CN108727400B - Compound for treating tumor - Google Patents
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Abstract
A compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof:
wherein R is1Is selected from
R2、R3Each independently selected from H, halogen, alkyl,
Or R2And R3The carbon atoms connected with the substituted heterocyclic compound form a 1-substituted or multi-substituted six-membered aromatic heterocyclic ring containing 1-2 heteroatoms; r4、R5、R6Each represents a 0 to 3 substitution on the benzene ring, R4、R5、R6Are each independently selected from H, halogen atoms, C1～6Alkyl radical, C1～6Alkoxy, hydroxy, amino, carboxyl, nitro, CH3O(CH2)nCH2O‑，
Wherein n is an integer of 1-6. The invention provides application of the compound in preparing a medicament for treating tumors. The compound of the invention has clear efficacy.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a compound for treating tumors.
Background
In recent years, with the pace of life increasing, people's pressure has further increased. Schizophrenia and cancer have become diseases that cannot be ignored in today's society, and seriously affect the normal development and normal public order of society. Since the 20 th century, the number of people infected with cancer has increased. Millions of patients die annually from cancer in the world, and cancer patients are mostly low-and medium-income populations. Cancer treatment can be performed by traditional Chinese medicine therapy, surgical resection, chemotherapy, radiotherapy, immunotherapy, monoclonal antibody therapy or other treatment methods, but there are few cases of complete cure. How to reduce the pain of cancer patients to the maximum extent and achieve good prevention and treatment effects is a problem which needs to be solved urgently by many researchers at present.
Disclosure of Invention
The invention aims to provide a novel compound for treating tumors.
The present invention provides a compound represented by formula (i) or a pharmaceutically acceptable salt thereof, or a solvate thereof:
wherein R is1Is selected from
R2、R3Each independently selected from H, halogen, alkyl,
Or R2And R3The carbon atoms connected with the substituted heterocyclic compound form a 1-substituted or multi-substituted six-membered aromatic heterocyclic ring containing 1-2 heteroatoms;
R4、R5、R6each represents a 0 to 3 substitution on the benzene ring, R4、R5、R6Are each independently selected from H, halogen atoms, C1～6Alkyl radical, C1～6Alkoxy, hydroxy, amino, carboxyl, nitro, CH3O(CH2)nCH2O-，
Wherein n is an integer of 1-6.
Further, said R4、R5、R6Are each independently selected from H, halogen atoms, C1～6Alkyl radical, C1～6Alkoxy radical, CH3O(CH2)nCH2O-，
Wherein n is an integer of 1-6.
Further, said R4、R5、R6Each independently selected from H, F, methyl, methoxy, CH3OCH2CH2O-，
Further, said R4、R5、R6Represents an unsubstituted or mono-substituted benzene ring. Further, said R1Selected from:
further, the six-membered aromatic heterocyclic ring is
Wherein R is7Is selected from
Further, the above compound is one of the following compounds:
the invention also provides a preparation method of the compound, which comprises the following steps: it comprises the following steps:
(I) Synthesis of Compounds 1-14:
(1) synthesis of intermediate h:
(2A) synthesizing compounds 1-7:
(2B) and (3) synthesizing a compound 8-14:
(II) Synthesis of Compounds 15-21:
(III) Synthesis of Compounds 22-43:
the invention provides application of the compound in preparing a medicament for treating tumors.
The medicine is used for treating colon cancer, fibrosarcoma, epidermoid carcinoma and breast cancer.
The invention provides application of the compound in preparing a medicament with the activity of inhibiting receptor tyrosine kinase (EGFR).
The invention provides application of the compound in preparing a medicament for treating tumors.
Wherein, the medicine is used for treating colon cancer, fibrosarcoma, epidermoid carcinoma and breast cancer.
The invention also provides application of the compound in preparing a medicament with the activity of inhibiting receptor tyrosine kinase (EGFR).
The invention also provides application of the compound in preparing a medicament for inhibiting neovascularization.
The invention designs and synthesizes 43 compounds in 5 series by the basic principle of medicinal chemistry. The activity of the compound cpd1-cpd21 in inhibiting colon cancer HT-29 and epidermal cancer A431 at a concentration of 10. mu.M was preliminarily tested by MTT method. Wherein, the compound cpd9 and the other 5 lead compounds show good inhibitory activity, wherein the inhibitory rate of the compound cpd9 on HT-29 and epidermal cancer respectively reaches 89.4 percent and 84.2 percent.
Further activity and mechanism studies were performed on the compound cpd 9. Using the MTT method, cpd9 was measured for inhibition of proliferation of colon cancer HT-29 and epidermal cancer A431 cells at various concentrations (0.3125, 0.625, 1.25, 2.5, 5.0, 12.5 and 25. mu.M) and its IC50 was calculated as 2.9. mu.M and 6.8. mu.M, respectively. The colon cancer cells HT-29 were treated with 2.5. mu.M cpd9 for 16 hours and significant apoptosis occurred.
The invention determines the inhibitory activity of a compound cpd1-cpd43 on receptor tyrosine kinase (EGFR) at a concentration of 10 mu M, wherein the inhibitory rates of the compounds cpd9 and cpd37 on the EGFR are 92.9 percent and 91.3 percent respectively. The inhibitory activity of cpd9 and cpd37 on EGFR was further determined at different concentrations (0.3125, 0.625, 1.25, 2.5, 5.0, 12.5 and 25 μ M) and its IC50 was calculated as 3.3 μ M and 3.9 μ M, respectively.
The ability of cpd9 to inhibit neovascularisation was determined using zebrafish embryos at concentrations of 1 μ M, 10 μ M and 20 μ M.
In conclusion, the compound has excellent antitumor activity and the capacity of inhibiting new vessels, and has a good application prospect.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix (C)a～Cb) Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, (C)1～C4) The alkyl group means an alkyl group having 1 to 4 carbon atoms.
Said C is1～C6Alkyl is C1、C2、C3、C4、C5、C6The alkyl group of (1) is a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like. C1-C6The alkoxy radicals of (a) also have the meanings corresponding to their radicals.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1: growth inhibition rate of HT-29 cell line by compound cpd1-cpd21
FIG. 2: growth inhibition rate of compound cpd1-cpd21 on A431 cell line
FIG. 3: cpd9 vs HT-29 and A431 cell growth inhibition curves
FIG. 4: cpd9 induces HT-29 apoptosis
FIG. 5: effect of cpd9 on zebrafish embryonal internode blood vessels, a is a negative (blank) control; b is the development condition of the zebra fish embryo new blood vessel dosed with cpd 910 mu M; c is the development condition of the zebra fish embryo new blood vessel dosed with cpd 920 mu M; d is a positive control, namely the angiogenesis condition of zebrafish embryos administered with Gefitinib 10 mu M.
Detailed Description
The raw materials and instruments used in the invention can be purchased from the market.
Example 1 Synthesis of Compound 1
The synthetic route is as follows:
the preparation method comprises the following steps:
(1) adding the compound a (10g, 1.0eq) and dichloromethane (100ml) into a three-neck flask, cooling to-78 ℃ under the protection of nitrogen, and adding a dichloromethane solution (1g/3ml) of boron tribromide (10 eq). After the addition, the reaction is carried out for 1h under the condition of heat preservation, the temperature is raised to 25 ℃, the system reacts for 4 to 6h, after the reaction is finished, 10ml of water is used for washing, anhydrous sodium sulfate is used for drying, the organic phase is concentrated to be dry, and the mixture is passed through a fast column to obtain 6.97g of a compound b, wherein the yield is as follows: 80.5 percent.
(2) The compound b (5g, 1.0eq) and pyridine (50ml) were added to a three-necked flask, and acetic anhydride (2.5eq) was added under nitrogen at a controlled temperature of less than 20 ℃. After the addition, the reaction is carried out for 1h, the temperature is raised to 25 ℃, the system is reacted for 4-6h, after the reaction is finished, the reaction liquid is poured into ice water, the pH value is adjusted to 6-7 by 3N hydrochloric acid, DCM is used for extraction, anhydrous sodium sulfate is used for drying, the organic phase is concentrated to be dry, and 6.14g of a compound c is obtained after passing through a fast column, and the yield is as follows: 83.4 percent.
(3) Compound c (6g, 1.0eq) and phosphorus oxychloride (50ml) were charged in a three-necked flask and N, N-dimethylaniline (2.5eq) was added under nitrogen. After the addition, heating to reflux reaction for 4-6h, after the reaction is finished, evaporating excessive phosphorus oxychloride, pouring the reaction liquid into ice water, extracting with DCM, drying with anhydrous sodium sulfate, concentrating the organic phase to dryness, and passing through a fast column to obtain 4.19g of a compound d, wherein the yield is as follows: 65.3 percent.
(4) Compound d (4g, 1.0eq), triethylamine (1.2eq) and dichloromethane (50mL) were added to a three-necked flask, the temperature was reduced to 0 ℃ in an ice bath, and a solution of compound e (1eq) in dichloromethane (1g/2mL) was added. After the addition, the temperature is raised to 25 ℃ for reaction for 4-6h, the reaction is finished, 10ml of water is used for washing, anhydrous sodium sulfate is used for drying, the organic phase is concentrated to be dry, and the fast column is used for obtaining 4.50g of a compound f, wherein the yield is as follows: 81 percent.
(5) Adding compound f (4g, 1.0eq), lithium hydroxide (2.0eq), ethanol (20ml) and water (30ml) into a three-necked flask, cooling to 0 ℃ in an ice bath, and adding Boc2O (1.2 eq). After the addition, heating to 25 ℃ for reaction for 4-6h, after the reaction is finished, adding sodium hydroxide (3eq), heating to 50 ℃ for reaction for 5-6h, pouring the reaction solution into ice water after the reaction is finished, adjusting the pH to 6-7 with 2N hydrochloric acid water, extracting with DCM, drying with anhydrous sodium sulfate, concentrating the organic phase to dryness, and passing through a fast column to obtain 3.75g of a compound g, wherein the yield is as follows: 90 percent.
(6) The compound g (3g, 1.0eq), p-toluenesulfonic acid (0.01eq), 4-piperidone (1.2eq) and toluene (50ml) were charged in a three-necked flask, and the temperature was raised to reflux to separate water. At the end of the reaction, the solvent is removed under reduced pressure at 50 ℃ and the column is cleared quickly, giving 3.21g of compound h, yield: 89 percent.
(7) The compound h (3g, 1.0eq), triethylamine (1.2eq) and dichloromethane (50mL) were added to a three-necked flask, the temperature was reduced to 0 ℃ in an ice bath, and a solution of benzoyl chloride (1eq) in dichloromethane (1g/2mL) was added. After the addition, heating to 25 ℃ for reaction for 4-6h, after the reaction is finished, washing with 10ml of water, drying with anhydrous sodium sulfate, concentrating an organic phase to dryness, adding ethyl acetate (20ml) for complete dissolution, cooling to below 0 ℃, introducing dry hydrogen chloride gas to saturation, keeping the temperature and stirring for 1-2h, separating out a large amount of solids, filtering out the solids, adding into 50ml of water, adjusting the pH of saturated sodium carbonate to 8-9, extracting with DCM, drying with anhydrous sodium sulfate, concentrating the organic phase to dryness, and passing through a fast column to obtain 3.13g of a target compound, wherein the yield is as follows: 75 percent.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.13-2.38(m，4H,CH2),3.29-3.39(m, 4H,CH2),4.0(s,1H,NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.63(s,2H,CH),7.70(s,1H,CH).8.03(s,2H,CH),8.49(s,1H,CH)。
The molecular formula is as follows: c26H20ClFN4O3Relative molecular mass: 490.91。
Example 2 Synthesis of Compound 2
Compound 2 was prepared by the same preparation method as example 1 except that benzoyl chloride in step (7) of example 1 was replaced with 2-fluorobenzoyl chloride,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),4.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH)7.29(s,1H, CH),7.40(s,1H, CH),7.41(s,1H, CH)7.42(s,1H, CH),8.00(s,1H, CH),8.01(s,1H, CH)8.49(s,1H, CH). The molecular formula is as follows: c26H19ClF2N4O3Relative molecular mass: 508.9.
example 3 Synthesis of Compound 3
Compound 3 can be produced by the same production method as in example 1 except that benzoyl chloride in step (7) of example 1 is used instead of p-fluorobenzoyl chloride,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),4.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.42(s,2H, CH),.8.12(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c26H19ClF2N4O3Relative molecular mass: 508.9.
example 4 Synthesis of Compound 4
Compound 4 can be produced by the same production method as in example 1 except that benzoyl chloride in step (7) in example 1 is replaced with 4-methylbenzoyl chloride,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.34(m, 3H, CH3)2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),4.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,2H, CH),.7.91(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c27H22ClFN4O3Relative molecular mass: 504.94.
example 5 Synthesis of Compound 5
Compound 5 can be produced by the same production method as in example 1 except that benzoyl chloride in step (7) in example 1 is replaced with p-methoxybenzoyl chloride,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),3.83(m, 3H, CH3)4.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.17(s,2H, CH),.7.92(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c27H22ClFN4O4Relative molecular mass: 520.94.
example 6 Synthesis of Compound 6
Compound 6 can be produced by the same production method as in example 1 except that benzoyl chloride in step (7) in example 1 is replaced with 4- (2-methoxyethoxy) benzoyl chloride,1H NMR(300MHz,CDCl3TMS, 25 ℃, 2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),3.30(m, 3H, CH3)3.79 (d, J ═ 7.1,2H, CH2),4.0(s,1H, NH)4.31(d, J ═ 7.1,2H, CH2)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.17(s,2H, CH),.7.92(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c29H26ClFN4O5Relative molecular mass: 564.99.
example 7 Synthesis of Compound 7
Compound 7 can be produced by replacing benzoyl chloride in step (7) in example 1 with 4- ((4-methylpiperazin-1-alkyl) methyl) benzoyl chloride by the same production method as in example 1,1H NMR(300MHz,CDCl3,25℃, TMS):δ＝2.13-2.38(m，4H,CH2) 2.26(m, 3H, CH3)2.35(m, 4H, CH2)2.48(m, 4H, CH2)3.29-3.39(m,4H, CH2),)4.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.41(s,2H, CH),.7.91(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c32H32ClFN6O3Relative molecular mass: 603.09.
example 8 Synthesis of Compound 8
The synthetic route is as follows:
steps (1) to (6) are exactly the same as in example 1;
the step (7) is as follows: the compound h (3g, 1.0eq) and dichloromethane (40mL) were added to a three-necked flask, cooled to 0 ℃ in an ice bath under nitrogen protection, and a solution of phenyl isocyanate (1.0eq) in dichloromethane (1g/2mL) was added. After the addition is finished, after the reaction is carried out for 30min under heat preservation, the temperature is raised to 25 ℃ for reaction for 2-3h, the reaction is finished, the organic phase is concentrated to be dry, ethyl acetate (20ml) is added for complete dissolution, the temperature is reduced to below 0 ℃, dry hydrogen chloride gas is introduced until the hydrogen chloride gas is saturated, the heat preservation and stirring are carried out for 1-2h, a large amount of solid is separated out, the solid is filtered out, the solid is added into 50ml of water, the pH is adjusted to 8-9 by saturated sodium carbonate, DCM is used for extraction, after anhydrous sodium sulfate is dried, the organic phase is concentrated to be dry, and the target compound 2.05g is: 66 percent.
1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.13-2.38(m, 4H, CH2),3.29-3.39(m,4H, CH2),4.0(s,1H, NH)6.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.19(s, 1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.43(s,2H, CH),.7.61(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c26H21ClFN5O3Relative molecular mass: 505.93.
Example 9 Synthesis of Compound 9
Compound 9 was obtained by the same production method as that of example 8 except that phenyl isocyanate in the step (7) of example 8 was replaced with 2-fluorophenyl isocyanate,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.13-2.38 (m，4H,CH2),3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H,NH)6.79(s,1H,CH),7.01(s, 1H,CH)7.16(s,1H,CH)7.20(s,1H,CH)7.22(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.96(s,1H,CH),8.49(s,1H,CH)。
the molecular formula is as follows: c26H20ClF2N5O3Relative molecular mass: 523.92.
example 10 Synthesis of Compound 10
the molecular formula is as follows: c26H20ClF2N5O3Relative molecular mass: 523.92.
Example 11 Synthesis of Compound 11
Compound 11 was obtained by the same production method as that of example 8 except that phenyl isocyanate in the step (7) of example 8 was replaced with 4-methyl phenyl isocyanate,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.13-2.38(m，4H,CH2),2.34(s，3H CH3)3.29-3.39(m,4H,CH2),4.0(s,1H,NH)6.0(s,1H, NH)6.79(s,1H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH),7.41(s,1H,CH), 7.21(s,2H,CH),.7.56(s,2H,CH),8.49(s,1H,CH)。
the molecular formula is as follows: c27H23ClFN5O3Relative molecular mass: 519.95.
Example 12 Synthesis of Compound 12
Compound 12 can be produced by the same production method as in example 8 except that phenyl isocyanate in step (7) in example 8 is used instead of 4-methoxyphenyl isocyanate,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.13-2.38(m，4H,CH2),3.29-3.39(m,4H,CH2),3.38(s，3H CH3),4.0(s,1H,NH)6.0(s,1H, NH)6.79(s,1H,CH),6.97(s,2H,CH),7.16(s,1H,CH)7.24(s,1H,CH),7.29(s,1H,CH), 7.41(s,1H,CH),7.51(s,2H,CH),8.49(s,1H,CH)。
the molecular formula is as follows: c27H23ClFN5O4Relative molecular mass: 535.95.
Example 13 Synthesis of Compound 13
Phenyl isocyanate in step (7) of example 8 was replaced with 4- (2-methoxyethoxy)) Phenyl isocyanate by the same production method as in example 8 gave compound 13,1H NMR(300MHz,CDCl325 ℃ TMS-. delta.2.13-2.38 (m,4H, CH2),2.26(m, 3H, CH3)2.35(m, 4H, CH2)2.48(m, 4H, CH2)3.29-3.39(m,4H, CH2),)4.0(s,1H, NH)6.0(s,1H, NH)6.79(s,1H, CH),6.97(s, 2H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),.7.51(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c29H27ClFN5O5Relative molecular mass: 580.01.
Example 14 Synthesis of Compound 13
Compound 14 was obtained by the same production method as in example 8 except that phenyl isocyanate in step (7) in example 8 was replaced with 4- ((4-methylpiperazin-1-alkyl) methyl) phenyl isocyanate,1H NMR(300MHz,CDCl325 ℃ and TMS. delta. is 2.13-2.38(m, 4H, CH2),2.26(m, 3H, CH3)2.35(m, 4H, CH2)2.48(m, 4H, CH2)3.29-3.39(m,4H, CH2),)4.0(s,1H, NH)6.0(s,1H, NH)6.79(s,1H, CH),7.16(s,1H, CH)7.24(s,1H, CH),7.29(s,1H, CH),7.41(s,1H, CH),7.21(s,2H, CH),.7.56(s,2H, CH),8.49(s,1H, CH). The molecular formula is as follows: c32H33ClFN7O3Relative molecular mass: 618.10.
Example 15 Synthesis of Compound 15
The synthetic route is as follows:
the preparation method comprises the following steps:
(1) potassium tert-butoxide (1.0eq), trimethyl sulfoxide iodide (1.1eq) and DMSO (50ml) were charged in a three-necked flask, and after stirring at room temperature (25 ℃ C.) for 30min, Compound i (10g, 1.0eq) was added. After the addition, the reaction is carried out at room temperature overnight, 200ml of water and 200ml of ethyl acetate are added after the reaction is finished, an organic phase is separated after the full stirring, the aqueous phase is extracted by 200ml of ethyl acetate again, the organic phase is combined, the saturated salt is washed, anhydrous sodium sulfate is dried, the organic phase is concentrated to be dry, and 8.03g of a compound j is obtained after the fast column chromatography, wherein the yield is as follows: 75 percent.
(2) Adding a compound j (8g, 1.0eq), a compound k (1.5eq), lithium perchlorate (1.7eq) and acetonitrile (50ml) into a three-necked bottle, heating to 80 ℃, stirring and reacting for 12-18h, cooling to room temperature after the reaction is finished, adding 200ml of ethyl acetate for dilution, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating an organic phase to dryness, and passing through a fast column to obtain 9.06g of a compound l, wherein the yield is as follows: and 63 percent.
(3) Adding compound l (8g, 1.0eq), cesium carbonate (1.5eq) and acetonitrile (50ml) into a three-necked flask, heating to 60 ℃, stirring for reaction for 6-8h, cooling to room temperature after the reaction is finished, adding 200ml of ethyl acetate for dilution, washing with saturated common salt water, drying with anhydrous sodium sulfate, concentrating an organic phase to dryness, and passing through a fast column to obtain 6.37g of compound m, wherein the yield is as follows: 84 percent.
(4) Adding morpholine (2.2eq) and anhydrous tetrahydrofuran (10ml) into a three-neck flask, cooling to-5 ℃ under the protection of nitrogen, adding DIBALH (2.0eq), after dripping, keeping the temperature for reaction for 3h, then adding a tetrahydrofuran solution (1g/3ml) of a compound m (6g, 1.0eq) into a reaction system, controlling the internal temperature to be less than 0 ℃ in the adding process, keeping the temperature for reaction for 30min after adding, adding DIBALH (1.1eq), keeping the temperature for reaction for 1h, quenching with 1N hydrochloric acid, washing with saturated salt water, back-extracting the water phase with ethyl acetate, combining the organic phase, drying with anhydrous sodium sulfate, concentrating the organic phase to dryness, passing through a fast column, obtaining 4.79g of the compound N, and obtaining the yield: 87 percent.
(5) Adding a compound n (4g, 1.0eq), a compound o and ethanol (50ml) into a three-necked bottle, then dropwise adding 10mg piperidine, heating to reflux for 4-6h, after the reaction is finished, washing with 10ml water, drying by using anhydrous sodium sulfate, concentrating an organic phase to dryness, adding ethyl acetate (20ml) to dissolve completely, cooling to below 0 ℃, introducing dry hydrogen chloride gas to saturation, stirring for 1-2h at the constant temperature, separating out a large amount of solids, filtering out the solids, adding into 50ml water, adjusting the pH to 8-9 by using saturated sodium carbonate, extracting by using DCM, drying by using the anhydrous sodium sulfate, concentrating the organic phase to dryness, and performing fast column chromatography to obtain 3.65g of a compound p, wherein the yield is as follows: 83 percent.
(6) Adding a compound p (3g, 1.0eq) and THF (50ml) into a three-neck flask, cooling to 0 ℃ under the protection of nitrogen, adding sodium hydride (1.5eq), stirring for 30min under heat preservation after the addition is finished, adding benzyl chloride (1.1eq), reacting for 1h under heat preservation, heating to room temperature for 4-6h, adding water for quenching after the reaction is finished, carrying out back extraction on an aqueous phase by using ethyl acetate, combining organic phases, drying by using anhydrous sodium sulfate, concentrating the organic phases to dryness, and passing through a fast column to obtain 2.39g of a target compound, wherein the yield is as follows: 64 percent
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.51(m,4H),3.66(s,2H), 4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
The molecular formula is as follows: c28H25FN2O3Relative molecular mass: 456.51.
example 16 Synthesis of Compound 16
Compound 16 can be produced by the same production method as that of example 15 except that benzyl chloride in step (6) of example 15 is replaced with 2-fluorobenzyl chloride. The molecular formula is as follows: c28H24F2N2O3Relative molecular mass: 474.50.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.51(m,4H),3.66(s,2H), 4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
example 17 Synthesis of Compound 17
The benzyl chloride in step (6) of example 15 was replaced with 4-fluorobenzyl chlorideCompound 17 was obtained by the same production method as in example 15. The molecular formula is as follows: c28H24F2N2O3Relative molecular mass: 474.50.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.51(m,4H),3.66(s,2H), 4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
example 18 Synthesis of Compound 18
Compound 18 was prepared by the same procedure as in example 15 except that benzyl chloride in step (6) of example 15 was replaced with 4-methylbenzyl chloride. The molecular formula is as follows: c29H27FN2O3Relative molecular mass: 470.53.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.34(s,3H),2.51(m,4H), 3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
example 19 Synthesis of Compound 19
Compound 19 was prepared by the same preparation method as in example 15 except that benzyl chloride in step (6) of example 15 was replaced with 4-methoxybenzyl chloride. The molecular formula is as follows: c29H27FN2O4Relative molecular mass: 486.53.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.51(m,4H),3.66(s,2H), 3.83(s,3H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
example 20 Synthesis of Compound 20
Compound 20 was prepared by the same preparation method as in example 15 except that benzyl chloride in step (6) of example 15 was replaced with 4- (2-methoxyethoxy) benzyl chloride.
1H NMR(300MHz,CDCl325 ℃, TMS): δ 1.97(m,4H),2.51(m,4H),3.30(s,3H), 3.66(s,2H),3.79(t, J ═ 7.1Hz,2H),4.28(s.2h),4.31(t, J ═ 7.1Hz,2H),7.05(m,6H),7.33(m,4H),7.56(s, 1H), 7.79(m,1H),8.0(s,1H, NH). The molecular formula is as follows: c31H31FN2O5Relative molecular mass: 530.59.
example 21 Synthesis of Compound 21
Compound 21 was prepared by the same preparation method as in example 15 except that benzyl chloride in step (6) in example 15 was replaced with 4- ((4-methylpiperazin-1-alkyl) methyl) benzyl chloride.
1H NMR(300MHz,CDCl3,25℃,TMS):δ＝1.97(m,4H),2.26(s,3H),2.35-2.48(m,8H), 3.66(s,2H),4.28(s.2H),7.05(m,6H),7.33(m,4H),7.56(s,1H),7.79(m,1H),8.0(s,1H,NH)。
The molecular formula is as follows: c34H37FN4O3Relative molecular mass: 568.68.
example 22 Synthesis of Compound 22
The synthetic route is as follows:
the preparation method comprises the following steps:
(1) compound d (10g, 1.0eq), and 6N hydrochloric acid (50ml) were added to a three-necked flask, heated to 50 ℃ for reaction for 4-6h, quenched, cooled to room temperature, extracted with DCM, dried over anhydrous sodium sulfate, concentrated to dryness in the organic phase, and passed through a flash column to give 5.95g of compound q, yield: 85 percent.
(2) Compound q (5g, 1.0eq), p-toluenesulfonic acid (0.01eq), 4-piperidone (1.2eq) and toluene (50ml) were charged in a three-necked flask, and the temperature was raised to reflux to remove water. At the end of the reaction, the solvent is removed under reduced pressure at 50 ℃ and the column is cleared quickly to give 6.14g of the compound r, yield: 87 percent.
(3) Adding a compound r (5g, 1.0eq) and THF (50ml) into a three-neck flask, cooling to 0 ℃ under the protection of nitrogen, adding sodium hydride (1.5eq), stirring for 30min under heat preservation after the addition is finished, adding 2-fluorobenzoyl chloride (1.1eq), reacting for 1h under heat preservation, heating to room temperature, reacting for 4-6h, adding water for quenching after the reaction is finished, back-extracting the water phase with ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, concentrating the organic phases to dryness, and passing through a fast column to obtain 5.18g of a compound raw20, wherein the yield is as follows: 72 percent
(4) Adding compound raw20(2g, 1.0eq), compound raw21(1.5eq), DIPEA (1.0eq) and isopropanol (50ml) into a three-necked flask, heating to 90 ℃ for reaction for 4-6h, directly concentrating to dryness after the reaction is finished, and passing through a fast column to obtain 1.45g of target compound, wherein the yield is as follows: and 55 percent.1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.38 (m,4H),2.82(s,3H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41 (m,3H),7.50(d,J＝7.5Hz,1H),8.00(m,2H),8.49(s,1H)。
The molecular formula is as follows: c28H22FN5O3S, relative molecular mass: 527.57.
example 23 Synthesis of Compound 23
Compound 23 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw22,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝0.90(t,J＝8.0Hz,3H),1.65(m,2H), 2.38(m,4H),2.86(m,2H),3.39(m,4H),4.0(s,1H,NH),6.73(m,1H),7.02(s,1H),7.24(s,1H), 7.41(m,3H),7.50(d,J＝7.5Hz,1H),8.00(m,2H),8.49(s,1H)。
the molecular formula is as follows: c30H26FN5O3S, relative molecular mass: 555.62.
example 24 Synthesis of Compound 24
Compound 24 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw23,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.38(m,4H),2.86(m,2H),3.39 (m,4H),4.0(s,1H, NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00 (m,4H),8.49(s, 1H). The molecular formula is as follows: c33H24FN5O3S, relative molecular mass: 589.64.
example 25 Synthesis of Compound 25
Compound 25 can be produced by the same production method as in example 22 except that raw21 in example 22 is replaced with raw24,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.34(s,3H),2.38(m,4H),2.86 (m,2H),3.39(m,4H),4.0(s,1H, NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00 (m,4H),8.49(s, 1H). The molecular formula is as follows: c34H26FN5O3S, relative molecular mass: 603.67.
example 26 Synthesis of Compound 26
Mixing all the materialsCompound 26 was obtained by substituting raw21 in example 22 with raw25 and carrying out the same preparation process as in example 22,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.38(m,4H),2.86(m,2H),3.39 (m,4H),4.0(s,1H, NH),5.35(s,1H, OH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H), 7.50(m,3H),8.00(m,4H),8.49(s, 1H). The molecular formula is as follows: c33H24FN5O4S, relative molecular mass: 605.64.
example 27 Synthesis of Compound 27
Compound 27 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw26,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.38(m,4H),2.86(m,2H),3.39 (m,4H),3.83(s.3h),4.0(s,1H, NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00 (m,4H),8.49(s, 1H). The molecular formula is as follows: c34H26FN5O4S, relative molecular mass: 619.66.
example 28 Synthesis of Compound 28
Compound 28 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw27,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.34(s,3H),2.38(m,4H),2.86 (m,2H),3.39(m,4H),4.0(s,1H, NH),6.73(m,1H),7.02(s,1H),7.24(s,1H),7.41(m,4H),7.50(m,3H),8.00 (m,4H),8.49(s, 1H). The molecular formula is as follows: c34H26FN5O3S, relative molecular mass: 603.67.
example 29 Synthesis of Compound 29
Compound 29 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw28,1H NMR(300MHz,CDCl3TMS, δ is 2.26(t,2H, J is 7.1Hz, CH2),2.26 (t,2H, J is 7.1, CH2),3.39(t,2H, J is 7.1Hz, CH2),3.39(t,2H, J is 7.1Hz, CH2),4.1(s,1H, NH),5.35(s,1H, OH),6.73(d,1H, J is 7.5Hz, CH),6.91(d,1H, J is 7.5Hz, CH),7.02(s, 1H, J is 1.5Hz, CH),7.24(s,1H, CH),7.32(s,1H, CH),7.34(dd,1H, J is 7.5, J is 7.5Hz, 7.5H, CH),7.5 (dd, 7.5H, J is 7.5Hz, 7.5H, J is 7.5H, J is 7.5H, J, 7.5H, 7.5 (dd, H, CH), 7.5H, J, dd, H, CH, 7.5Hz, 7.5H, 7.5H, J (dd, 7.5H, J, dd, H, 7.5H, 7.5,7, CH),8.01(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH). The molecular formula is as follows: c33H24FN5O4S, relative molecular mass: 605.64.
example 30 Synthesis of Compound 30
Compound 30 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw29,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.40(t,2H,J＝7.1Hz,CH2), 2.40(t,2H,J＝7.1Hz,CH2),3.37(t,2H,J＝7.1Hz,CH2),3.37(t,2H,J＝7.1Hz,CH2),4.1 (s,1H,NH),6.70(d,1H,J＝7.5Hz,CH),7.02(s,1H,CH),7.24(s,1H,CH),7.39(dd,1H, CH),7.41(s,1H,CH),7.44(d,1H,J＝7.5,8.0Hz,CH),7.45(d,1H,J＝7.5Hz,CH),7.46(dd, 1H,J＝7.5,7.5Hz,CH),7.50(d,1H,J＝7.5Hz,CH),7.89(d,1H,J＝7.5Hz,CH),8.00(dd, 1H,J＝7.5,7.5Hz,CH),8.01(d,1H,J＝5.0,7.5Hz,CH),8.01(s,1H,CH),8.51(s,1H,CH)。
the molecular formula is as follows: c33H23ClFN5O3S, relative molecular mass: 624.08.
example 31 Synthesis of Compound 31
Compound 31 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw30,1H NMR(300MHz,CDCl3TMS, 25 ℃, 2.44(t,2H, J, 7.1Hz, CH2), 2.44(t,2H, J, 7.1Hz, CH2),3.34(t,2H, J, 7.1Hz, CH2),3.34(t,2H, J, 7.1Hz, CH2),4.0(s,1H, NH),6.73(d,1H, J, 7.5Hz, CH),7.02(2,1H, CH),7.24(s,1H, CH),7.40(dd,1H, J, 7.5Hz, 7.41(s,1H, CH),7.42(d,1H, 7.5,8.0, CH),7.50(d, 7.5H, J, 7.5Hz, 7.5H, J, 7.5H, 7.5Hz, 7.5H, J, 7.5H, J, 7.5H, J, 7.8.5, 1H, CH),8.65(s, 1H, CH). The molecular formula is as follows: c33H23FN6O5S, relative molecular mass: 634.64.
example 32 Synthesis of Compound 32
Compound 32 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw31,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.33(t,2H,J＝7.1Hz,CH2), 2.33(t,2H,J＝7.1Hz,CH2),3.39(t,2H,J＝7.1Hz,CH2),3.39(t,2H,J＝7.1Hz,CH2),3.9 (s,1H,NH),6.73(s,1H,J＝7.5Hz,CH),7.02(s,1H,CH),7.24(s,1H,CH),7.24(d,1H,J＝ 7.5,8.0Hz,CH),7.40(dd,1H,J＝7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J＝7.5,8.0 Hz,CH),7.50(d,1H,J＝7.5Hz,CH),7.65(d,1H,J＝5.0,7.5Hz,CH),7.99(s,1H,CH),8.00 (dd,1H,J＝5.0,7.5,7.5Hz,CH),8.01(d,1H,J＝5.0,7.5Hz,CH),8.51(s,1H,CH)。
the molecular formula is as follows: c33H22ClF2N5O3S, relative molecular mass: 642.07.
example 33 Synthesis of Compound 33
By replacing raw21 in example 22 with raw32 and carrying out the same production process as in example 22, compound 33 was produced,1H NMR(300MHz,CDCl3TMS, δ is 2.38(t,2H, J is 7.1Hz, CH2),2.38(t,2H, J is 7.1Hz, CH2),3.39(t,2H, J is 7.1Hz, CH2),3.39(t,2H, J is 7.1Hz, CH2),4.1(s,1H, NH),6.73(d,1H, J is 7.5Hz, CH),7.04(s,1H, CH),7.24(s,1H, CH),7.30(d,1H, J is 7.5,8.0Hz, CH),7.30(d,1H, J is 7.5, 7.0 Hz, 7.30(d,1H, J is 7.5,8.0Hz, CH),7.41(d,1H, J is 7.5, 7.0 Hz, 7.7.41 (H, 7.5, 7.7.5, 7.7H, J is 7.5, 7.0 Hz, 7.7.7H, 7.5, 7.7H, 7H, 7.5, 7.7H, 7H, 7.5, 7.7.5, 7H, 7.7H, 7.5, 7H, 7.7.7H, 7.7.5, 7H, 7.5, 7H, 7.5,7.5Hz, CH),8.03(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH). The molecular formula is as follows: c33H23F2N5O3S, relative molecular mass: 607.63.
example 34 Synthesis of Compound 34
Compound 34 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw33,1H NMR(300MHz,CDCl325 ℃, TMS): δ ═ 2.24(s,3H, CH3),2.37(t,2H, CH2),2.38(t,2H, CH2),3.09(t,2H, J ═ 7.1Hz, CH2),3.39(t,2H, J ═ 7.1Hz, CH2),3.39(t,2H, J ═ 7.1Hz, CH2),4.0(s,1H, NH),4.27(t,2H, J ═ 7.1Hz, CH2),6.28(d,1H, J ═ 10.9Hz, CH),6.68(d,1H, J ═ 7.5Hz, CH),6.70(s,1H, CH),7.24(s,1H, CH),7.40 (ddh, 1H, J ═ 7.5,7.5H, J ═ 7.5Hz, 7.5,7.5H, 7.8, 7.5 (d, 7.8, 7.5H, 7.5, J ═ 7.5Hz, 7.7, 7.5,7.5H, 7.8, J ═ 7.5,7, 7.8, 7.7.5 Hz, 7, 7.5Hz, 7, 7.5H, 7.5Hz, 7, 7.8, 7, 7.5Hz, 7.5H, 7, 7.8, 7.5Hz, 7, 8.49(s,1H, CH),8.82(d,1H, J ═ 10.9Hz, CH),16.55 (OH). The molecular formula is as follows: c34H29ClFN5O6Relative molecular mass: 658.08.
example 35 Synthesis of Compound 35
Compound 35 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw34,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.36(s,3H,CH3),2.38(t,2H,J ＝7.1Hz,CH2),2.38(t,2H,J＝7.1Hz,CH2),3.09(t,2H,J＝7.1Hz,CH2),3.39(t,2H,J＝ 7.1Hz,CH2),3.39(t,2H,J＝7.1Hz,CH2),4.0(s,1H,NH),4.27(t,2H,J＝7.1Hz,CH2), 6.28(d,1H,J＝10.0Hz,CH),6.46(s,1H,J＝8.0Hz,CH),6.72(d,1H,J＝5.0,7.5Hz,CH), 7.24(s,1H,CH),7.32(d,1H,J＝7.5Hz,CH),7.40(dd,1H,J＝7.5,7.5Hz,CH),7.41(s,1H, CH),7.42(d,1H,J＝7.5,8.0Hz,CH),8.00(dd,1H,J＝5.0,7.5,7.5Hz,CH),8.01(d,1H,J＝ 5.0,7.5Hz,CH),8.49(s,1H,CH),8.82(d,1H,J＝10.0Hz,CH),16.77(OH)。
the molecular formula is as follows: c34H29F2N5O6Relative molecular mass: 641.62.
example 36 Synthesis of Compound 36
Compound 36 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw35,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.30(s,3H,CH3),2.38(t,2H,J ＝7.1Hz,CH2),2.38(t,2H,J＝7.1Hz,CH2),3.09(t,2H,J＝7.1Hz,CH2),3.39(t,2H,J＝ 7.1Hz,CH2),3.39(t,2H,J＝7.1Hz,CH2),4.1(s,1H,NH),4.27(t,2H,J＝7.1Hz,CH2),6.28 (d,1H,J＝10.3Hz,CH),7.00(d,1H,J＝7.5Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J＝7.5, 7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J＝7.5,8.0Hz,CH),7.45(s,1H,CH),7.94(d,1H, J＝7.6Hz,CH),8.00(dd,1H,J＝5.0,7.5,7.5Hz,CH),8.01(d,1H,J＝5.0,7.5Hz,CH),8.49 (s,1H,CH),8.82(d,1H,J＝10.3Hz,CH),16.77(OH)。
the molecular formula is as follows: c34H29FN6O8Relative molecular mass: 668.63.
example 37 Synthesis of Compound 37
Compound 37 can be produced by the same production method as in example 22 except that raw21 in example 22 is replaced with raw36,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.27(s,3H,CH3),2.38(t,2H,J ＝7.1Hz,CH2),2.38(t,2H,J＝7.1Hz,CH2),3.09(t,2H,J＝7.1Hz,CH2),3.40(t,2H,J＝ 7.1Hz,CH2),3.40(t,2H,J＝7.1Hz,CH2),4.1(s,1H,NH),4.27(t,2H,J＝7.1Hz,CH2),6.12 (s,1H,CH),6.28(d,1H,J＝10.6Hz,CH),7.13(d,1H,J＝7.5Hz,CH),7.22(d,1H,J＝7.5 Hz,CH),7.24(s,1H,CH),7.40(dd,1H,J＝7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J ＝7.5,8.0Hz,CH),8.00(dd,1H,J＝5.0,7.5,7.5Hz,CH),8.01(d,1H,J＝5.0,7.5Hz,CH), 8.49(s,1H,CH),8.82(d,1H,J＝10.6Hz,CH),16.60(OH)。
the molecular formula is as follows: c34H29ClFN5O6Relative molecular mass: 658.08.
example 38 Synthesis of Compound 38
By replacing raw21 in example 22 with raw37 and carrying out the same production process as in example 22, compound 38 was produced,1H NMR(300MHz,CDCl325 ℃, TMS): δ 2.27(s,3H, CH3),2.39(t,2H, J ═ 7.1Hz, CH2),2.39(t,2H, J ═ 7.1Hz, CH2),3.09(t,2H, J ═ 7.1Hz, CH2),3.36(t,2H, J ═ 7.1Hz, CH2),3.36(t,2H, J ═ 7.1Hz, CH2),4.0(s,1H, NH),4.29(t,2H, J ═ 7.1Hz, CH2),6.28(d,1H, J ═ 10.9Hz, CH),6.44(CH),6.45(CH),7.24(s,1H, CH),7.40(dd,1H, 7.5 (dd, 7H, 7.5H, J ═ 7.5,7.5H, 7.5 (dd, 7.5H, 7.5,7.5H, J ═ 7.5,7.5 (dd, 7.5H, 7.5,7.5H, 7.8H, 5H, J ═ 7.8H, 5 (d, 5Hz, 5H, 7.8H, 5H, 7., 1H, J ═ 10.9Hz, CH),16.77 (OH). The molecular formula is as follows: c34H29F2N5O6Relative molecular mass: 641.62.
example 39 Synthesis of Compound 39
Compound 39 can be produced by the same production method as in example 22 except that raw21 in example 22 is replaced with raw38,1H NMR(300MHz,CDCl3TMS, δ is 2.27(s,3H, CH3),2.40(t,2H, J is 7.1Hz, CH2),2.40(t,2H, J is 7.1Hz, CH2),3.09(t,2H, J is 7.1Hz, CH),3.41(t,2H, J is 7.1Hz, CH2),3.41(t,2H, J is 7.1Hz, CH2),4.2(s,1H, NH),4.27(t,2H, J is 7.1Hz, CH2),6.16(J is 5.0Hz, CH),6.28(d,1H, J is 10.5Hz, CH),6.88(dd,1H, J7.5, 8.0, 6.5 Hz, 7.8H, 7.5H, 7.7H, 7.5, 7.8, 7H, 7.5 (dd, 7.5Hz, 7.5H, 7.8, 7.5H, 7.7.7.8, 7.8, 7.5H, 7.7.8, 7.8, 7H, 7.5H, 7, 7.8, 7.5, 7.8, 7H, 7.8, 7.5, 7H, 7.8, 7, 1H, J ═ 5.0,7.5,7.5Hz, CH),8.01(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH),8.82(d,1H, J ═ 10.5Hz, CH),16.77 (OH). The molecular formula is as follows: c34H29FN6O8Relative molecular mass: 668.63.
example 40 Synthesis of Compound 40
Compound 40 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw39,1H NMR(300MHz,CDCl3TMS, 25 ℃,2.26 (s,3H, CH3),2.40(t,2H, J-7.1 Hz, CH2),2.40(t,2H, J-7.1 Hz, CH2),3.09(t,2H, J-7.1 Hz, CH2),3.39(t,2H, J-7.1 Hz, CH2),3.39(t,2H, J-7.1 Hz, CH2),4.0(s,1H, NH),4.28(t,2H, J-7.1 Hz, CH2), 6.18(s,1H, CH),6.28(d,1H, J-10.3 Hz, CH),6.36(d,1H, J-7.5, CH 7.5, 7.8 (ddh, 7H, J-7.5 Hz), 7.8H, J-7.5H, J-7.8, ddh, 7.5, 7H, 7.8H, J-ddh, 7.5, 7.8H, 7H, 7.5, 7H, 7.8, 7.5, J-ddh, 7.8H, 7.8, 7H, 7, 7.8, 7H, 7H, 7, 7.8, 7, 7.5,7.5Hz, CH),8.01(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH),8.83(d,1H, J ═ 10.3Hz, CH),16.77 (OH). The molecular formula is as follows: c34H30FN5O6Relative molecular mass: 623.63.
example 41 Synthesis of Compound 41
Compound 41 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw40,1H NMR(300MHz,CDCl325 ℃, TMS): δ ═ 2.17(s,3H, CH3),2.28(s,3H, CH3),2.39(t,2H, J ═ 7.1Hz, CH2),2.39(t,2H, J ═ 7.1Hz, CH2),3.10(t,2H, J ═ 7.1Hz, CH2),3.40(t,2H, J ═ 7.1Hz, CH2),3.40(t,2H, J ═ 7.1Hz, CH2),4.1(s,1H, NH),4.25(t,2H, J ═ 7.1Hz, CH2),6.06(s,1H, J ═ 1.5Hz, CH),6.28(d,1H, J ═ 10.8, CH ═ 6.5 Hz, CH, 7.5H, 7.7.5H, 7.7, 7.5H, 7.7.7, 7.5H, 7.7, 7.5H, 7H, 7.5H, 7.7.7H, 7.5H, 7H, 7.7.7.8, 7H, 7.5H, 7H, CH),8.01(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH),8.82(d,1H, J ═ 10.8Hz, CH),16.77 (OH). The molecular formula is as follows: c35H32FN5O6Relative molecular mass: 637.66.
example 42 Synthesis of Compound 42
Compound 42 was obtained by the same production method as in example 22 except that raw21 in example 22 was replaced with raw41,1H NMR(300MHz,CDCl3,25℃,TMS):δ＝2.28(s,3H,CH3),2.39(t,2H,J ＝7.1Hz,CH2),2.39(t,2H,J＝7.1Hz,CH2),3.10(t,2H,J＝7.1Hz,CH2),3.40(t,2H,J＝7.1 Hz,CH2),3.40(t,2H,J＝7.1Hz,CH2),3.9(s,1H,NH),4.28(t,2H,J＝7.1Hz,CH2),6.28(d, 1H,J＝10.5Hz,CH),6.74(d,J＝7.5Hz,CH),6.74(d,J＝7.5Hz,CH),7.24(s,1H,CH),7.40 (dd,1H,J＝7.5,7.5Hz,CH),7.41(s,1H,CH),7.42(d,1H,J＝7.5,8.0Hz,CH),7.55(dd,1H, J＝7.5Hz,CH),7.55(dd,1H,J＝7.5Hz,CH),8.00(dd,J＝5.0,7.5,7.5Hz,CH),8.01(d,J＝ 5.0,7.5Hz, CH),8.50(s,1H, CH),8.82(d,1H, J ═ 10.4Hz, CH),16.79(OH) molecular formula: c34H30FN5O6Relative molecular mass: 623.63.
example 43 Synthesis of Compound 43
Compound 43 can be produced by the same production method as in example 22 except that raw21 in example 22 is replaced with raw42,1H NMR(300MHz,CDCl325 ℃, TMS): δ ═ 2.16(s,3H, CH3),2.30(s,3H, CH3),2.39(t,2H, J ═ 7.1Hz, CH2),2.39(t,2H, J ═ 7.1Hz, CH2),3.10(t,2H, J ═ 7.1Hz, CH2),3.40(t,2H, J ═ 7.3Hz, CH2),3.40(t,2H, J ═ 7.3Hz, CH2),4.1(s,1H, NH),4.28(t,2H, J ═ 7.1Hz, CH2),6.30(d,1H, J ═ 10.5Hz, CH),6.45(s,1H, CH),6.63(d,1H, J ═ 7.5Hz, CH, 7.5 (s, 7H, J ═ 7.5Hz, 7.5H, 7.7, 7.5H, J ═ 7, 7.5H, 7.5 (ddh, 7H, 7.5Hz, 7H, 7.5H, 7, CH),8.01(d,1H, J ═ 5.0,7.5Hz, CH),8.49(s,1H, CH),8.82(d,1H, J ═ 10.5Hz, CH),16.77 (OH). The molecular formula is as follows: c35H32FN5O6Relative molecular mass: 637.66.
the beneficial effects of the present invention are demonstrated by the compound activity test below.
Test example 1 inhibition of tumor cells HT-29 and A431 by the Compounds of the present invention
HT-29 and A431 cells were seeded in 96-well plates, 3000 per well, in 3 replicates. The inoculation is followed by 48h by dosing (positive control is the pyroxsulatinib SU-11248) at a compound concentration of 10 μ M (compound dissolved in 0.1% DMSO), and incubation is continued for 72h after dosing. After the treatment, 5mg/ml MTT20 μ l was added to each well and incubated at 37 ℃ for 4 h; after incubation for 4h at 37 ℃, the culture medium is removed, 180 mu l of DMSO is added, and the mixture is kept still at 37 ℃ for at least 30min, so that the purple praline particles are fully dissolved. Preheating the microplate reader for 20min, reading OD value on the microplate reader, detecting the wavelength of 490nm, and finally calculating the growth inhibition rate of the tumor cells. The results are shown in FIGS. 1 and 2. Compound 9 was taken and tested for its effect on tumor cell survival at the remaining concentrations, and the results are shown in figure 3.
Test example 2 apoptosis test of HT-29 cells induced by cpd9
HT-29 cells were treated with 2.5. mu.M cpd9 for 16 hours, genomic DNA was extracted, cells were fixed with 4% paraformaldehyde, and cells were stained with Hoechst, and the results are shown in FIG. 4. We found that cpd 9-treated cells showed significant DNA ladders, suggesting that apoptosis had occurred (fig. 4A). Meanwhile, microscopic observation shows that the cells after the drug treatment have shrinkage, rounding and shedding, and Hoechst staining with a reactive dye specifically combined with DNA shows that the cell nuclei after the drug treatment are cracked into fragments to generate apoptosis (fig. 4B).
Test example 3 test of in vitro receptor tyrosine kinase inhibitory Activity of the Compound cpd1-cpd43
Enzyme linked immunosorbent assay (ELISA)
(1) The enzyme reaction substrate Poly (Glu, Tyr)4/1 was diluted to 20. mu.g/ml with potassium ion-free PBS (10mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4), the plate was coated with 125. mu.L/empty, after reaction at 37 ℃ for 12-15 hours, the liquid in the air was discarded, the plate was washed 3 times with 200. mu.L/well T-PBS (potassium ion-free PBS containing 0.1% Tween-20) for 7 minutes each, and the plate was dried at 37 ℃ for about 2 hours.
(2) mu.L of ATP solution diluted with reaction buffer (50mM HEPES pH 7.4, 50mM MgCl2, 0.5mM MnCl2, 0.2mM Na3VO4, 1mM DTT) was added to each well, 1. mu.L of test compound was added to each well, and 50. mu.L of EGFR kinase domain recombinant protein diluted with reaction buffer was added to initiate the reaction, with no ATP control well being provided for each experiment. After reaction for 1 hour at 37 ℃ with a shaker (100rpm), the wells were discarded and the plate was washed three times with T-PBS.
(3) After adding 99100. mu.L/well of the antibody PY (the antibody was diluted with T-PBS 1/500 containing BSA 5 mg/ml), and allowing to react at 37 ℃ for half an hour in a shaker, the liquid in the well was discarded, and the plate was washed three times with T-PBS.
(4) Adding 100 mu L/well of goat anti-mouse secondary antibody labeled by horseradish peroxidase (the antibody is diluted by T-PBS 1/2000 containing BSA 5 mg/ml), placing the mixture in a shaker at 37 ℃ for half an hour, then discarding the liquid in the well, and washing the plate by T-PBS three times.
(5) To the reaction mixture was added 2mg/ml of OPD developer 100. mu.L/well (diluted with 0.1M citric acid-sodium citrate buffer containing 0.03% H2O 2), and the reaction mixture was left at 25 ℃ for 5 minutes in the absence of light.
(6) The reaction was stopped by adding 2M H2SO 450. mu.L/well and reading at 490nm using a wavelength tunable wet microplate reader VERSAmax.
And (4) analyzing results: the inhibition (%) of the sample was [1- (compound OD value-no enzyme control well OD value)/(negative control well OD value-no enzyme control well OD value) ]. 100%.
TABLE 1 test results of in vitro receptor tyrosine kinase inhibitory activity of cpd1-cpd43 compound
Test example 4 Zebra fish test
(1) Treatment of zebrafish embryos
One day before screening, selecting and placing Tgfll, eGFP (+/+) gene-loaded zebra fish homozygote and AB wild zebra fish in a mating box, illuminating in the morning to stimulate spawning the next day, collecting embryos within half an hour, placing the embryos in a culture dish containing an embryo culture solution, and placing the culture dish in an incubator at 28.5 ℃. When embryos developed from 10hpf, they were transferred to 24-well plates containing embryo culture medium, with 10 embryos placed in each well for use. When the embryo develops from 12hpf, the prepared liquid medicine is sequentially added into a 24-pore plate, and the experiment is repeated three times.
(2) The embryos developed to 48hpf and were observed with an OLYMPUS MVX10 slide fluorescent microscope. The embryo indexes effective in resisting angiogenesis are selected as follows: compared with the embryo of a wild AB zebra fish in the same period, the embryo of the AB zebra fish has normal development in the gross morphology; (vii) embryos with reduced and missing fluorescence expression intensity of flil gene or abnormal expression of blood vessel fluorescence distribution disorder;
(3) analysis of angiogenesis inhibition
Each group of embryos is taken out, placed in a culture solution containing an anesthetic, photographed by adopting an OLYMPUS MVX10 type fluorescence microscope, and subjected to length measurement on zebra fish internodes (10 human internodes after yolk) by utilizing FV10-ASW 1.7Viewer software, wherein the scale bar is 10 mm.
(4) cpd9 anti-zebra fish embryo body internode blood vessel screening result
The degree of inhibition of blood vessels was gradually increased when the cpd9 was applied at concentrations of 10. mu.M and 20. mu.M, but the whole embryo developed normally, with more than 80% of the drug solution developing different degrees of angiogenesis inhibition, as shown in FIG. 5.
In conclusion, the compound has excellent antitumor activity and the capacity of inhibiting new vessels, and has a good application prospect.
Claims (5)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is1Is selected from
R2、R3Each independently selected from H,
Or R2And R3The carbon atoms connected with the substituted hexabasic aromatic heterocyclic ring form a 1-substituted hexabasic aromatic heterocyclic ring;
R4、R5、R6respectively represent no substitution or one substitution on a benzene ring, R4、R5、R6Are each independently selected from H, halogen atoms, C1～6Alkyl radical, C1～6Alkoxy radical, CH3O(CH2)nCH2O-，
Wherein n is an integer of 1-6;
the 1-substituted six-membered aromatic heterocyclic ring is
2. A compound of claim 1, wherein R is4、R5、R6Each independently selected from H, F, methyl, methoxy, CH3OCH2CH2O-，
3. A compound of claim 1, wherein R is1Is selected from
4. The compound of claim 1, wherein: the compound is one of the following compounds:
5. a process for the preparation of the compounds according to claim 4, characterized in that: it comprises the following steps:
(I) Synthesis of Compounds 1-14:
(1) synthesis of intermediate h:
(2A) synthesizing compounds 1-7:
(2B) and (3) synthesizing a compound 8-14:
(II) Synthesis of Compounds 15-21:
synthesis of (tri) Compounds 22-43
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