,3H),3.15–3.02(m,5H),2.55(s,3H),2.33(s,6H),2.04(dd,J＝44.3,13.2Hz,4H),1.37(s,6H),0.87(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C30H43N5O3S(M+H+):554.3087；found:554.3088.
Example 96
5- (Acrylamidomethyl) -3- (Ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (96)
Figure BDA0003027517040000382
Step 1.5-cyano-3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (96a)
Conversion of 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one to 3- (aminomethyl) -6-methyl-4- ((methyl-d)3) Thio) pyridin-2 (1H) -one, Compound 26e was replaced with Compound 95b, and the remaining required starting materials, reagents and preparation were the same as in example 34, step five, to provide a white solid.1H NMR(400MHz,CD3OD)δ7.64(d,J＝1.6Hz,1H),7.45(d,J＝1.5Hz,1H),6.29(s,1H),4.52(s,2H),3.53–3.42(m,3H),3.19–3.11(m,3H),3.06(s,2H),2.41(s,3H),2.30(s,3H),2.08–1.97(m,4H),1.35(d,J＝6.6Hz,6H),0.88(t,J＝7.0Hz,3H).m/z(M+H+):499.29.
Step 2.5- (aminomethyl) -3- (ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (96b)
Compound 26f was changed to compound 96a, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,CD3OD)δ7.48(s,1H),7.20(s,1H),6.28(s,1H),4.50(s,2H),4.10(s,2H),3.39–3.30(m,3H),3.13–3.03(m,5H),2.36(s,3H),2.30(s,3H),2.12–2.06(m,2H),1.98(t,J＝11.8Hz,2H),1.35(d,J＝6.6Hz,6H),0.88(t,J＝7.0Hz,3H).m/z(M+H+):503.32.
Step 3.5- (Acrylamidomethyl) -3- (Ethyl (1-isopropylpiperidin-4-yl) amino) -2-methyl-N- ((6-methyl-4- ((methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) Benzamide (96)
The compound 34g was replaced with the compound 96b, and the remaining required starting materials, reagents and preparation were the same as in example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.24(s,1H),7.07(s,1H),6.35–6.16(m,3H),5.67(dd,J＝10.0,1.9Hz,1H),4.50(s,2H),4.38(s,2H),3.47(tt,J＝20.9,9.6Hz,3H),3.13–2.92(m,5H),2.31(d,J＝8.4Hz,6H),2.06(d,J＝12.9Hz,2H),1.96(s,2H),1.35(s,3H),1.34(s,3H),0.85(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C30H40D3N5O3S(M+H+):557.3275；found:557.3272.
Example 97
5-Acrylamidomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (97)
Figure BDA0003027517040000391
Step 1.5-bromo-3- ((4, 4-difluorocyclohexyl) amino) -2-methylbenzoic acid methyl ester (97a)
The compound tetrahydro-2H-pyran-4-one was replaced with the compound 4, 4-difluorocyclohex-1-one, and the remaining required starting materials, reagents, and preparation were the same as in example 26, to give a white solid.1H NMR(400MHz,CDCl3)δ7.27(d,J＝1.9Hz,1H),6.84(d,J＝1.9Hz,1H),3.90(s,3H),3.64(s,1H),3.49–3.41(m,1H),2.25(s,3H),2.20–2.10(m,4H),2.02–1.87(m,2H),1.68–1.61(m,2H).m/z(M+H+):362.05.
Step 2.5-bromo-3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methylbenzoic acid methyl ester (97b)
Compound 26b was replaced with 97a and the remaining required starting materials, reagents and preparation were the same as in step two of example 26.1H NMR(400MHz,CDCl3)δ7.71(d,J＝3.0Hz,1H),7.36(d,J＝2.1Hz,1H),3.90(s,3H),3.04(q,J＝7.0Hz,2H),2.95–2.88(m,1H),2.44(s,3H),2.11–2.01(m,2H),1.83–1.65(m,6H),0.92–0.84(m,3H).m/z(M+H+):390.08.
Step 3.5-cyano-3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methylbenzoic acid methyl ester (97c)
Compound 26c was changed to 97b and the remaining required starting materials, reagents and preparation were the same as in step three of example 26.1H NMR(400MHz,CDCl3)δ7.88(d,J＝1.7Hz,1H),7.50(d,J＝1.8Hz,1H),3.94(s,3H),3.09(q,J＝7.0Hz,2H),2.98–2.90(m,1H),2.57(s,3H),2.13–2.02(m,2H),1.77(dtd,J＝22.2,12.3,11.0,6.5Hz,6H),0.89(t,J＝7.0Hz,3H).m/z(M+H+):337.16.
Step 4.5-cyano-3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methylbenzoic acid (97d)
Compound 1d was replaced with compound 97c, and the remaining required starting materials, reagents and preparation were the same as in example 1, step four, to give a white solid.1H NMR(400MHz,CD3OD)δ7.58(d,J＝1.6Hz,1H),7.54(d,J＝1.8Hz,1H),3.13(q,J＝7.0Hz,2H),3.09–3.02(m,1H),2.51(s,3H),2.08–1.98(m,2H),1.87–1.70(m,6H),0.90(t,J＝7.0Hz,3H).m/z(M+H+):323.15.
Step 5.5-cyano-3- (((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (97e)
Compound 26e was replaced with compound 97d, and the remaining desired starting materials, reagents and preparation were the same as in example 34, step five, affording a white solid. .1H NMR(400MHz,CD3OD)δ7.58(d,J＝1.8Hz,1H),7.42(d,J＝1.7Hz,1H),6.30(s,1H),4.55(s,2H),3.14(q,J＝6.9Hz,2H),3.08–3.00(m,1H),2.56(s,3H),2.41(s,3H),2.31(s,3H),2.06–2.00(m,2H),1.87–1.71(m,6H),0.89(t,J＝6.9Hz,3H).m/z(M+H+):489.21.
Step 6.5- (aminomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (97f)
Compound 26f was replaced with compound 97e, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,DMSO-d6)δ7.85(t,J＝4.6Hz,2H),7.42(s,1H),7.10(s,1H),6.10(s,1H),4.32(d,J＝4.5Hz,2H),3.92(s,2H),3.00(q,J＝7.2Hz,3H),2.46(s,3H),2.21(s,3H),2.18(s,3H),1.95(d,J＝11.4Hz,2H),1.82–1.72(m,4H),1.60(d,J＝11.7Hz,2H),0.80(t,J＝6.9Hz,3H).m/z(M+H+):493.24.
Step 7.5- (Acrylamidomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (97)
The compound 34g was replaced with the compound 96b, and the remaining required starting materials, reagents and preparation were the same as in example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.19(s,1H),7.03(s,1H),6.29–6.21(m,3H),5.67(dd,J＝9.5,2.6Hz,1H),4.52(s,2H),4.38(s,2H),3.10–3.02(m,3H),2.53(s,3H),2.31–2.28(m,6H),2.01–1.95(m,2H),1.78–1.63(m,6H),0.83(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C28H36F2N4O3S(M+H+):547.2436；found:547.2432.
Example 98
5- (Acrylamidomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (98)
Figure BDA0003027517040000401
Step 1.5-cyano-3- (((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (98a)
Conversion of 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one to 3- (aminomethyl) -6-methyl-4- ((methyl-d)3) Thio) pyridin-2 (1H) -one, Compound 26e was replaced with Compound 95b, and the remaining required starting materials, reagents and preparation were the same as in example 34, step five, to provide a white solid.1H NMR(400MHz,CD3OD)δ7.58(d,J＝1.7Hz,1H),7.42(d,J＝1.6Hz,1H),6.30(s,1H),4.54(s,2H),3.13(q,J＝7.0Hz,2H),3.10–3.04(m,1H),2.41(s,3H),2.32(s,3H),2.07–1.99(m,2H),1.85–1.71(m,6H),0.89(t,J＝7.0Hz,3H).m/z(M+H+):492.22.
Step 2.5- (aminomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (98b)
Compound 26f was replaced with compound 98a, and the remaining required starting materials, reagents and preparation were the same as in step six of example 28 to give a white solid.1H NMR(400MHz,CD3OD)δ7.42(s,1H),7.18(s,1H),6.30(s,1H),4.53(s,2H),4.11(s,2H),3.16–3.11(m,2H),3.09–3.04(m,1H),2.36(s,3H),2.32(s,3H),2.05–1.98(m,2H),1.87–1.71(m,6H),0.89(t,J＝6.9Hz,3H).m/z(M+H+):496.26.
Step 3.5- (Acrylamidomethyl) -3- ((4, 4-difluorocyclohexyl) (ethyl) amino) -2-methyl-N- ((6-methyl-4- (methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) benzamide (98)
The compound 34g was replaced with the compound 96b, and the remaining required starting materials, reagents and preparation were the same as in example 34 to give a white solid.1H NMR(400MHz,CD3OD)δ7.19(d,J＝1.8Hz,1H),7.02(d,J＝1.7Hz,1H),6.30–6.19(m,3H),5.73–5.63(m,1H),4.52(s,2H),4.38(s,2H),3.11–3.01(m,3H),2.29(s,6H),2.02–1.89(m,2H),1.84–1.66(m,6H),0.84(t,J＝7.0Hz,3H).HRMS(ESI)calcd for C28H33D3F2N4O3S(M+H+):550.2664；found:550.2663.
Example 99
(R) -5- (Acrylamidomethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (99)
Figure BDA0003027517040000402
Step 1. tert-butyl (R, E) -4- (1- ((3- (2-bromo-5-nitrophenyl) -4-methoxy-4-oxobut-2-en-2-yl) amino) ethyl) piperidine-1-carboxylate (99b)
Acetic acid (0.13mL,4.52mmol) was added dropwise to a solution of (R) -4- (1-aminoethyl) piperidine-1-carboxylic acid tert-butyl ester (793.6mg,3.48mmol) and 99a (550mg,1.74mmol) in ethanol and reacted at 85 ℃ overnight. After the reaction is finished, the white solid is obtained by decompressing, concentrating and column chromatography.1H NMR(500MHz,CDCl3)δ8.07(s,1H),7.96(dd,J＝8.7,2.6Hz,1H),7.77(d,J＝8.7Hz,1H),3.77(s,3H),3.75(dt,J＝12.3,7.1Hz,2H),3.63(dt,J＝7.6,6.9Hz,1H),3.43(dt,J＝12.3,7.1Hz,2H),2.53(s,2H),1.69(dd,J＝7.1,1.4Hz,3H),1.44(s,7H),1.18(dd,J＝6.8,1.5Hz,3H).m/z(M+H+):528.15.
Step 2.(R) -1- (1- (1- (1- (tert-butoxycarbonyl) piperidin-4-yl) ethyl) -2-methyl-5-nitro-1H-indole-3-carboxylic acid methyl ester (99c)
The compound 99b (126.11g,261.95mmol), sodium methoxide (21.23g,392.93mmol), 2-dicyclohexylphosphine-2 ',6' -diisopropoxybiphenyl (3.67g,7.86mmol) and Ruphos preconalyst (generation III) (4.38g,5.24mmol) were added to the 1, 4-dioxane solution, evacuated, charged with N2 and reacted at 100 ℃ overnight. After the reaction is finished, carrying out column chromatography by decompression concentration to obtain a white solid.1H NMR(500MHz,DMSO)δ8.86(s,1H),8.03(d,J＝9.1Hz,1H),7.96(d,J＝9.1Hz,1H),4.41–4.31(m,1H),4.07(s,1H),3.89(s,3H),3.77(s,1H),2.79(s,3H),2.40(q,J＝21.1,10.4Hz,1H),1.93(d,J＝15.4Hz,1H),1.60(d,J＝6.8Hz,3H),1.37(s,10H),1.17(t,J＝7.1Hz,1H),0.97(q,J＝20.8,12.1Hz,1H),0.84(d,J＝6.0Hz,1H),0.66(d,J＝12.2Hz,1H).m/z(M+H+):446.22.
Step 3.(R) -2-methyl-5-nitro-1- (1- (piperidin-4-yl) ethyl) -1H-indole-3-carboxylic acid methyl ester (99d)
Under ice-bath conditions, compound 99c (104.0g,259.67mmol) was added to 100mL of a 4M solution of hydrochloric acid in 1, 4-dioxane, the ice-bath was removed, and the mixture was stirred at room temperature. After the reaction is finished, adjusting the pH value to 7-8 under the ice bath condition, separating out white solid, carrying out suction filtration and drying to obtain white solid, and directly putting the white solid into the next step. M/z (M + H)+):346.17.
Step 4.(R) -2-methyl-5-nitro-1- (1- (1- (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxylic acid methyl ester (99e)
Compound 93d was replaced with compound 99d, and the remaining required starting materials, reagents and preparation were the same as in example 93, step five, to give a white solid.1H NMR(500MHz,DMSO-d6)δ8.86(s,1H),8.03(d,J＝9.2Hz,1H),7.98(d,J＝9.3Hz,1H),4.49–4.30(m,1H),4.17–3.99(m,1H),3.89(s,3H),3.31–3.23(m,1H),2.90(d,J＝12.6Hz,1H),2.79(s,3H),2.60(t,J＝11.3Hz,1H),2.07(m,J＝20.7,8.5Hz,1H),1.60(d,J＝4.7Hz,3H),1.51–1.34(m,1H),1.20–1.07(m,2H),0.81(t,J＝13.1Hz,1H).m/z(M+H+):428.17.
Step 5.(R) -5- (Acrylamidomethyl) -2-methyl-N- ((6-methyl-4- (methylthio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (99)
The compound 87a was replaced with the compound 99e, and the other required starting materials, reagents and preparation methods were the same as in example 87.1H NMR(500MHz,CDCl3)δ9.76(s,1H),8.12(t,J＝8.2Hz,1H),7.84(t,J＝9.2Hz,1H),7.41(d,J＝1.5Hz,1H),7.25(dd,J＝7.4,1.4Hz,1H),7.21(d,J＝7.4Hz,1H),6.41(q,J＝0.9Hz,1H),6.35(dd,J＝16.8,9.9Hz,1H),5.91(dd,J＝16.8,3.1Hz,1H),5.81(dd,J＝10.0,3.0Hz,1H),4.46–4.33(m,3H),4.24(dd,J＝12.5,8.2Hz,1H),4.00(m,1H),3.28(dd,J＝12.4,8.9Hz,1H),3.22(dd,J＝12.4,8.9Hz,1H),2.99(t,J＝7.1Hz,4H),2.51(d,J＝17.9Hz,5H),2.34(d,J＝1.0Hz,3H),1.95(m,1H),1.71(q,J＝7.1Hz,4H),1.33(dd,J＝6.8,1.4Hz,3H).HRMS(ESI)calcd for C31H38F3N5O3S(M+H+):618.2647；found:618.2645.
Example 100
(R) -5- (Acrylamidomethyl) -2-methyl-N- ((6-methyl-4- (methyl-d)3) Thio) -2-oxo-1, 2-dihydropyridin-3-yl) methyl) -1- (1- (1- (2,2, 2-trifluoroethyl) piperidin-4-yl) ethyl) -1H-indole-3-carboxamide (100)
Figure BDA0003027517040000411
Changing compound 87a to compound 99e and changing 3- (aminomethyl) -6-methyl-4- (methylthio) pyridin-2 (1H) -one to 3- (aminomethyl) -6-methyl-4- ((methyl-d)3) Thio) pyridin-2 (1H) -one, the remaining required starting materials, reagents and procedure for preparation were the same as in example 87.1H NMR(500MHz,CDCl3)δ9.62(s,1H),8.20(t,J＝8.3Hz,1H),7.84(t,J＝9.2Hz,1H),7.41(d,J＝1.5Hz,1H),7.25(dd,J＝7.4,1.4Hz,1H),7.21(d,J＝7.4Hz,1H),6.42(q,J＝0.9Hz,1H),6.35(dd,J＝16.8,9.9Hz,1H),5.91(dd,J＝16.8,3.1Hz,1H),5.81(dd,J＝10.0,3.0Hz,1H),4.46–4.39(m,1H),4.42–4.31(m,2H),4.24(dd,J＝12.5,8.2Hz,1H),4.02(m,1H),3.34–3.24(m,1H),3.26–3.16(m,1H),2.99(t,J＝7.1Hz,4H),2.52(s,2H),2.34(d,J＝0.9Hz,3H),1.95(m,1H),1.71(q,J＝7.1Hz,4H),1.34(dd,J＝6.8,1.5Hz,3H).HRMS(ESI)calcd for C31H35D3F3N5O3S(M+H+):621.2836；found:621.2833.
Biological activity assay
The first test example: molecular level histone methyltransferase EZH2 activity inhibition assay
Histone methyltransferase EZH2 enzyme activity inhibition IC50Evaluation experiment
The purpose of the test is as follows:
determination of the inhibitory Activity of the Compounds of the invention on EZH2 protein
The test reagents and apparatus are shown in Table 1.
TABLE 1 test reagent and instrument for molecular level histone methyltransferase EZH2 activity inhibition experiment
Figure BDA0003027517040000412
Positive control compound: tazemetostat (EPZ6438) purchased from Selleck, cat # S7128; GSK126 was purchased from Selleck, cat # S7061, a control compound above, formulated in DMSO as 10mM stock, stored at-20 ℃.
The instrument comprises the following steps: TECAN spark enzyme-linked immunosorbent assay (ELISA) instrument
Test method
HTRF method:
Figure BDA0003027517040000413
the technique combines two techniques of Fluorescence Resonance Energy Transfer (FRET) and Time Resolved Fluorescence (TRF). This technique uses XL665 as a Donor (Donor) and a chelate label of Eu element having a cryptate structure, and is based on Fluorescence Resonance Energy Transfer (FRET) between the Donor and an acceptor (second fluorescent label) of Eu cryptate. When the two fluorophores are close due to the interaction of the biomolecules, part of the energy captured by the cryptate is released when excited, and the emission wavelength is 620 nm; another part of the energy is transferred to the acceptor (acceptor) with an emission wavelength of 665 nm. The emission at 665nm is generated only by FRET by the donor (donor). Therefore, when biomolecules interact, there are two excitation lights 620nm and 665 nm; when there is no interaction, there is only 620nm excitation light.
Enzyme reaction:
1. enzyme reaction buffer (1 ×): 50mM Tris-HCl, pH 8.8,10mM NaCl,4mM DTT,4mM MgCl2,0.01％Tween20.
2. Compounds used in the experiment, EZH2 enzyme and substrate were diluted to the desired concentrations with the above buffers to prepare 384-well plates, and reagents were added to the 384-well plates in the following order: add 4. mu.L of inhibitor (2.5X) to each well, then add 2. mu.L of EZH2 enzyme (5X), incubate for 5min at room temperature, add 4. mu. L H3(1-50) K27me 1-biotin peptide/SAM mixture (2.5X). Cover the reaction kettle and incubate for 4h at room temperature in the dark.
Each experiment is provided with two pairs of holes, and a positive control group and a negative control group
And (3) detection:
1. prepare 2 times of final concentration provided by anti-H3K27 me3-Eu (K) product instruction and 100nM SA-XL665 with 1 XDeprotection Buffer, mix them into mixed solution (2X), add 10. mu.L of mixed solution into each well, incubate for 60min at room temperature in the dark.
2. The cover was opened and the emitted wavelengths of light at 620nm and 665nm were detected with an HTRF compatible reader.
And (4) analyzing results:
the fluorescence intensity value of the sample well measured at 665nm was F1, the fluorescence intensity value of the sample well measured at 620nm was F2, the fluorescence intensity value of the positive control at 665nm was a1, the fluorescence intensity value at 620nm was a2, the fluorescence intensity value of the negative control at 665nm was B1, and the fluorescence intensity value at 620nm was B2.
The inhibition ratio is [1- (F1/F2-B1/B2)/(A1/A2-B1/B2) ] x 100%
Respectively drawing competitive inhibition curves by using Graphpad prism software with the inhibition rate (%) as the ordinate and the compound concentration as the abscissa, and calculating the concentration (IC) at which the binding rate of the compound and EZH2 protein is 50% by using the obtained regression equation50)。
The results of the in vitro enzymatic activity of the compound inhibitor EZH2 of the present invention are shown in Table 2 below, wherein the letter A indicates IC50The value is less than or equal to 50 nM; letter B denotes 50nM < IC50Value of
Less than or equal to 150 nM; letter C denotes 150nM < IC50The value is less than or equal to 450 nM; letter C denotes 450nM < IC50The value is less than or equal to 1350 nM.
TABLE 2 level of inhibition of histidine methyltransferase EZH2 enzyme activity by compounds
Example numbering EZH2 Example numbering EZH2 Example numbering EZH2
1 A 35 A 69 D
2 A 36 A 70 D
3 A 37 A 71 B
4 A 38 A 72 B
5 A 39 A 73 B
6 A 40 A 74 B
7 A 41 A 75 C
8 A 42 A 76 B
9 B 43 A 77 C
10 A 44 A 78 A
11 C 45 A 79 B
12 A 46 A 80 D
13 A 47 A 81 D
14 B 48 A 82 C
15 C 49 A 83 D
16 A 50 A 84 D
17 B 51 A 85 D
18 C 52 A 86 C
19 C 53 A 87 A
20 C 54 A 88 A
21 B 55 A 89 A
22 D 56 A 90 A
23 D 57 A 91 A
24 C 58 A 92 A
25 B 59 A 93 A
26 A 60 A 94 A
27 A 61 A 95 A
28 A 62 D 96 A
29 B 63 C 97 A
30 A 64 C 98 A
31 A 65 B 99 A
32 A 66 B 100 A
33 A 67 B EPZ6438 A
34 A 68 C
Test example two: cell-level histone methyltransferase EZH2 activity inhibition assay
The purpose of the test is as follows: the effect of the test compounds on the proliferative effect of Pfeiffer, KARPAS422 cells was evaluated.
Observation indexes are as follows: inhibition rate of compound on proliferation of each cell
The detection method comprises the following steps: CCK-8 cell counting kit (Dojindo)
The test principle is as follows:
cell growth can be manifested as an increase in the number of cells and an increase in the volume of cells, which is usually within a certain range, and can be increased by continued division. CCK-8 color reagent can reduce tetrazolium salt WST-8[2- (2-methoxy-4-nitrophenyl) -3- (4-nitro-phenyl) -5- (2, 4-disulpho-phenyl) -2H-tetrazolium to produce water-soluble yellow product, formazan, by using dehydrogenase which the cell has, the number of living cells is proportional to the number of formazan dyes produced, and the number of living cells can be detected in cell proliferation and toxicity analysis experiments.
Acting time: 6Days
Reagents, consumables and instruments:
the experimental water is distilled water produced by national medicine group; all the reagents are purchased from chemical reagents of national medicine group, Inc.; the full-wavelength enzyme standard instrument for the experimental reading plate is a product of Molecular Device company, and the model is as follows: SpectraMax 190.
Compound preparation:
the compound was centrifuged at 12000g for 5min, DMSO was added to make a 10mM stock solution, vortexed uniformly and sonicated for 10min for use, and stored at-40 deg.C (compounds with special storage requirements were modified as appropriate). Compounds were diluted from stock solutions to the tested concentrations with physiological saline (DMSO concentration in the system did not exceed 0.5%) at the time of testing.
The test method comprises the following steps:
inhibition of Pfeiffer and KARPAS422 cell proliferation by compounds was detected using the CCK-8 cell counting kit (Dojindo). The method comprises the following specific steps: pfeiffer, KARPAS422 cells in logarithmic growth phase were seeded at appropriate density in 96-well culture plates at 190 μ L per well, after overnight incubation, compounds at different concentrations were added for 6Days, and a solvent control group (negative control) was set. After the compound acts on 6Days of cells, the influence of the compound on cell proliferation is detected by a CCK-8 cell counting kit (Dojindo), 20 mu L of CCK-8 reagent is added into each hole, the hole is placed in an incubator at 37 ℃ for 2 to 4 hours, and then a SpectraMax 190 reading is carried out by a full-wavelength microplate reader, and the measurement wavelength is 450 nm.
The inhibition (%) of the tumor cell growth by the compound was calculated using the following formula:
inhibition (%) - (OD control well-OD administration well)/OD control well X100%
Calculating corresponding IC according to the inhibition rate of each concentration50。
The results of the activity measurements of the inhibitors of the present invention on the inhibition of Pfeiffer and KARPAS422 cell activity are shown in Table 3 below, wherein the letter A indicates IC50The value is less than or equal to 50 nM; letter B denotes 50nM < IC50The value is less than or equal to 150 nM; letter C denotes 150nM < IC50The value is less than or equal to 450 nM; letter D denotes 450nM < IC50The value is less than or equal to 1350 nM; letter E denotes IC50Value of>1350nM。
TABLE 3 measurement of Pfeiffer, KARPAS422 cell Activity inhibition by Compounds
Example numbering KARPAS422 IC50 Pfeiffer IC50 Example numbering KARPAS422 IC50 Pfeiffer IC50
8 D A 44 B A
12 A A 45 C B
13 E C 46 C A
26 D B 47 A A
27 D B 48 B A
28 B C 49 B A
30 A A 50 C C
31 D B 52 A A
34 B A 53 C C
37 B B 54 D C
38 B A 87 D A
39 B A 88 D A
40 B A 89 B A
41 C C EPZ6438 C A
Test example three: compound 34, 37 and EPZ6438 cell proliferation inhibition assay
The purpose of the test is as follows: evaluation of the Effect of test Compounds on the proliferative Effect of different cell lines
Test cell lines: pfeiffer, KAPRAS-422, RL, SU-DHL-10, HT, KAPRAS-1106P, WLL-1, SU-DHL-2, U2932, DB, WSU-DLCL2, OPM-2
The rest of the test examples are the same as the second test example
The results of the assays for inhibition of various cellular activities by compounds 34, 37 of the invention and the positive control EPZ6438 are shown in figure 1.
As shown in FIG. 1, compounds 34 and 37 have strong cell killing ability on Pfeiffer, KAPRAS-422, RL, SU-DHL-10, HT and other cell lines, and are stronger than positive control drug EPZ 6438. Among them, compound 34 had potent cell proliferation inhibitory effect on HT cell line containing WT EZH2, but positive control EPZ6438 did not, indicating that EZH2 covalent inhibitor 34 has stronger cell proliferation inhibitory ability and wider cell proliferation inhibitory range than EPZ 6438.
Test example four: covalent verification test for Compound 34 and Compound 37-SAM Competition test
The experimental basis is as follows:
the positive control EPZ6438 is a non-covalent reversible inhibitor of EZH2 and is in a competitive relationship with the cofactor SAM, the IC of which is measured in the enzyme activity assay50The values decreased with increasing SAM concentration (Proc Natl Acad Sci USA.2013, 110, 7922-. The Cys663 of the target EZH2 protein is developed into a covalent inhibitor which can generate Michael addition reaction with the protein to generate covalent bonds and irreversibly occupy a drug binding pocket, so the covalent inhibitor does not have a competitive relationship with a cofactor SAM, and is particularly represented as enzyme activity IC of the covalent inhibitor50The value does not decrease with increasing SAM concentration.
As shown in FIG. 2, IC's for Compounds 34 and 3750As SAM concentration increased and remained unchanged, it exhibited completely different kinetic properties from EPZ6438, thereby verifying that compounds 34 and 37 are covalent irreversible inhibitors of EZH 2.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (10)

  1. An EZH2 covalent irreversible inhibitor comprising a compound having a structure represented by formula (i) or formula (ii) or a salt thereof
    Figure FDA0003027517030000011
    Wherein:
    R1is selected from
    Figure FDA0003027517030000012
    RaSelected from hydrogen, halogen or Rd；
    Rb、RcEach independently selected from hydrogen or Rd；
    X is selected from halogen;
    Rdis selected from C1-C6Alkyl and substituted C1-C6Alkyl radical, C2-C6Alkenyl and substituted C2-C6Alkenyl radical, C2-C6Alkynyl and substituted C2-C6Alkynyl, C3-C6Cycloalkyl and substituted C3-C6Cycloalkyl, 4-12 membered heterocyclyl and substituted 4-12 membered heterocyclyl;
    or Ra、RbTogether with the carbon atom to which they are attached form a 2-5 membered heterocyclyl or substituted 2-5 membered heterocyclyl containing 0 or 1 additional heteroatoms;
    R2selected from hydrogen, C1-C6Alkyl and deuterated or substituted C thereof1-C6Alkyl and deuterate thereof, C3-C6Cycloalkyl or substituted C3-C6Cycloalkyl radical, C3-C6Heterocycloalkyl or substituted C3-C6A heterocycloalkyl group;
    y is selected from CH and N;
    q is selected from NR3R4、OR3Or S (O)mNR3R4；
    R3Selected from hydrogen, C1-C6Alkyl or substituted C1-C6Alkyl radical, C2-C6Alkenyl or substituted C2-C6Alkenyl radical, C2-C6Alkynyl or substituted C2-C6Alkynyl, C3-C6Cycloalkyl or substituted C3-C6Cycloalkyl, 4-12 membered heterocyclyl or substituted 4-12 membered heterocyclyl;
    R4selected from hydrogen, C1-C6Alkyl or substituted C1-C6Alkyl radical, C3-C6Cycloalkyl or substituted C3-C6A cycloalkyl group;
    R5selected from hydrogen, C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C6Cycloalkyl radical, C3-C6Cycloalkyl, halogen, hydroxy, cyano, trifluoromethyl or heterocycloalkyl;
    R6、R12each independently selected from hydrogen and its isotope, C1-C6Alkyl radical, C3-C6Cycloalkyl or C3-C6A heterocycloalkyl group;
    or R5、R6Together with the carbon atom to which they are attached and the nitrogen atom form a 5-12 membered heterocyclic group or a substituted 5-12 membered heterocyclic group containing 0 or 1 additional heteroatom;
    R7、R8、R10each independently selected from hydrogen, deuterium, halogen, C1-C3Alkyl or C3-C6A cycloalkyl group;
    R9、R11each independently selected from hydrogen, halogen or Re；
    ReSelected from the group consisting of substituted: c1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkylamino radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl or 4-12 membered heterocyclyl and deuterated versions thereof;
    or R9、R10Together with the carbon atom to which they are attached form a 5-12 membered heterocyclyl or substituted 5-12 membered heterocyclyl containing 0 or 1 additional heteroatoms;
    m is 0, 1 or 2;
    n is 0, 1,2, or 3.
  2. 2. The EZH2 covalent irreversible inhibitor of claim 1 wherein R isdThe substituents in (a) are one or more-J-T groups;
    Ra、Rbthe substituent in the substituted 2-to 5-membered heterocyclic group in (A) is one or more-J1-T1A group;
    R3c substituted in1-C6Alkyl, substituted C2-C6Alkenyl, substituted C2-C6Alkynyl, substituted C3-C6The substituents in cycloalkyl, substituted 4-12 membered heterocycloalkyl are one or more-J-T groups;
    R5、R6wherein the substituents in the substituted 5-to 12-membered heterocyclic group are one or more-J1-T1A group;
    R9、R10wherein the substituents in the substituted 5-to 12-membered heterocyclic group are one or more-J1-T1A group;
    wherein:
    j is selected from a bond or substituted C1-C6An alkylene group;
    t is selected from hydrogen, halogen, cyano, hydroxy, -NRfRg、-C(O)Rf、-ORf、-C(O)O-Rf、-C(O)NRfRg、-NRfC(O)Rg、-NRhC(O)NRfRg、-NRfC(O)ORhOr Ri；
    Rf、Rg、RhEach independently selected from hydrogen or Rj，RjIs selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl,5-or 6-membered heteroaryl or aryl, RjIs covered by one or more-J1-T1Substituted by groups;
    or Rf、RgTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms, said 4-12 membered heterocyclyl being substituted with one or more-J1-T1Substituted by groups;
    Riis selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heteroaryl or aryl, RiIs covered by one or more-J1-T1Substituted by groups;
    J1selected from a bond or substituted C1-C6An alkylene group;
    T1selected from hydrogen, halogen, cyano, hydroxy, -NRkRl、-C(O)Rk、-ORk、-C(O)O-Rk、-C(O)NRkRl、-NRkC(O)Rl、-NRoC(O)NRkRl、-NRkC(O)ORoOr Rp；
    Rk、Rl、RoEach independently selected from hydrogen or Rq，RqSelected from the group consisting of substituted: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-or 6-membered heteroaryl or aryl;
    or Rk、RlTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms, said heterocyclyl being optionally selected from halogen, hydroxy, oxo, C1-C6Alkyl, ORx、-NRxRy、-C(O)Rx、-O(CH2)nORxSubstituted with one or more groups of (a);
    Rpis selected from C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-to 6-membered heteroaryl, or aryl;
    Rx、Ryeach independently selected from hydrogen or Rz，RzSelected from the following groups or substituted groups: c1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C3-C6Cycloalkyl, 4-12 membered heterocyclyl, 5-or 6-membered heteroaryl or aryl; rzSubstituted by one or more of halogen, hydroxy, 5-or 6-membered heteroaryl or aryl or substituted 5-or 6-membered heteroaryl or aryl,
    or Rx、RyTogether with the N atom to which they are attached form a 4-12 membered heterocyclyl containing 0 or 1 additional heteroatoms;
    or-J1-T1Is an oxo group;
    or-J-T is oxo.
  3. 3. The EZH2 covalent irreversible inhibitor of claim 2 wherein J or J1C substituted in1-C6The substituents in the alkylene group are independently selected from halogen, cyano, hydroxy or C1-C6One or more groups of alkoxy groups.
  4. 4. The EZH2 covalent irreversible inhibitor of claim 2 wherein the additional heteroatom is C, N, O, S or P;
    Rqthe substituent in (1) is halogen, hydroxyl, 5-or 6-membered heteroaryl or aryl or substituted 5-or 6-membered heteroaryl or aryl.
  5. 5. The EZH2 covalent irreversible inhibitor of claim 3 wherein the substituent in the substituted 5-or 6-membered heteroaryl or aryl is C1-C6One or more of alkyl, hydroxyl or oxo.
  6. 6. The EZH2 covalent irreversible inhibitor of claim 1 which isCharacterized in that R2C substituted in1-C6Alkyl and deuterated and substituted C thereof3-C6Cycloalkyl, substituted C3-C6The substituents in the heterocycloalkyl radicals being halogen, cyano, hydroxy, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkyl, amino, C1-C6Alkylamino, di-C1-C6Alkylamino or 4-12 membered heterocyclyl;
    R4c substituted in1-C6Alkyl, substituted C3-C6The substituents in cycloalkyl being halogen, cyano, hydroxy, amino or C3-C5One or more groups of cycloalkyl;
    Rewherein the substituent is deuterium atom, halogen, cyano, hydroxy, C1-C6Alkoxy radical, C1-C6Alkylthio radical, C1-C6Alkyl, -OC (O) -, amino, C1-C6Alkylamino, di-C1-C6One or more groups of alkylamino or 4-12 membered heterocyclyl;
    halogen is F, Br, Cl or I.
  7. 7. The EZH2 covalent irreversible inhibitor according to any one of claims 1 to 6, wherein the EZH2 covalent irreversible inhibitor is any one of the compounds numbered 1 to 100:
    Figure FDA0003027517030000021
    Figure FDA0003027517030000031
    Figure FDA0003027517030000041
    Figure FDA0003027517030000051
  8. 8. use of the EZH2 covalent irreversible inhibitor of any one of claims 1 to 7 for the manufacture of a medicament for inhibiting EZH2 or for the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.
  9. 9. The use according to claim 8, wherein the medicament comprises an effective amount of a compound of formula (i) or (ii) or a salt or mixture thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  10. 10. Use according to claim 8, characterized in that the tumor or cancer is lymphoma, leukemia, breast cancer, lung cancer, prostate cancer, ovarian cancer, liver cancer, melanoma, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, rectal cancer, stomach cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, bone cancer, kidney cancer, bladder cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, glioma, glioblastoma, head and neck tumor or myeloma.
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