CN115160310B - Alternanthene derivatives as CDK2/Topo I inhibitors, preparation method thereof and antitumor application thereof - Google Patents

Alternanthene derivatives as CDK2/Topo I inhibitors, preparation method thereof and antitumor application thereof Download PDF

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CN115160310B
CN115160310B CN202210505333.4A CN202210505333A CN115160310B CN 115160310 B CN115160310 B CN 115160310B CN 202210505333 A CN202210505333 A CN 202210505333A CN 115160310 B CN115160310 B CN 115160310B
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CN115160310A (en
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赵庆春
黄耀广
许子华
刘文武
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General Hospital of Shenyang Military Region
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Abstract

The invention provides a white leaf rattan derivative serving as a CDK2/Topo I inhibitor, a preparation method thereof and an anti-tumor application, and the synthetic method is simple and mild; part of the derivative is capable of inhibiting CDK2 and Topo I simultaneously; 3. the antitumor cell proliferation activity of the derivative is obviously enhanced. The compound provided by the invention has an important role in tumor treatment as a lead compound.

Description

Alternanthene derivatives as CDK2/Topo I inhibitors, preparation method thereof and antitumor application thereof
Technical Field
The invention relates to the technical field of synthesis and medical application of organic compounds, in particular to the technical field of preparation of anticancer drugs, and specifically relates to a sinomenine derivative serving as a CDK2/Topo I inhibitor, a preparation method thereof and application of targeting CDK2 and Topo I in antitumor.
Background
In recent years, the discovery of molecular targets and the continued understanding of cellular function have helped improve the main therapeutic class of small molecule chemotherapeutic drugs as cancer treatments. The implications from natural products have been the injection of new energy for the development of small molecule chemotherapeutics.
Natural products are a research hotspot due to their high bioavailability and low toxicity. The characteristic structure of the indoloquinoline alkaloid is a four-ring nucleus formed by fusing indole and quinoline, and a representative natural product is sinomenine extracted from roots of the western non-shrubs sanguinolentena. Most studies of sinomenine target DNA, i.e. by binding to the DNA itself or the DNA-enzyme complex to form a stable target inhibitor complex, affect DNA replication, transcription and translation, ultimately leading to tumor cell death.
The cell division cycle controls cell proliferation, and its checkpoints ensure genomic stability. Unregulated progression in the cell cycle is a hallmark of cancer. Members of the cyclin dependent protein kinase (CDK) family are identified as serine/threonine specific protein kinases that drive the cell cycle upon activation of expression of a cyclin chaperone. Among them, CDK2 has been most studied, and deregulation thereof, leading to uncontrolled cell proliferation, is a precursor to cancer. In the late G1 phase, CDK2/cyclin E phosphorylates retinoblastoma (Rb) protein fully, initiates S phase of the cell cycle, and CDK2/cyclin a then maintains phosphorylation of Rb protein, ensuring cell cycle progression and promoting S/G2 transition. CDK2 is a core regulator and functional component of the apoptotic pathway in addition to controlling the cell cycle.
Studies have shown that CDK2 and Topo I are upstream and downstream targets for each other, and Topo I regulates supercoiled templates by binding and catalyzing the cleavage of DNA strands in the nucleus to control the topological state of DNA. Topo I inhibitors act by stabilizing Topo I-DNA complexes to inhibit Topo I activity or to directly disrupt DNA as DNA damaging agents. It is well known that the DNA damage response triggers phosphorylation of the checkpoint kinase ATM. ATM activates CHK2 by inhibiting CDC25 phosphatase and downstream CDK2 to prevent the cell cycle. Interestingly, inactivation of CDK2 directly leads to DNA damage and stimulates DDR. CDK2 appears to play a different role depending on the cellular state. Thus, the link between Topo I and CDK2 is complex and intimate. There is currently no report on a CDK2/Topo I dual-target inhibitor, and it is a meaningful attempt to study both dual-target drugs.
Disclosure of Invention
The invention provides a sinomenine derivative serving as a CDK2/Topo I inhibitor, a preparation method thereof and an anti-tumor application, and aims to provide a novel sinomenine derivative with CDK2/Topo I double-target inhibition activity and indicate the application thereof in the anti-tumor.
The technical scheme is as follows: an antineoplastic derivative of sinomenine or its pharmaceutically acceptable salt has a structure shown in formula I:
Figure BDA0003635730810000021
wherein R is 1 Aliphatic amines, such as morpholine, piperazine, piperidine, pyrrole, homopiperazine or the products of ethylene, propylene, butylene and amino groups substituted by boc; r is R 2 Aromatic groups such as pyridine, benzene, pyrazole rings substituted with substituents which are amido, alkoxy or halogen; x is N or O and extended S.
The following compounds, or pharmaceutically acceptable salts thereof, are selected from:
Figure BDA0003635730810000022
Figure BDA0003635730810000031
a process for the preparation of a compound comprising the steps of:
(1) Chloridizing phenoxyacetic acid by thionyl chloride to obtain an acyl chloride compound 2; then amide condensation is carried out on the compound 2 and 2-amino-5-bromobenzoic acid to obtain a compound 5-1; then, polyphosphoric acid is used as a dehydrating agent to react for 2 hours at 130 ℃ to obtain a compound 6-1; then reflux chloridizing by phosphorus oxychloride to obtain an intermediate compound 7-1;
or 2-amino-5-bromobenzoic acid is subjected to amide condensation by chloroacetyl chloride to obtain a compound 4; nucleophilic substitution with 5-10 times of aniline to obtain compound 5-2; then, polyphosphoric acid is used as a dehydrating agent to react for 2 hours at 130 ℃ to obtain a compound 6-2; then reflux chloridizing by phosphorus oxychloride to obtain an intermediate compound 7-2;
(2) Nucleophilic substitution is carried out on 11 sites of two intermediate compounds 7-1 or 7-2 by using aliphatic amine, and Suzuki coupling is carried out on the obtained product with boric acid ester or boric acid after crude treatment to obtain a compound ZLHQ-1b, a compound ZLHQ-1d, a compound ZLHQ-1f, a compound ZLHQ-5j, a compound ZLHQ-5k, a compound ZLHQ-5l, a compound ZLHQ-5n, a compound ZLHQ-1a, a compound ZLHQ-1c, a compound ZLHQ-2a, a compound ZLHQ-2b, a compound ZLHQ-2c, a compound ZLHQ-3d, a compound ZLHQ-3b, a compound ZLHQ-3c, a compound ZLHQ-3d, a compound ZLHQ-4a, a compound ZLHQ-4b, a compound ZLHQ-4c, a compound ZHQ-4 d or a compound with a protecting group of 4 Hq-4;
(3) Removing Boc in an acidic solvent to obtain a compound ZLHQ-5c, a compound ZLHQ-5h, a compound ZLHQ-5a, a compound ZLHQ-5b, a compound ZLHQ-5d, a compound ZLHQ-5e, a compound ZHQ-5 f, a compound ZLHQ-5g, a compound ZHQ-5 i or a compound ZHQ-1 e.
Preferably, the borate or boric acid in step (2) is an intermediate compound 10, 4-pyridineboronic acid, 3-pyridineboronic acid, 2-fluoropyridine-5-boronic acid, 1-methyl-4-pyrazoleboronic acid pinacol ester, (1H-pyrazol-4-yl) boronic acid, 3-methoxyphenylboronic acid, 4-hydroxymethylphenylboronic acid, benzo-1, 4-dioxane-6-boronic acid, benzo [ d ] [1,3] dioxol-5-ylboronic acid or 2-hydroxymethylphenylboronic acid.
Preferably, the intermediate compound 10 is prepared by amide condensation of 5g of 2-amino-4-bromopyridine and acyl chloride in THF solvent to obtain a product 9, and then carrying out a uterine reaction, and protecting for 12h at 110 ℃ with nitrogen gas.
Preferably, the acyl chloride is cyclopropaneacyl chloride, cyclobutyl chloride, cyclopentanoyl chloride, cyclohexanoyl chloride or phenylpropionyl chloride.
Preferably, the fatty amine in step (2) is 3- (4-morpholino) -1-propylamine, morpholine, N-dimethylethane-1, 2-diamine, (S) -pyrrolidin-3-ol, tetrahydropyrrole, 4-t-butoxycarbonylaminopiperidine, propanolamine, N-Boc-1, 3-propanediamine, N-Boc-piperazine, N-Boc-homopiperazine, 3-t-butoxycarbonylaminopiperidine, (R) -3-t-butoxycarbonylaminopyrrolidine, (S) -3-t-butoxycarbonylaminopyrrolidine, N-Boc-ethylenediamine or N-Boc-1, 4-butanediamine.
Preferably, the acidic solvent in the step (3) is a mixture of dichloromethane and trifluoroacetic acid in equal volume ratio or ethyl acetate hydrochloride.
The compound or the pharmaceutically usable salt thereof is applied to the preparation of antitumor drugs.
The use of a compound of the invention or a pharmaceutically acceptable salt thereof for the preparation of a CDKs inhibitor or a TopoI inhibitor.
Compared with the prior art, the invention has the following remarkable characteristics: 1. the synthesis method is simple and mild; 2. part of the derivative is capable of inhibiting CDK2 and Topo I simultaneously; 3. the antitumor cell proliferation activity of the derivative is obviously enhanced. Therefore, the compounds have important roles in tumor treatment as lead compounds.
Drawings
FIG. 1 is a schematic diagram of a process for preparing key intermediate compound 7;
FIG. 2 is a schematic diagram of a process for preparing key intermediate compound 10;
FIG. 3 is an evaluation of Topo I activity by the compound ZLHQ-5f.
Detailed Description
The invention is described in more detail below with reference to the drawings accompanying the specification. The solvents used in the present invention are commercially available chemical or analytical pure. The structure of the compound was determined by Nuclear Magnetic Resonance (NMR). NMR was performed using Bruker AVANCE-300/500 NMR, and the solvent was CDCl 3 、DMSO-d 6 Or heavy water, internal standard TMS.
Example 1 intermediate compound 7
As shown in fig. 1, in fig. 1 (a), thionyl chloride, chloroform, was refluxed for 4 hours; (b) 2-amino-5-bromobenzoic acid, acetonitrile, for 2 hours at room temperature; (c) Chloroacetyl chloride, 1, 4-dioxane, DMF, room temperature, 6 hours; (d) Aniline, acetonitrile, backFlow, 24 hours; (e) polyphosphoric acid, 130 ℃, for 2 hours; (f) phosphorus oxychloride, refluxing, 2 hours. (g) various acid chlorides, pyridine, THF,2h; (h) (BPIN) 2 ，Pd(dppf)Cl 2 Potassium acetate, 1, 4-dioxane, N 2 And (3) 12h. Specifically, 5g of commercial phenoxyacetic acid is dissolved in 30ml of chloroform, 5ml of thionyl chloride is added, and after refluxing for 4 hours, the solvent is removed under reduced pressure to obtain a compound 2; acetonitrile is used as a solvent, and reacts with 8g of 2-amino-5-bromobenzoic acid to obtain a compound 5-1; then dissolving in 150g of polyphosphoric acid, reacting for 2 hours at 130 ℃, pouring ice water after cold contraction, adjusting the PH to be alkaline by NaOH, carrying out suction filtration, and drying to obtain a compound 6-1; and (3) refluxing and chlorinating phosphorus oxychloride to obtain a compound 7-1.
8g of commercially available 2-amino-5-bromobenzoic acid is dissolved in 10ml of DMF and 10ml of 1, 4-dioxane, 7ml of chloroacetyl chloride is slowly added dropwise under ice bath, the room temperature is overnight, a large amount of water is added, yellow solid is separated out, and the compound 4 is obtained through suction filtration; acetonitrile is taken as a solvent, and a plurality of aniline is added for refluxing for 24 hours to obtain a compound 5-2; and then PPA ring-closing and phosphorus oxychloride chlorination to obtain the compound 7-2.
Example 2 intermediate compound 10
As shown in fig. 2, (a) various acid chlorides, pyridine, THF,2h; (b) (BPIN) 2 ，Pd(dppf)Cl 2 Potassium acetate, 1, 4-dioxane, 110 ℃, N 2 And (3) 12h. Specifically, 5g of 2-amino-4-bromopyridine was amide-condensed with various acid chlorides (1.1 eq) in THF solvent to give the product compound 9, which was then subjected to the utero reaction (3 eq potassium acetate, 1.5eq (BPIN) 2 ，0.5％eqPd(dppf)Cl 2 ) And (3) protecting the intermediate compound 10 by nitrogen at 110 ℃ for 12 hours. The acyl chloride is cyclopropaneacyl chloride, cyclobutanoyl chloride, cyclopentanoyl chloride, cyclohexanoyl chloride or phenylpropionoyl chloride. The acyl chloride is the intermediate compound 10-1 when the acyl chloride is cyclopropanecarbonyl chloride, the intermediate compound 10-2 when the acyl chloride is cyclobutanecarbonyl chloride, the intermediate compound 10-3 when the acyl chloride is cyclopentene chloride, the intermediate compound 10-4 when the acyl chloride is cyclohexenyl chloride, and the intermediate compound 10-5 when the acyl chloride is phenylpropionyl chloride.
Example 3N- (4- (11- ((3-morpholinopropyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-1 b)
Figure BDA0003635730810000061
3- (4-morpholino) -1-propylamine (5-10 eq) and a catalytic amount of NaI were placed in an eggplant-shaped bottle. When it was melted at 170 ℃, the intermediate compound 7-1 was added to react for 2 hours, and the reaction was detected in time. The system was cooled after the reaction was completed. Pulping with methanol, suction filtering, washing twice, drying, and directly carrying out SUZUKI coupling. New obtained intermediate (1 eq), intermediate compound 10-1 (1.2 eq), pd (dppf) Cl 2 (0.5% eq), cs2CO3 (3 eq) in 1, 4-dioxane: water=4:1 solvent, N 2 Exchanging 3 times. The reaction mixture was heated to 95℃and under N 2 Stirring is carried out for 12 hours under protection. After the solvent was distilled off under reduced pressure, the mixture was purified by silica gel column chromatography (PE/EA) to give the final product compound ZLHQ-1b. Yield 57%, pale yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.91(s,1H),8.73(d,J＝2.0Hz,1H),8.55(d,J＝1.7Hz,1H),8.44(d,J＝5.2Hz,1H),8.21(dd,J＝7.6,1.2Hz,1H),8.09(d,J＝8.9Hz,1H),7.93(dd,J＝8.9,1.9Hz,1H),7.74–7.59(m,4H),7.48(ddd,J＝7.9,6.6,1.6Hz,1H),4.00(q,J＝6.7Hz,2H),3.52(t,J＝4.6Hz,4H),2.48(t,J＝6.9Hz,2H),2.36(d,J＝4.6Hz,4H),2.08(tt,J＝7.5,4.9Hz,1H),1.93(p,J＝7.0Hz,2H),0.92–0.80(m,4H)； 13 CNM R(100MHz,DMSO-d 6 ):δ173.29,157.90,153.39,149.63,148.85,147.54,147.07,136.31,133.26,132.81,130.81,130.38,126.83,123.81,123.55,122.07,121.43,118.64,117.89,112.59,111.63,66.60(2C),55.37,53.83(2C),43.56,28.09,14.72,8.13(2C).HR-ESI-MS:522.2481[M+H] + ,(calcdforC 31 H 31 N 5 O 3 ,522.2500).
Example 4N- (4- (11- (4-aminopiperidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-1 d)
Figure BDA0003635730810000071
Morpholine instead of 3- (4-morpholinyl) -1-propylamine, compound ZLHQ-1d was synthesized following the procedure of example 3. Yield 48%, yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.94(s,1H),8.64(d,J＝1.6Hz,1H),8.52–8.43(m,2H),8.35–8.21(m,2H),8.05(dd,J＝8.8,2.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.74(t,J＝7.5Hz,1H),7.60–7.48(m,2H),3.82(dt,J＝12.6,3.9Hz,2H),3.53–3.42(m,2H),2.93(dq,J＝9.5,4.7,4.0Hz,1H),2.08(td,J＝7.8,3.8Hz,1H),2.01(dd,J＝13.1,3.7Hz,2H),1.75–1.61(m,2H),0.87(dtd,J＝10.2,8.0,4.9Hz,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.40,158.73,153.51,149.26,148.91,148.44,147.76,140.82,137.85,134.19,131.83,130.73,126.88,124.39,123.45,122.82,122.72,122.34,117.37,112.95,111.32,67.16(2C),52.78(2C),14.79,8.24(2C).HR-ESI-MS:469.1514[M+H] + ,(calcdforC 28 H 24 N 4 O 3 ,469.1521).
Example 5N- (4- (11- ((2- (dimethylamino) ethyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-1 f)
Figure BDA0003635730810000072
Compound ZLHQ-1f was synthesized following the procedure of example 3, substituting N, N-dimethylethane-1, 2-diamine for 3- (4-morpholinyl) -1-propylamine. Yield 61%, yellow solid.
1HNMR(600MHz,DMSO-d6):δ10.93(s,1H),8.72(s,1H),8.54(d,J＝1.7Hz,1H),8.46(d,J＝5.3Hz,1H),8.25(d,J＝7.6Hz,1H),8.14(d,J＝8.8Hz,1H),7.97(d,J＝8.9Hz,1H),7.81–7.69(m,2H),7.64(d,J＝5.1Hz,1H),7.51(t,J＝7.4Hz,1H),4.28(s,2H),3.49(s,2H),2.90(s,6H),2.07(t,J＝5.9Hz,1H),0.91–0.80(m,4H)；13CNMR(150MHz,DMSO-d6):δ173.36,158.13,153.41,149.50,148.94,147.23,135.41,133.27,133.17,131.04,130.32,127.09,124.06,123.26,122.15,121.62,118.64,117.97,112.99,111.60,57.46,43.30(2C),40.51,14.73,8.18(2C).HR-ESI-MS:466.2228[M+H]+,(calcdforC28H27N5O2,466.2238).
Example 6 (S) -N- (4- (11- (3-hydroxypyrrolidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 j)
Figure BDA0003635730810000081
(S) -pyrrolidin-3-ol instead of 3- (4-morpholinyl) -1-propylamine, compound ZLHQ-5j was synthesized following the procedure of example 3. Yield 55% pale yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.91(s,1H),8.63(d,J＝2.0Hz,1H),8.54(d,J＝1.7Hz,1H),8.41(d,J＝5.2Hz,1H),8.26–8.19(m,1H),8.11(d,J＝8.8Hz,1H),7.94(dd,J＝8.8,1.9Hz,1H),7.75(d,J＝8.3Hz,1H),7.72–7.65(m,1H),7.53(dd,J＝5.2,1.7Hz,1H),7.48(t,J＝7.4Hz,1H),5.16(s,1H),4.55–4.45(m,2H),4.41(dd,J＝10.7,4.4Hz,1H),4.11(s,1H),3.87(d,J＝10.6Hz,1H),2.15(tq,J＝8.3,4.2Hz,1H),2.06(pt,J＝7.6,3.2Hz,2H),0.93–0.80(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.37,157.62,153.45,150.68,149.35,149.12,146.80,138.89,137.02,131.87,131.01,129.84,126.78,124.67,123.98,122.88,122.15,121.21,117.38,112.70,111.23,69.67,62.38,51.91,34.52,14.78,8.19(2C).HR-ESI-MS:465.1918[M+H] + ,(calcd forC 28 H 24 N 4 O 3 ,465.1921).
Example 7N- (4- (11- (pyrrolidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-5 k)
Figure BDA0003635730810000082
The compound ZLHQ-5k was synthesized in accordance with the procedure of example 3 in place of 3- (4-morpholinyl) -1-propylamine in 37% yield as a pale yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.90(s,1H),8.65(d,J＝2.0Hz,1H),8.55(d,J＝1.7Hz,1H),8.41(d,J＝5.2Hz,1H),8.23(d,J＝7.6Hz,1H),8.12(d,J＝8.9Hz,1H),7.94(dd,J＝8.8,2.0Hz,1H),7.75(d,J＝8.2Hz,1H),7.72–7.64(m,1H),7.57–7.44(m,2H),4.13(q,J＝7.5,7.0Hz,4H),2.06(m,5H),0.86(ddt,J＝10.9,5.3,3.1Hz,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.38,157.72,153.45,149.43,149.15,148.52,138.56,137.39,132.90,131.91,130.97,130.29,126.59,124.66,123.98,123.22,122.12,121.75,117.42,112.70,111.23,54.07(2C),26.25(2C),14.77,8.19(2C).HR-ESI-MS:449.1956[M+H] + ,(calcdforC 28 H 24 N 4 O 2 ,449.1972).
Example 8 1 tert-butyl (ZLHQ-5 l) carbamate (2- (2- (cyclopropanecarboxamide) pyridin-4-yl) benzofuran [3,2-b ] quinolin-11-yl) piperidin-4-yl)
Figure BDA0003635730810000091
The compound ZLHQ-5l was synthesized in 49% yield as a white powder according to the procedure of example 3, substituting 3- (4-morpholinyl) -1-propylamine with 4-t-butoxycarbonylaminopiperidine.
1 HNMR(400MHz,CDCl 3 ):δ8.69(s,1H),8.51(s,1H),8.31(t,J＝7.3Hz,2H),8.24(d,J＝8.9Hz,1H),7.95(d,J＝8.8Hz,1H),7.55(dt,J＝12.8,8.0Hz,2H),7.38(t,J＝7.5Hz,2H),3.79(d,J＝12.8Hz,2H),3.52(t,J＝12.3Hz,2H),2.18(d,J＝12.3Hz,2H),1.96(s,1H),1.93–1.82(m,2H),1.58(m,1H),1.44(s,9H),0.87(d,J＝7.2Hz,2H),0.85(m,4H)； 13 CNMR(150MHz,CDCl 3 ):δ172.65,158.81(2C),155.37,152.35,149.90,148.35,147.56,140.79,138.94,133.43,130.95,129.87,126.46,123.63(2C),123.10,122.81,122.55,117.29,112.16,111.44,79.40,51.56(2C),33.42,29.57(2C),28.51(3C),16.12,8.65(2C).HR-ESI-MS:578.2738[M+H] + ,(calcdforC 34 H 35 N 5 O 4 ,578.2762).
Example 9N- (4- (11- (4-aminopiperidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 c)
Figure BDA0003635730810000092
Compound ZLHQ-5l was dissolved in dichloromethane: trifluoroacetic acid=1: 1, adding saturated sodium bicarbonate into the mixture for precipitation at room temperature for 1 hour, and carrying out vacuum filtration to obtain a compound ZLHQ-5c, wherein the yield is 83% and the compound is a pale yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.94(s,1H),8.64(d,J＝1.6Hz,1H),8.52–8.43(m,2H),8.35–8.21(m,2H),8.05(dd,J＝8.8,2.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.74(t,J＝7.5Hz,1H),7.60–7.48(m,2H),3.82(dt,J＝12.6,3.9Hz,2H),3.53–3.42(m,2H),2.93(dq,J＝9.5,4.7,4.0Hz,1H),2.08(td,J＝7.8,3.8Hz,1H),2.01(dd,J＝13.1,3.7Hz,2H),1.75–1.61(m,2H),0.87(dtd,J＝10.2,8.0,4.9Hz,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ178.16,163.39,158.32,154.05,153.95,153.01,152.64,145.40,143.75,138.74,136.47,135.50,131.60,129.07,128.40,127.77(2C),127.10,122.09,117.65,116.16,84.39,56.29(2C),53.23,40.78(2C),19.51,13.01(2C).HR-ESI-MS:478.2235[M+H] + ,(calcdforC 29 H 27 N 5 O 2 ,478.2238).
Example 10N- (4- (11- ((3-hydroxypropyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-5 m)
Figure BDA0003635730810000101
The compound ZLHQ-5m was synthesized in accordance with the procedure of example 3, in place of 3- (4-morpholinyl) -1-propylamine, in 33% yield as a pale yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.91(s,1H),8.76(d,J＝1.9Hz,1H),8.54(d,J＝1.7Hz,1H),8.45(dd,J＝5.3,3.5Hz,1H),8.22(dd,J＝7.6,1.2Hz,1H),8.10(d,J＝8.9Hz,1H),7.94(dd,J＝8.9,1.8Hz,1H),7.76(d,J＝8.2Hz,1H),7.72–7.61(m,3H),7.48(td,J＝7.5,1.0Hz,1H),4.59(t,J＝5.1Hz,1H),4.15–4.06(m,1H),3.64(q,J＝6.0Hz,2H),3.18(d,J＝5.2Hz,2H),2.07(td,J＝7.4,3.8Hz,1H),1.95(p,J＝6.5Hz,2H),0.86(dtd,J＝10.4,8.3,5.2Hz,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.30,157.96,153.39,149.61,148.86,147.56,147.12,136.36,133.28,132.77,130.78,130.39,126.81,123.81,123.53,122.05,121.46,118.64,117.90,112.73,111.62,59.00,49.06,42.46,34.51,14.72,8.14(2C).HR-ESI-MS:453.1913[M+H] + ,(calcdforC 27 H 24 N 4 O 3 ,453.1921).
Example 11 tert-butyl 3- ((2- (2- (cyclopropylamido) pyridin-4-yl) benzofuran [3,2-b ] quinolin-11-yl) amino) propyl) carbamate (ZLHQ-5 n)
Figure BDA0003635730810000111
The compound ZLHQ-5N was synthesized according to the procedure of example 3, in 61% yield, as white powder, substituting 3- (4-morpholinyl) -1-propylamine with N-Boc-1, 3-propanediamine.
1 HNMR(400MHz,CDCl 3 ):δ8.85(s,1H),8.78(d,J＝5.3Hz,1H),8.62(q,J＝5.6,5.1Hz,2H),8.42(d,J＝9.1Hz,1H),8.25(d,J＝9.1Hz,1H),7.91–7.80(m,3H),7.74–7.61(m,2H),4.48(d,J＝6.3Hz,2H),4.11(s,9H),3.90(t,J＝5.8Hz,2H),3.74–3.58(m,2H),2.11(td,J＝8.1,4.0Hz,1H),1.49–1.15(m,4H)； 13 CNMR(100MHz,CDCl 3 ):δ177.79,161.95,161.39,155.90,154.25,151.85,150.73,150.40,140.50,137.34,136.43,134.26,132.57,130.73,132.57,127.24,126.38,126.02,124.36,121.72,121.65,115.88,83.62,50.10,45.05,33.53,32.05,19.24,12.39(2C).HR-ESI-MS:552.2613[M+H] + ,(calcdforC 32 H 33 N 5 O 4 ,552.2605).
Example 12N- (4- (11- ((3-aminopropyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 h)
Figure BDA0003635730810000112
Ethyl acetate hydrochloride is added into the compound ZLHQ-5n to react for 1 hour at room temperature, and the compound ZLHQ-5h is obtained through vacuum suction filtration, and the yield is 93 percent, and is a light yellow solid.
1 HNMR(400MHz,DeuteriumOxide):δ7.76(d,J＝5.8Hz,1H),7.58(s,1H),7.43–7.24(m,6H),7.07(t,J＝7.3Hz,1H),6.83(s,1H),3.90(t,J＝7.9Hz,2H),3.16(t,J＝7.7Hz,2H),2.14(p,J＝7.9Hz,2H),1.60(s,1H),1.07–1.01(m,2H),0.94(s,2H)； 13 CNMR(150MHz,DeuteriumOxide):δ177.32,165.70,157.26,156.50,147.82,141.83,137.56,136.94,134.08,130.84,129.58,125.13,121.92,120.51,116.30,114.80,114.64,112.87,109.78,86.00,69.73,42.55,39.47,29.57,14.96,10.06(2C).HR-ESI-MS:452.2074[M+H] + ,(calcdforC 27 H 25 N 5 O 2 ,452.2081).
Example 13N- (4- (11- (piperazin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-5 a)
Figure BDA0003635730810000121
N-Boc-piperazine was used instead of 4-t-butoxycarbonylaminopiperidine, and N-Boc-piperazine was reacted at 170℃with the addition of intermediate 7-1 for 2 hours. The system was cooled after the reaction was completed. Pulping with methanol, suction filtering, washing twice, drying, and directly carrying out SUZUKI coupling. New obtained intermediate (1 eq), intermediate 10-1 (1.2 eq), pd (dppf) Cl 2 (0.5% eq), cs2CO3 (3 eq) in 1, 4-dioxane: water=4:1 solvent, N 2 Exchanging 3 times. The reaction mixture was heated to 95℃and under N 2 Stirring is carried out for 12 hours under protection. After the solvent was distilled off under reduced pressure, the mixture was purified by silica gel column chromatography (PE/EA) to obtain an intermediate. Via V dichloromethane: v trifluoroacetic acid=1: 1, removing Boc in the mixed solution at room temperature for 1 hour, adding saturated sodium bicarbonate for precipitation, and carrying out vacuum filtration to obtain a compound ZLHQ-5a, wherein the yield is 64 percent, and the compound is a light yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.94(s,1H),8.62(d,J＝1.6Hz,1H),8.48(d,J＝2.1Hz,1H),8.45(d,J＝5.2Hz,1H),8.27(dd,J＝8.5,7.1Hz,2H),8.05(dd,J＝8.9,2.1Hz,1H),7.84–7.78(m,1H),7.74(ddd,J＝8.4,7.1,1.4Hz,1H),7.53(td,J＝7.4,1.1Hz,1H),3.80(t,J＝5.0Hz,4H),3.41(t,J＝5.0Hz,4H),2.06(m,1H),0.95–0.81(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.48,158.76,153.48,149.22,148.98,148.51,147.69,140.92,137.24,134.60,131.96,130.78,127.03,124.51,123.42,122.79,122.63,122.40,117.60,112.92,111.58,50.06(2C),44.31(2C),14.81,8.26(2C).HR-ESI-MS:464.2067[M+H] + ,(calcdforC 28 H 25 N 5 O 2 ,464.2081).
Example 14N- (4- (11- (4-Aminoazepan-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 b)
Figure BDA0003635730810000122
The compound ZLHQ-5b was synthesized according to the procedure of example 13 in 69% yield as a yellow solid instead of 4-t-butoxycarbonylaminopiperidine.
1 HNMR(400MHz,DMSO-d 6 ):δ10.92(d,J＝13.3Hz,1H),8.67(d,J＝2.1Hz,1H),8.61(d,J＝1.6Hz,1H),8.42(d,J＝5.2Hz,1H),8.22(dd,J＝17.7,8.2Hz,2H),8.00(dd,J＝8.9,2.1Hz,1H),7.77(d,J＝8.2Hz,1H),7.70(t,J＝7.7Hz,1H),7.56–7.44(m,2H),3.77(ddd,J＝12.3,8.9,5.5Hz,4H),3.06(q,J＝6.2Hz,4H),2.49(p,J＝1.8Hz,2H),2.05(td,J＝7.6,3.8Hz,1H),1.98(m,1H),1.28–1.12(m,2H),0.93–0.78(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.36,158.38,153.54,149.23,149.21148.11,148.05,140.77,140.60,133.69,131.57,130.60,126.72,124.36,124.26,123.58,123.15,122.27,117.39,112.84,111.30,79.64,58.85,54.90,50.56,48.38,45.78,32.04,29.48,14.76,8.24(2C).HR-ESI-MS:478.2238[M+H] + ,(calcdforC 29 H 27 N 5 O 2 ,478.2238).
Example 15N- (4- (11- (3-aminopiperidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 d)
Figure BDA0003635730810000131
3-Boc Aminopiperidine instead of 4-Boc Aminopiperidine compound ZLHQ-5d was synthesized in 70% yield as a yellow solid following the procedure of example 13.
1 HNMR(400MHz,DMSO-d 6 ):δ12.06(d,J＝13.4Hz,1H),8.76(d,J＝7.8Hz,4H),8.63(s,1H),8.58–8.48(m,3H),8.33(d,J＝8.9Hz,1H),8.04(d,J＝8.4Hz,1H),7.90(d,J＝6.3Hz,2H),7.66(t,J＝7.8Hz,1H),4.63(d,J＝12.6Hz,1H),4.17(s,1H),4.06(t,J＝11.0Hz,1H),3.92(t,J＝11.0Hz,1H),3.79(s,1H),2.20(dt,J＝12.5,6.1Hz,2H),2.09–1.93(m,1H),1.02(d,J＝6.0Hz,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ174.50,158.18,151.40,150.63,145.66,145.41,140.16(d,J＝31.1Hz),138.69,133.99,133.29,130.67,125.85,125.23,124.58,122.86,120.36,118.05,117.72,113.62,112.33,54.88,53.75,47.24,28.01,23.58,15.03,9.02(2C).HR-ESI-MS:478.2228[M+H] + ,(calcdforC 29 H 27 N 5 O 2 ,478.2238).
EXAMPLE 16 (R) -N- (4- (11- (3-aminopyrrolidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-5 e)
Figure BDA0003635730810000141
(R) -3-Boc-1, 3-propane diamine was replaced with (R) -3-t-Butoxycarbonyl aminopyrrolidine, and when melted at 170 ℃, intermediate compound 7-1 was added to react for 2 hours. The system was cooled after the reaction was completed. Pulping with methanol, suction filtering, washing twice, drying, and directly carrying out SUZUKI coupling. New obtained intermediate (1 eq), intermediate compound 10-1 (1.2 eq), pd (dppf) Cl 2 (0.5% eq), cs2CO3 (3 eq) in 1, 4-dioxane: water=4:1 solvent, N 2 Exchanging 3 times. The reaction mixture was heated to 95℃and under N 2 Stirring is carried out for 12 hours under protection. After the solvent was distilled off under reduced pressure, the mixture was purified by silica gel column chromatography (PE/EA) to obtain an intermediate. Removing Boc by ethyl acetate hydrochloride solution at room temperature for 1 hour, adding saturated sodium bicarbonate for precipitation, and performing vacuum filtration to obtain a compound ZLHQ-5e, wherein the yield is 55% and the compound is a pale yellow solid.
1 HNMR(400MHz,DeuteriumOxide):δ7.98(d,J＝1.9Hz,1H),7.87(d,J＝6.4Hz,1H),7.50–7.42(m,2H),7.36(d,J＝8.9Hz,1H),7.31(dd,J＝6.5,1.9Hz,1H),7.28–7.20(m,2H),6.96(ddd,J＝8.0,5.6,2.4Hz,1H),6.89(d,J＝1.8Hz,1H),4.58(dd,J＝12.7,6.3Hz,1H),4.31(ddd,J＝27.5,12.1,5.8Hz,1H),4.19(p,J＝6.8Hz,1H),4.06(p,J＝5.8Hz,1H),2.41(dq,J＝13.5,7.1Hz,1H),2.16(dq,J＝13.0,6.5Hz,1H),1.52(td,J＝7.7,3.9Hz,1H),0.92–0.78(m,4H)； 13 CNMR(100MHz,DeuteriumOxide):δ177.68,156.85,152.66,147.81,144.03,139.49,139.10,136.01,134.31,133.55,129.75,128.67,126.10,125.02,121.92,120.60,116.86,116.73,115.26,112.92,110.64,57.46,53.74,49.65,29.30,15.32,10.17(2C).HR-ESI-MS:464.2087[M+H] + ,(calcdforC 28 H 25 N 5 O 2 ,464.2081).
EXAMPLE 17 (S) -N- (4- (11- (3-aminopyrrolidin-1-yl) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-5 f)
Figure BDA0003635730810000142
(S) -3-Boc-aminopyrrolidine instead of N-Boc-1, 3-propanediamine, compound ZLHQ-5f was synthesized in accordance with the procedure of example 16 in 45% yield as a yellow solid.
1 HNMR(600MHz,DMSO-d 6 ):δ10.91(s,1H),8.66(d,J＝23.3Hz,1H),8.54(d,J＝17.5Hz,1H),8.41(d,J＝5.1Hz,1H),8.22(d,J＝7.7Hz,1H),8.11(d,J＝8.8Hz,1H),7.94(d,J＝9.1Hz,1H),7.75(d,J＝8.4Hz,1H),7.68(q,J＝7.5Hz,1H),7.55(d,J＝5.1Hz,1H),7.48(t,J＝7.3Hz,1H),4.41–4.34(m,1H),4.27(dd,J＝9.8,5.6Hz,1H),4.20(td,J＝10.1,9.6,5.0Hz,1H),3.82(dd,J＝9.8,4.7Hz,1H),3.67(p,J＝5.4Hz,1H),2.16(dq,J＝12.5,6.6Hz,1H),2.05(dtt,J＝21.9,11.6,5.1Hz,1H),1.83(dq,J＝12.1,6.3Hz,1H),0.89–0.82(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.42,158.68,158.37,153.40,149.72,149.01,145.42,144.30,133.40,130.30,130.12,127.37,125.28,124.20,122.73,121.78,120.20,117.88,116.30,112.48,111.73,55.95,50.65,50.28,30.54,14.79,8.21(2C).HR-ESI-MS:464.2079[M+H] + ,(calcdforC 28 H 25 N 5 O 2 ,464.2081).
Example 18N- (4- (11- ((2-aminoethyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 g)
Figure BDA0003635730810000151
N-Boc-ethylenediamine instead of N-Boc-1, 3-propylenediamine, the compound ZLHQ-5g was synthesized according to the procedure of example 16 in 67% yield as a yellow solid.
1 HNMR(400MHz,DeuteriumOxide):δ7.87(s,2H),7.51–7.31(m,6H),7.07(t,J＝7.2Hz,1H),6.87(s,1H),4.21(t,J＝6.9Hz,2H),3.37(t,J＝6.8Hz,2H),1.56(q,J＝6.6,4.7Hz,1H),0.97(d,J＝7.7Hz,2H),0.91(t,J＝3.9Hz,2H)； 13 CNMR(100MHz,DeuteriumOxide):δ177.16,156.87,149.84,147.16,141.42,139.53,136.89,136.65,134.24,130.34,128.67,127.94,125.17,121.76,121.39,120.35,115.55,114.24,114.11,112.94,108.60,42.79,39.34,15.09,10.42(2C).HR-ESI-MS:438.1925[M+H] + ,(calcdforC 26 H 23 N 5 O 2 ,438.1925).
Example 19N- (4- (11- ((4-aminobutyl) amino) benzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-5 i)
Figure BDA0003635730810000161
The compound ZLHQ-5i was synthesized in 57% yield as a yellow solid following the procedure of example 13, substituting N-Boc-1, 4-butanediamine for N-Boc-1, 3-propanediamine.
1 HNMR(400MHz,DMSO-d 6 ):δ10.93(s,1H),8.93(s,1H),8.53(d,J＝1.7Hz,1H),8.44(d,J＝5.2Hz,1H),8.33(d,J＝7.0Hz,1H),8.18–8.09(m,4H),7.99(d,J＝9.0Hz,1H),7.83(d,J＝8.4Hz,1H),7.79–7.67(m,2H),7.50(t,J＝7.5Hz,1H),4.00(q,J＝6.2Hz,2H),2.87(s,2H),2.09(td,J＝7.5,3.9Hz,1H),1.83(dq,J＝23.8,7.8Hz,4H),0.90–0.82(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.34,172.45,157.84,153.36,149.16,148.88,133.13,132.90,131.27,124.06,122.55,121.96,118.21,118.06,112.98,111.56,44.39,39.08,28.23,24.81,21.56,14.73,8.16.HR-ESI-MS:466.2216[M+H] + ,(calcdforC 28 H 27 N 5 O 2 ,466.2238).
Example 20N- (4- (11- ((3-morpholinopropyl) amino) -10H-indoline [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-1 a)
Figure BDA0003635730810000162
7-2 instead of 7-1, the compound ZLHQ-1a was synthesized according to the procedure of example 3 in 68% yield as yellow solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.95(s,1H),8.95(s,1H),8.55(s,1H),8.47(d,J＝5.2Hz,1H),8.26(t,J＝6.8Hz,1H),8.12(d,J＝8.9Hz,1H),7.80(d,J＝8.3Hz,1H),7.70(d,J＝5.6Hz,3H),7.35(d,J＝8.4Hz,1H),4.17(s,2H),3.59(m,4H),2.51(m,4H),2.08(ddd,J＝12.4,5.7,3.7Hz,3H),1.92(s,2H),0.89–0.83(m,4H).HR-ESI-MS:521.2636[M+H] + ,(calcdforC 31 H 32 N 6 O 2 ,521.2660).
Example 21N- (4- (11-morpholin-10H-Indolo [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanemethylamine (ZLHQ-1 c)
Figure BDA0003635730810000163
7-2 instead of 7-1, the compound ZLHQ-1c was synthesized according to the procedure of example 4 in 55% yield as a white solid.
1 HNMR(400MHz,DMSO-d 6 ):δ10.98(s,1H),8.60(s,1H),8.54(d,J＝2.4Hz,1H),8.45(dd,J＝10.9,6.6Hz,2H),8.33–8.18(m,2H),7.79–7.65(m,2H),7.59(dd,J＝5.3,1.9Hz,1H),7.38(td,J＝7.1,6.2,1.8Hz,1H),4.07–4.01(m,4H),3.91(t,J＝4.5Hz,4H),2.08(td,J＝7.6,3.9Hz,1H),0.90–0.84(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.49,158.83,158.51,153.53,149.28,148.37,144.21,138.95,133.82,132.24,129.19,124.95,123.84,122.62,121.27,120.36,117.40,113.58,111.36,67.15(2C),52.70(2C),14.79,8.28(2C).HR-ESI-MS:464.2059[M+H] + ,(calcdforC 28 H 25 N 5 O 2 ,464.2081).
Example 22N- (4- (11- ((3-aminopropyl) amino) -10H-indoline [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopropanecarboxamide (ZLHQ-1 e)
Figure BDA0003635730810000171
Compound 7-2 instead of compound 7-1, compound ZLHQ-1e was synthesized in 61% yield as a yellow solid following the procedure of example 13.
1 HNMR(400MHz,DMSO-d 6 ):δ10.90(s,1H),8.80(d,J＝27.7Hz,1H),8.56(d,J＝1.6Hz,1H),8.41(dd,J＝10.8,6.1Hz,1H),8.24(d,J＝7.7Hz,1H),8.10(dd,J＝9.2,4.0Hz,1H),7.86(dd,J＝8.9,1.9Hz,1H),7.74–7.46(m,3H),7.21(q,J＝7.5Hz,2H),6.67(brs,1H),3.93(d,J＝28.4Hz,2H),3.16–2.81(m,2H),2.07(td,J＝7.8,3.9Hz,1H),1.93–1.71(m,2H),0.91–0.82(m,4H)； 13 CNMR(100MHz,DMSO-d 6 ):δ173.29,153.37,149.93,148.81,146.67,145.76,143.69,136.76,131.49,130.32,129.07,124.92,122.14,121.42,121.19,119.61,119.36,118.08,117.75,112.59,111.43,79.65,42.79,38.14,31.97,14.74,8.13.HR-ESI-MS:451.2255[M+H] + ,(calcdforC 27 H 26 N 6 O,451.2241).
Example 23N- (4- (11-Morpholinylbenzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclobutylcarboxamide (ZLHQ-2 a)
Figure BDA0003635730810000181
The intermediate compound 10-2 was synthesized as the procedure of example 4, in place of compound 10-1, to yield compound ZLHQ-2a in 71% yield as a white solid.
1 HNMR(400MHz,CDCl 3 ):δ8.76(d,J＝1.7Hz,1H),8.64–8.56(m,1H),8.40(d,J＝7.8Hz,1H),8.38–8.31(m,2H),8.07(s,1H),8.02(dd,J＝8.8,2.1Hz,1H),7.66–7.58(m,2H),7.47(ddd,J＝8.0,6.9,1.3Hz,1H),7.41(dd,J＝5.3,1.7Hz,1H),4.14–4.07(ddd,4H),3.78–3.71(ddd,4H),3.32–3.19(m,1H),2.52–2.37(m,2H),2.35–2.22(m,2H),2.15–1.85(m,2H)； 13 CNMR(150MHz,CDCl 3 ):δ156.78,141.85,135.35,133.38,131.54,131.17,130.51,124.10,120.97,117.40,114.02,113.13,109.94,106.69,106.44,105.77,105.72,105.49,100.68,95.13,94.83,50.49(2C),35.70(2C),23.92,8.20(2C).,1.02.HR-ESI-MS:479.2058[M+H] + ,(calcdforC 29 H 26 N 4 O 3 ,479.2078).
Example 24N- (4- (11-Morpholinylbenzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclopentanecarboxamide (ZLHQ-2 b)
Figure BDA0003635730810000182
The intermediate compound 10-3 was synthesized as the procedure of example 4, in place of compound 10-1, to yield compound ZLHQ-2b, 73% as a white solid. No suitable deuterated solvent was found to dissolve the compound, no nmr data. HR-ESI-MS:493.2213[ M+H ]] + ,(calcdforC 20 H 28 N 4 O 3 ,493.2234).
Example 25N- (4- (11-Morpholinylbenzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) cyclohexanecarboxamide (ZLHQ-2 c)
Figure BDA0003635730810000183
The intermediate compound 10-4 was synthesized as the procedure of example 4, replacing compound 10-1, with the compound ZLHQ-2c in 56% yield as a white solid.
1 HNMR(400MHz,CDCl 3 ):δ8.70(d,J＝1.7Hz,1H),8.51(d,J＝2.1Hz,1H),8.36(d,J＝7.7Hz,1H),8.30(d,J＝5.3Hz,1H),8.26(d,J＝8.9Hz,1H),7.98(dd,J＝8.8,2.1Hz,1H),7.67–7.54(m,2H),7.44(t,J＝7.6Hz,1H),7.37(dd,J＝5.3,1.7Hz,1H),4.06(m,J＝4.6Hz,4H),3.71(t,J＝4.5Hz,4H),2.33(tt,J＝11.8,3.6Hz,1H),2.00–1.92(m,2H),1.83(dd,J＝13.3,3.7Hz,2H),1.73–1.44(m,3H),1.38–1.14(m,3H)； 13 CNMR(100MHz,CDCl 3 ):δ175.54,158.83,152.39,150.47,148.52,148.00,147.32,141.07,138.24,134.43,131.18,129.69,127.07,123.83,123.36,122.83,122.51,122.41,117.68,112.20,112.13,67.44(2C),52.62(2C),46.39,29.64(2C),25.62,25.57(2C).HR-ESI-MS:507.2371[M+H] + ,(calcdforC 21 H 30 N 4 O 3 ,507.2391).
EXAMPLE 26N- (4- (11-morpholinylbenzofuran [3,2-b ] quinolin-2-yl) pyridin-2-yl) benzamide (ZLHQ-2 d)
Figure BDA0003635730810000191
The intermediate compound 10-5 was synthesized as the procedure of example 4, replacing compound 10-1, with the compound ZLHQ-2d in 45% yield as a white solid.
1 HNMR(400MHz,CDCl 3 )δ8.81(d,J＝1.7Hz,1H),8.54(d,J＝2.1Hz,1H),8.38–8.29(m,2H),8.23(d,J＝8.8Hz,1H),7.98(dd,J＝8.9,2.1Hz,1H),7.93(dd,J＝7.1,1.9Hz,2H),7.65–7.36(m,8H),4.04(q,J＝6.9,5.7Hz,4H),3.66(q,J＝5.7Hz,4H)； 13 CNMR(100MHz,CDCl 3 ):δ170.33,162.79,156.42,154.50,152.13,151.09,142.45,138.35,136.34,135.28,133.36,132.76(2C),131.26(2C),131.09,127.84,127.27,126.93,126.41,126.13,121.99,116.39,116.12,71.37(2C),56.59(2C).HR-ESI-MS:501.1921[M+H] + ,(calcdforC 31 H 24 N 4 O 3 ,501.1921).
EXAMPLE 27 11-morpholin-2- (pyridin-4-yl) benzofuran [3,2-b ] quinoline (ZLHQ-3 a)
Figure BDA0003635730810000201
/>
The compound ZLHQ-3a was synthesized in accordance with the procedure of example 4, in 87% yield, as a white solid, instead of compound 10-1.
1 HNMR(400MHz,CDCl 3 ):δ8.78–8.72(m,2H),8.53(d,J＝2.1Hz,1H),8.37(dd,J＝14.6,8.0Hz,2H),7.97(dd,J＝8.8,2.1Hz,1H),7.71–7.59(m,4H),7.48(td,J＝7.3,6.9,1.2Hz,1H),4.11–4.04(m,4H),3.74–3.67(m,4H)； 13 CNMR(150MHz,CDCl 3 ):δ158.92,150.46(2C),148.84,148.07,147.58,141.39,137.72,134.46,131.10,130.50,126.74,123.75,122.78,122.49,122.45,121.77(2C),112.19(2C),67.52(2C),52.63(2C).HR-ESI-MS:382.1550[M+H] + ,(calcdforC 24 H 19 N 3 O 2 ,382.1550).
Example 28-morpholin-2- (pyridin-3-yl) benzofuran [3,2-b ] quinoline (ZLHQ-3 b).
Figure BDA0003635730810000202
3-Pyridineboronic acid in place of Compound 10-1, compound ZLHQ-3b was synthesized according to the procedure of example 4 in 66% yield as a white solid.
1 HNMR(400MHz,CDCl 3 )δ9.03(d,J＝2.3Hz,1H),8.67(dd,J＝4.8,1.6Hz,1H),8.45(d,J＝2.1Hz,1H),8.37(dd,J＝13.8,8.2Hz,2H),8.04(dt,J＝7.9,2.0Hz,1H),7.93(dd,J＝8.8,2.1Hz,1H),7.70–7.58(m,2H),7.51–7.42(m,2H),4.15–4.03(m,4H),3.70(t,J＝4.6Hz,4H)； 13 CNMR(150MHz,CDCl 3 ):δ158.86,148.75,148.54,148.43,147.00,141.41,137.59,136.37,134.57,134.31,130.99,130.38,127.25,123.85,123.81,123.70,122.78,122.44,122.10,112.16,67.52(2C),52.58(2C).HR-ESI-MS:382.1540[M+H] + ,(calcdforC 24 H 19 N 3 O 2 ,382.1550).
Example 29 2- (6-Fluoropyridin-3-yl) -11-morpholinylbenzofuran [3,2-b ] quinoline (ZLHQ-3 c)
Figure BDA0003635730810000211
2-Fluoropyridine-5-boronic acid was synthesized in accordance with the procedure of example 4 in place of compound 10-1 in 80% yield as a white solid.
1 HNMR(400MHz,CDCl 3 ):δ8.59(d,J＝2.6Hz,1H),8.41–8.30(m,3H),8.15–8.10(m,1H),7.86(dd,J＝8.9,2.1Hz,1H),7.69–7.59(m,2H),7.47(t,J＝7.3Hz,1H),7.10(dd,J＝8.5,3.0Hz,1H),4.09–4.02(m,4H),3.68(t,J＝4.5Hz,4H)； 13 CNMR(100MHz,CDCl 3 ):δ164.48,162.09,158.89,148.75,147.17,146.17,146.02,141.54,139.89,139.82,137.31,134.66,134.61,133.16,130.95,130.66,126.96,123.95,123.68,122.89,122.31,121.97,112.16,109.94,109.57,67.50,52.54.HR-ESI-MS:400.1443[M+H] + ,(calcdforC 24 H 18 FN 3 O 2 ,400.1456).
Example 30 2- (1-methyl-1H-pyrazol-4-yl) -11-morpholinylbenzofuran [3,2-b ] quinoline (ZLHQ-3 d)
Figure BDA0003635730810000212
The compound ZLHQ-3d was synthesized in 79% yield as white solid following the procedure of example 4, substituting 1-methyl-4-pyrazolylboronic acid pinacol ester for compound 10-1.
1 HNMR(400MHz,CDCl 3 ):δ8.38(d,J＝7.7Hz,1H),8.30(d,J＝2.0Hz,1H),8.25(d,J＝8.7Hz,1H),7.93–7.89(m,1H),7.81(dd,J＝8.8,2.0Hz,1H),7.76(s,1H),7.66–7.58(m,2H),7.46(ddd,J＝8.1,6.8,1.4Hz,1H),4.11–4.04(m,4H),4.02(s,3H),3.68(t,J＝4.5Hz,4H)； 13 CNMR(100MHz,CDCl 3 ):δ158.70,147.40,146.5,141.47,137.02,130.64,129.92,129.49,127.30,126.81,124.07,123.59,123.11,122.89,122.30,119.06,112.06,67.57,52.49(2C),39.24(2C).HR-ESI-MS:385.1651[M+H] + ,(calcdforC 23 H 20 N 4 O 2 ,385.1659).
Example 31 11-morpholin-2- (1H-pyrazol-4-yl) benzofuran [3,2-b ] quinoline (ZLHQ-3 e)
Figure BDA0003635730810000221
(1H-pyrazol-4-yl) boronic acid in place of compound 10-1, compound ZLHQ-3e was synthesized following the procedure of example 4 in 61% yield as a white solid.
1 HNMR(400MHz,CDCl 3 ):δ8.40–8.25(m,2H),8.20(dq,J＝10.3,6.4,5.9Hz,1H),8.00(q,J＝7.1,6.1Hz,2H),7.88(dt,J＝11.2,5.9Hz,1H),7.63(ddt,J＝15.7,11.6,6.9Hz,2H),7.47(dt,J＝15.9,7.8Hz,1H),4.08(dt,J＝9.8,4.7Hz,4H),3.74–3.59(m,4H),3.45–3.26(m,1H)； 13 CNMR(100MHz,CDCl 3 ):δ162.57,151.22,149.93,145.29,141.34,134.77,133.51,133.12,131.07,127.86,127.82,127.66,126.34,126.30,126.11,123.16,116.00,71.40(2C),56.31(2C).HR-ESI-MS:371.1490[M+H] + ,(calcdforC 22 H 18 N 4 O 2 ,371.1503).
Example 32 2- (3-methoxyphenyl) -11-morpholinylbenzofuran [3,2-b ] quinoline (ZLHQ-4 a)
Figure BDA0003635730810000222
3-Methoxyphenylboronic acid was synthesized in accordance with the procedure of example 4, in place of compound 10-1, to yield 77% of compound ZLHQ-4a as a white solid.
1 HNMR(400MHz,CDCl 3 ):δ8.36(d,J＝2.1Hz,1H),8.33(d,J＝7.7Hz,1H),8.24(d,J＝8.8Hz,1H),7.88(dd,J＝8.8,2.1Hz,1H),7.61–7.49(m,2H),7.42–7.33(m,2H),7.26(dt,J＝7.6,1.3Hz,1H),7.23–7.15(m,2H),4.04–3.94(m,4H),3.84(s,3H),3.63(t,J＝4.5Hz,4H)； 13 CNMR(150MHz,CDCl 3 ):δ159.15,157.74,146.92,145.83,141.32,140.28,136.57(2C),129.74,129.07,128.80,126.79,122.69,122.57,121.86,121.36,120.76,118.86,112.27,111.83,111.07,66.52,54.36,51.53.HR-ESI-MS:411.1692[M+H] + ,(calcdforC 26 H 22 N 2 O 3 ,411.1703).
Example 33 (4- (11-morpholinylbenzofuran [3,2-b ] quinolin-2-yl) phenyl) methanol (ZLHQ-4 b)
Figure BDA0003635730810000231
The compound ZLHQ-4b was synthesized in 66% yield as a white solid by following the procedure of example 4, substituting the compound 10-1 with 4-hydroxymethylphenylboronic acid.
1 HNMR(400MHz,CDCl 3 ):δ8.39(d,J＝7.7Hz,1H),8.28(d,J＝2.0Hz,1H),8.24(d,J＝8.7Hz,1H),7.70(dd,J＝8.7,2.0Hz,1H),7.67–7.57(m,3H),7.50–7.38(m,4H),4.74–4.69(m,2H),3.96(dd,J＝5.6,3.6Hz,4H),3.68–3.62(m,4H),2.54(s,1H)； 13 CNMR(150MHz,CDCl 3 ):δ158.75,148.11,146.58,141.32,141.26,138.27,137.58,137.34,130.79,130.48,129.84(2C),129.24,129.07,128.02(2C),127.99,124.17,123.60,123.35,122.85,122.41,112.10,67.50,63.20(2C),52.51(2C).HR-ESI-MS:411.1692[M+H] + ,(calcdforC 26 H 22 N 2 O 3 ,411.1703).
Example 34 2- (2, 3-Dihydrobenzo [ b ] [1,4] dioxan-6-yl) -11-morpholino benzofuran
[3,2-b ] quinoline (ZLHQ-4 c)
Figure BDA0003635730810000232
The compound ZLHQ-4c was synthesized in 75% yield as white solid following the procedure of example 4, substituting benzo-1, 4-dioxane-6-boric acid for compound 10-1.
1 HNMR(400MHz,CDCl 3 ):δ8.41–8.34(m,2H),8.28(d,J＝8.8Hz,1H),7.90(dd,J＝8.9,2.1Hz,1H),7.68–7.56(m,2H),7.45(ddd,J＝8.0,6.7,1.5Hz,1H),7.30–7.21(m,3H),7.02(d,J＝8.3Hz,1H),4.34(s,4H),4.09–4.02(m,4H),3.68(t,J＝4.5Hz,4H)； 13 CNMR(100MHz,CDCl 3 ):δ158.74,147.81,146.73,143.96,143.56,141.42,137.30,137.18,134.39,130.61,129.85,127.57,123.88,123.53,123.02,122.29,120.94,120.43,117.90,116.11,112.07,67.56(2C),64.50(2C),52.51(2C).HR-ESI-MS:439.1638[M+H] + ,(calcdforC 27 H 22 N 2 O 4 ,439.1652).
Example 35 2- (2, 3-Dihydrobenzo [ d ] [1,3] dioxol-5-yl) -11-morpholinofuran [3,2-b ] quinoline (ZLHQ-4 d)
Figure BDA0003635730810000241
Compound ZLHQ-4d was synthesized in 55% yield as white solid following the procedure of example 4, substituting benzo [ d ] [1,3] dioxol-5-ylboronic acid for compound 10-1.
1 HNMR(400MHz,CDCl 3 ):δ8.38(d,J＝7.7Hz,1H),8.34(d,J＝2.1Hz,1H),8.28(d,J＝8.8Hz,1H),7.88(dd,J＝8.8,2.2Hz,1H),7.68–7.57(m,2H),7.46(ddd,J＝8.0,6.7,1.4Hz,1H),7.24–7.16(m,2H),6.97(d,J＝8.5Hz,1H),6.05(s,2H),4.09–4.02(m,4H),3.69(t,J＝4.5Hz,4H)； 13 CNMR(100MHz,CDCl 3 ):δ158.75,148.44,147.85,147.46,146.69,141.43,137.52,137.32,135.21,130.68,129.86,127.69,123.85,123.57,122.96,122.32,121.10,121.04,112.08,108.87,107.79,101.32(2C),67.56(2C),52.52(2C).HR-ESI-MS:425.1477[M+H] + ,(calcdforC 26 H 20 N 2 O 4 ,425.1496).
Example 36 (2- (11-morpholinofuran [3,2-b ] quinolin-2-yl) phenyl) methanol (ZLHQ-4 f)
Figure BDA0003635730810000242
2-hydroxymethylphenylboronic acid, instead of compound 10-1, compound ZLHQ-4f was synthesized following the procedure of example 4, in 69% yield as a white solid.
1 HNMR(400MHz,DMSO-d 6 ):δ8.41(d,J＝2.1Hz,1H),8.29(d,J＝7.6Hz,1H),8.22(d,J＝8.8Hz,1H),8.06(dd,J＝8.8,2.1Hz,1H),7.81(dd,J＝8.3,2.2Hz,3H),7.78–7.70(m,1H),7.57–7.46(m,3H),5.28(brs,1H),4.59(s,2H),4.00–3.93(m,4H),3.65(t,J＝4.5Hz,4H)； 13 CNMR(150MHz,DMSO-d 6 ):δ158.61,147.52,146.78,142.67,140.93,138.64,137.68,137.17,131.66,130.22,127.88,127.79,127.50,127.30,126.70,124.37,123.67,122.82,122.28,121.60,112.93,67.21(2C),63.09,52.70(2C).HR-ESI-MS:411.1712[M+H] + ,(calcdforC 26 H 22 N 2 O 3 ,411.1703).
Example 37: evaluation of antitumor cell proliferation Activity of target Compound
Measured by MTT method. Cells grown in exponential phase were seeded in 96-well plates (3×10 per well) 3 Individual) and incubated overnight. The compounds were then added at different concentrations and incubated for 72 hours. Thereafter, 20. Mu.L of 10% MTT (5 mg/mL, PBS) reagent was added to each well, and incubated in an incubator for another 4 hours. Subsequently, the supernatant was discarded, 100 μLDMSO was added and the mixture was shaken for 8min. The absorbance of the cells was measured at 490nm on a microplate reader. Percent growth inhibition = 100-100× (OD Sample of -OD Blank space )/(OD Control -OD Blank space ). Calculation of IC using nonlinear regression analysis (percent growth versus concentration) 50 The values are detailed in tables 1-3.
TABLE 1 antiproliferative Activity of the compound ZLHQ-1
Figure BDA0003635730810000251
/>
Figure BDA0003635730810000252
a GI 50 Values are the mean ± SD of at least two independent experiments, in triplicate.
Table 2: antiproliferative activity of compounds ZLHQ-2, 3, 4
Figure BDA0003635730810000253
/>
Figure BDA0003635730810000261
/>
Figure BDA0003635730810000271
a GI 50 Values are the mean ± SD of at least two independent experiments, in triplicate.
Table 3: antiproliferative activity of compound ZLHQ-5
Figure BDA0003635730810000272
Figure BDA0003635730810000273
/>
Figure BDA0003635730810000281
a GI 50 Values are the mean ± SD of at least two independent experiments, in triplicate.
Through three rounds of structural optimization, a series of compounds with good cytotoxic activity are discovered, and the cytotoxic activity of the compounds is obviously stronger than that of a sinomenine mother nucleus, so that the optimization is proved to be remarkable in effect. Next, we selected the compounds with better activity to test their enzyme activity.
Example 38: evaluation of CDK2 enzyme Activity of Compounds with better antiproliferative Activity
Detection was performed using the mobilisyshift assay, diniciclib and Palbociclib as reference standards. 6 compounds with better antitumor cell proliferation activity are selected for measuring the enzyme activity of CDK2, and the details are shown in Table 4. The best CDK2 activity was found to be the compound ZLHQ-5f.
Table 4: evaluation of CDK2 and CDK4 enzyme Activity of Compounds having better anti-tumor cell proliferation Activity
Figure BDA0003635730810000282
/>
Figure BDA0003635730810000291
a The IC50 data was tested once. b Percentage inhibition at 1 μm. c Percent inhibition at 10 μm. d ND: not tested.
Example 39: studies of anti-TopoI Activity of Compound ZLHQ-5f
Comet experiments to determine the inhibitory effect of the compound ZLHQ-5f on TopoI. The results are shown in FIG. 3, and the agarose gel electrophoresis patterns in FIG. 3 show the effect of different concentrations of the compound ZLHQ-5f on DNATopoI activity; lane 1, dna control; lane 2, topology i+ DNA; lane 3, 20 μm Camptothecin (CPT) +dna+topoi; lane 4:20 mu MZLHQ-5f+DNA+TopoI, lane 5:100 mu MZLHQ-5f+DNA+TopoI, lane 6:500 mu MZLHQ-5f+DNA+TopoI. FIG. 3 shows that the compound ZLHQ-5f can restore DNA supercoiled, and shows remarkable TopoI inhibition activity.

Claims (6)

1. A sinomenine derivative or a pharmaceutically acceptable salt thereof selected from:
Figure FDA0004237014800000011
Figure FDA0004237014800000021
Figure FDA0004237014800000031
2. a process for the preparation of a compound of the structure of claim 1, comprising the steps of:
(1) Chloridizing phenoxyacetic acid by thionyl chloride to obtain an acyl chloride compound 2; then amide condensation is carried out on the compound 2 and 2-amino-5-bromobenzoic acid to obtain a compound 5-1; then, polyphosphoric acid is used as a dehydrating agent to react for 2 hours at 130 ℃ to obtain a compound 6-1; then reflux chloridizing by phosphorus oxychloride to obtain an intermediate compound 7-1;
or 2-amino-5-bromobenzoic acid is subjected to amide condensation by chloroacetyl chloride to obtain a compound 4; nucleophilic substitution with 5-10eq aniline to obtain compound 5-2; then, polyphosphoric acid is used as a dehydrating agent to react for 2 hours at 130 ℃ to obtain a compound 6-2; then the intermediate compound 7-2 is obtained by reflux chlorination of phosphorus oxychloride,
Figure FDA0004237014800000041
(2) Nucleophilic substitution is carried out on 11 sites of two intermediate compounds 7-1 or 7-2 by using aliphatic amine, and Suzuki coupling is carried out on the obtained product with boric acid ester or boric acid after rough treatment to obtain a compound ZLHQ-1b, a compound ZLHQ-1d, a compound ZLHQ-1f, a compound ZLHQ-5j, a compound ZLHQ-5k, a compound ZLHQ-5m, a compound ZLHQ-1a, a compound ZLHQ-1c, a compound ZLHQ-2a, a compound ZLHQ-2b, a compound ZLHQ-2c, a compound ZLHQ-2d or a product compound with a boc protecting group;
(3) Removing Boc in an acidic solvent to obtain a compound ZLHQ-5c, a compound ZLHQ-5h, a compound ZLHQ-5a, a compound ZLHQ-5b, a compound ZLHQ-5d, a compound ZLHQ-5e, a compound ZLHQ-5f, a compound ZLHQ-5g, a compound ZLHQ-5i or a compound ZLHQ-1e;
the boric acid ester or boric acid in the step (2) is an intermediate compound 10;
the preparation process of the intermediate compound 10 comprises the steps of amide condensation of 5g of 2-amino-4-bromopyridine and acyl chloride in a THF solvent to obtain a product 9, then carrying out a uterine reaction, protecting for 12h at 110 ℃ with nitrogen to obtain the intermediate compound 10,
Figure FDA0004237014800000042
the acyl chloride is cyclopropaneacyl chloride, cyclobutyl chloride, cyclopentanoyl chloride, cyclohexanoyl chloride or benzoyl chloride;
the fatty amine in the step (2) is 3- (4-morpholinyl) -1-propylamine, morpholine, N-dimethylethane-1, 2-diamine, (S) -pyrrolidin-3-ol, tetrahydropyrrole, 4-tert-butoxycarbonylaminopiperazine, propanolamine, N-Boc-1, 3-propanediamine, N-Boc-piperazine, N-Boc-homopiperazine, 3-tert-butoxycarbonylaminopiperidine, (R) -3-tert-butoxycarbonylaminopyrrolidine, (S) -3-tert-butoxycarbonylaminopyrrolidine, N-Boc-ethylenediamine or N-Boc-1, 4-butanediamine.
3. The method for producing a compound according to claim 2, wherein the acidic solvent in the step (3) is a mixture of dichloromethane and trifluoroacetic acid in an equal volume ratio or ethyl acetate hydrochloride.
4. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an antitumor medicament.
5. Use of a compound ZLHQ-1d, ZLHQ-5e, ZLHQ-5f, ZLHQ-5h, ZLHQ-5j or a pharmaceutically acceptable salt thereof as defined in claim 1 for the preparation of a CDK2 inhibitor.
6. Use of a compound ZLHQ-5f, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, in the preparation of a CDK2/Topo I inhibitor.
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