CN112574094B - Indolone derivatives and pharmaceutical use thereof - Google Patents

Indolone derivatives and pharmaceutical use thereof Download PDF

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CN112574094B
CN112574094B CN202011467844.9A CN202011467844A CN112574094B CN 112574094 B CN112574094 B CN 112574094B CN 202011467844 A CN202011467844 A CN 202011467844A CN 112574094 B CN112574094 B CN 112574094B
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indolone
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CN112574094A (en
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赵立峰
邓俊丰
张力丹
褚以文
宋雪娇
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Chengdu University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention provides an indolone derivative and pharmaceutical application thereof. The structure of the indolone derivative is shown as a formula (A). Experimental results show that the compound provided by the invention has obviously improved pharmacokinetic properties compared with BIBF1120, has excellent inhibitory effects on VEGFR, FGFR and PDGFR, can be used as VEGFR, FGFR and/or PDGFR inhibitors, angiogenesis inhibitors and drugs for preventing and/or treating various tumors including squamous cell carcinoma, and has wide application prospects.
Figure DDA0002835070840000011

Description

Indolone derivatives and pharmaceutical use thereof
Technical Field
The invention belongs to the technical field of chemical medicine, and particularly relates to an indolone derivative and pharmaceutical application thereof.
Background
The Nintedanib (BIBF1120) is an orally active triple kinase inhibitor and can simultaneously act on a key receptor family of 3 involved in the angiogenesis process, namely a Vascular Endothelial Growth Factor Receptor (VEGFR), a Fibroblast Growth Factor Receptor (FGFR) and a platelet-derived growth factor receptor (PDGFR). BIBF1120 has the following structural formula:
Figure BDA0002835070820000011
as a novel angiogenesis inhibitor, BIBF1120 can inhibit the formation of blood vessels around and inside tumors, and then reduce the oxygen and nutrient supply of tumors, resulting in the shrinkage and death of tumor cells, thereby achieving an antitumor effect. Compared with the traditional chemotherapy method, the anti-tumor treatment method has the advantage of small side effect. The research finds that the BIBF1120 has better curative effect on various tumors such as liver cancer, lung cancer, rectal cancer, uterine cancer, brain cancer metastatic intestinal cancer, pharyngeal squamous cell carcinoma and the like.
However, the anti-tumor effect and pharmacokinetic properties of BIBF1120 are still to be further improved. Due to the complex metabolic processes of biological systems, the pharmacokinetic properties of drugs in organisms are influenced by various factors and show corresponding complexity. The change in pharmacokinetic properties of deuterated drugs represents a great chance and unpredictability compared to corresponding non-deuterated drugs. Deuteration at some sites, not only does not prolong half-life, but may shorten it (Scott l. harbeson, Roger d. tung. deuterium in Drug Discovery and Development, P405-406.), deteriorating its pharmacokinetic properties; on the other hand, hydrogen at some positions on a drug molecule is also not easily deuterated due to steric hindrance and the like, so that the deuteration of the drug is not random and a site capable of deuteration is unpredictable.
Therefore, development of more vascular kinase inhibitors with novel structures, better inhibitory activity and more excellent pharmacokinetic properties has important significance for treating various diseases such as liver cancer, lung cancer, rectal cancer, uterine cancer, brain cancer metastatic intestinal cancer, pharyngeal squamous cell carcinoma and the like.
Disclosure of Invention
The invention aims to provide an indolone derivative and application thereof in preparing VEGFR (vascular endothelial growth factor receptor), FGFR (fibroblast growth factor receptor) and/or PDGFR (platelet-derived growth factor receptor) inhibitors.
The invention specifically provides a compound shown as a formula (A) or a pharmaceutically acceptable salt thereof:
Figure BDA0002835070820000021
wherein R is1、R2Each independently selected from C1-C6 alkyl and deuterated C1-C6 alkyl;
R3selected from C1-C6 alkyl, halogenated C1-C6 alkyl,
Figure BDA0002835070820000022
R4～R11Each independently selected from H or deuterium;
and when R is2Is methyl, R3Is methyl, R4～R11When it is hydrogen, R1Is not methyl.
Further, R1、R2Each independently selected from C1-C3 alkyl and deuterated C1-C3 alkyl;
R3selected from C1-C2 alkyl, halogenated C1-C2 alkyl,
Figure BDA0002835070820000023
The halogen is preferably fluorine.
Further, R1、R2Each independently selected from methyl or deuterated methyl, preferably-CD3；
R3Selected from CF3、CHF2、CH2F、CH2CF3、CH2CHF2、CH2CH2F、
Figure BDA0002835070820000024
R4～R11Both H or both D.
Further, the compound is selected from one of the following compounds:
Figure BDA0002835070820000031
Figure BDA0002835070820000041
the invention also provides a preparation method of the compound or the pharmaceutically acceptable salt thereof, which is characterized by comprising the following steps: the method comprises the step of taking a compound (A-1) and a compound (A-2) as raw materials to react to obtain the compound shown in the formula (A)
Figure BDA0002835070820000051
Wherein R is1～R11As described above.
Further, the molar ratio of the compound (A-1) to the compound (A-2) is 1: 1; the solvent for the reaction is methanol.
The invention also provides an antitumor drug which is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding common auxiliary materials in the field of pharmacy.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof in preparing VEGFR, FGFR and/or PDGFR inhibitors; the VEGFR is preferably VEGFR2, the FGFR is preferably FGFR1, and the PDGFR is preferably PDGFR alpha.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof in preparing angiogenesis inhibitors.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating tumors, wherein the tumors are preferably liver cancer, lung cancer, rectal cancer, uterine cancer, brain cancer metastatic intestinal cancer and pharyngeal squamous cell cancer.
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.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix. For example, C1～C6The alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
Deuterated C1-C6 alkyl refers to a group wherein one or more hydrogens of the C1-C6 alkyl group are replaced with deuterium.
Halogenated C1-C6 alkyl refers to C1-C6 alkyl groups in which one or more hydrogens are replaced with halogens.
Halogen is fluorine, chlorine, bromine or iodine.
Experimental results show that the compound provided by the invention has obviously improved pharmacokinetic properties compared with BIBF1120, has excellent inhibition effects on Vascular Endothelial Growth Factor Receptors (VEGFR), Fibroblast Growth Factor Receptors (FGFR) and platelet-derived growth factor receptors (PDGFR), can be used as VEGFR, FGFR and/or PDGFR inhibitors, can be used as angiogenesis inhibitors, and can be used as a medicament for preventing and/or treating various tumors including squamous cell carcinoma, and has wide application prospects.
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 is a graph showing the tumor growth curves of the groups tested in vivo, wherein 6004 is the compound ZLF6004 and the control group is the vehicle control group.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 preparation of methyl- (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6001)
Figure BDA0002835070820000061
The synthetic route is as follows:
Figure BDA0002835070820000062
Figure BDA0002835070820000071
the method comprises the following steps: preparation of methyl m-nitrobenzoate (2)
Adding 1.0g m-nitrobenzoic acid into 8mL methanol, adding 4% concentrated sulfuric acid, performing microwave reaction at 100 ℃ for 10 minutes, adding dichloromethane, and sequentially using saturated NaHCO3Washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and spin-drying to obtain 0.95g product. The yield thereof was found to be 85.8%.
Step two: preparation of methyl 4- (2-methoxy-2-acetyl) -3-nitrobenzoate (3)
1.97g potassium tert-butoxide (18mmol) was dissolved in 20mL DMF, cooled to-10 ℃ and a mixed solution of methyl m-nitrobenzoate (1.36g,7.5mmol) and methyl chloroacetate (0.73mL,8.3mmol) dissolved in 4mL DMF was added dropwise to the solution, after addition was complete, the reaction was allowed to react at-10 ℃ until no starting material was detected, the reaction was poured into a mixed solution of ice water (25mL) and concentrated hydrochloric acid (8.5mL), extracted with ethyl acetate, washed with saturated brine, dried and spin-dried. Column chromatography gave 1.20g (63.3%) of the crude product.
Step three: preparation of methyl 2-indolone-6-carboxylate (4)
4- (2-methoxy-2-acetyl) -3-nitrobenzoic acid (3) (0.97g, 3.83mmol) was dissolved in 20mL of acetic acid, and 130mg of 10% Pd/C was added and reacted at room temperature under a hydrogen pressure of 50psi for 2.5 h. The catalyst was removed by filtration, the solvent evaporated, triturated with ethyl acetate, washed, filtered and dried under vacuum at 100 ℃ to give 2.8g of product 4 (38.2%).
Step four: preparation of methyl 1-chloroacetyl-2-indolone-6-carboxylate (5)
At room temperature, methyl 2-indolone-6-carboxylate 4(2.0g, 10.35mmol) was suspended in 12ml of toluene, chloroacetic anhydride (2.7g,15.5mmol) was added to the suspension, heating and refluxing were carried out for 3h, cooling was carried out to 80 ℃, methylcyclohexane (6ml) was added for 30min, the suspension was stirred and cooled to room temperature, the crude product was filtered by suction, washed with cold methanol (4ml), and dried to give 2.55g (92.6%) of a white solid.
Step five: (E) preparation of methyl (6) -1-chloroacetyl-3- (methoxy (phenyl) methylene) -2-indolone-6-carboxylate
At the ambient temperature, 1-chloroacetyl-2-indolone-6-methyl formate 5(0.6g,2.3mmol) is suspended in toluene (5ml), acetic anhydride (0.81g, 7.85mmol) is added into the suspension, the system is heated to 110 ℃, trimethyl orthobenzoate (1.0g,5.4mmol) is added within 1h, the reaction is continued for 3h, the volatile product is volatilized out, toluene (4ml) is added to keep the system concentration unchanged, the system is cooled to 5 ℃, the mixture is stirred for 1h, crude products are obtained by suction filtration, and the crude products are washed by mixed liquid of toluene, toluene and ethyl acetate (1: 1) in sequence and dried to obtain 0.8g (93.0%) pale yellow solid.
Step six: (E) preparation of methyl (7) -methyl 3- (methoxy (phenyl) methylene) -2-indolone-6-carboxylate
A solution of potassium hydroxide (82mg,1.2mmol) in methanol (1ml) was added to a suspension of methyl (E) -1-chloroacetyl-3 (methoxy (phenyl) methylene) -2-indolinone-6 carboxylate 6(1.6g, 2mmol) in methanol (3ml) at 63 deg.C, the reaction stirred for a further 30min, cooled to 0 deg.C, stirred for a further 2h at 0 deg.C, filtered off with suction, washed with methanol and dried to give 0.95g (74.9%) of a yellow solid.
Step seven: 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide (9)
N-methyl-4-nitroaniline (1.25g, 8.22mmol) was added to ethyl acetate (3mL), heated to 60 deg.C, and chloroacetic anhydride (1.63g, 9.5mmol) was added as a solution in ethyl acetate (5mL) over 15 minutes, refluxed for 1h, cooled to 75 deg.C, then 8mL cyclohexane was added, crystals were precipitated at 60 deg.C, cooled to 0 deg.C, stirred for 1h, filtered, washed with cyclohexane, and dried to give 1.48g (78.8%) of white crystals.
Step eight: preparation of N- (4-nitrophenyl) -N-methyl-2- (4-Boc-piperazine-1-substituted) acetamide (10)
1g of 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide 8 are dissolved in 8mL of toluene, heated to 40 ℃ and added dropwise within 30minN-Boc-piperazine(2.1g, 2.5eq), stirring with heating for 2h (55 ℃), cooling to room temperature, washing with water (5mL), diluting the toluene solution system with 10mL of isopropanol, adding 100mg Pd/C (10%), introducing hydrogen (4bar), stirring at room temperature for 3h, filtering to remove the catalyst, spinning off the solvent, recrystallizing the residue with ethyl acetate/petroleum ether, washing with petroleum ether, and drying to give 1.35g (91.1%) of white crystals.
Step nine: preparation of N- (4-nitrophenyl) -N-methyl-2- (piperazine-1-substituted) acetamide (11)
1g N- (4-aminophenyl) -N-methyl-2- (4-Boc-piperazine-1-substituted) acetamide was dissolved in 10mL of CCM and stirred in an ice bath. Trifluoroacetic acid (1.1ml, 6.0eq) was added dropwise over 2min, after completion of the addition, stirring at room temperature for 2h, spin-drying under reduced pressure, adding a saturated aqueous solution of sodium bicarbonate, extracting with DCM, and spin-drying anhydrous magnesium sulfate dried organic solvent to give 1.40g (94.4%) of an oily liquid.
Step ten: preparation of N- (4-nitrophenyl) -N-methyl-2- (4- (1-fluoro-ethyl-1-substituted) acetamide (12)
1g N- (4-nitrophenyl) -N-methyl-2- (4-piperazin-1-substituted) acetamide was dissolved in 10mL of EDCM and stirred in ice bath. 1-fluoro-2-iodoethane (1.11ml, 6.0eq) was added dropwise over 2min, stirred in an ice bath for 2h, filtered, spin-dried under reduced pressure, added with saturated aqueous sodium bicarbonate, extracted with DCM, and organic solvent dried over anhydrous magnesium sulfate to give 0.88g (79.3%) of a yellow solid.
Step eleven: preparation of N- (4-aminophenyl) -N-methyl-2- (4- (1-fluoroethyl-1-substituted) acetamide (13)
1g N- (4-aminophenyl) -N-methyl-2- (4-piperazin-1-substituted) acetamide was dissolved in 10mL of ethanol and 4 aqueous solution, and stirred in ice bath. 130mg of 10 percent Pd/C is added to react for 2.5 hours at room temperature under the condition of normal pressure hydrogenation. The catalyst was removed by filtration, the solvent evaporated, triturated with ethyl acetate, washed, filtered and dried under vacuum at 100 ℃ to give 83g of product 13 (92.2%).
Step twelve: preparation of methyl- (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N-acetylamino) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6001)
(E) A suspension of methyl (7, 0.5mg, 1.62mmol) methyl (3-methoxy (phenyl) methylene) -2-indolone-6-carboxylate and N- (4-aminophenyl) -N-methyl-2- (4- (1-fluoroethyl-1-substituted) acetamide 13(0.48mg, 1.70mmol) in methanol (1.8ml) was heated under reflux for 8h, slowly cooled to 10 ℃ and stirred at 10 ℃ for a further 1h, filtered, washed with cold methanol and dried to give 0.75g (83.3%) yellow solid.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.77(s,3H),3.07(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H),2.31(s,4H),2.22(s,4H).
ESI-MS m/z:570.6[M-H]-.
Example 2 preparation of methyl (Z) -3- (((4- (2- (4- (difluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6002)
Figure BDA0002835070820000091
Synthesis procedure the procedure described in example 1 was followed, except that 1, 1-difluoro-2-iodoethane was used instead of the starting material 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6002. The yield of the last reaction step was 75%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.06(s,3H),2.66(td,J＝15.7,4.2Hz,4H),2.39(s,4H),2.22(s,4H).
ESI-MS m/z:588.6[M-H]-.
Example 3 preparation of methyl (Z) -3- (((4- (2- (4- (trifluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6003)
Figure BDA0002835070820000092
Synthesis procedure the procedure described in example 1 was followed, except that the starting material 1-fluoro-2-iodoethane was replaced with trifluoro-2-iodoethane, to synthesize the compound ZLF 6003. The yield of the last reaction step was 72%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.20–3.01(m,5H),2.72(s,2H),2.48–2.39(s,4H),2.23(s,4H).
ESI-MS m/z:606.6[M-H]-.
Example 4 preparation of methyl- (Z) -3- (((4- (2- (4- (2- (2-methoxyethyl) ethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6004)
Figure BDA0002835070820000101
Synthesis procedure the procedure described in example 1 was followed, except that 1-iodo-2 (2-methoxyethyl ether) ethane was used instead of the starting material 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6004. The yield of the last reaction step was 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.07(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H),2.31(s,4H),2.22(s,4H).
ESI-MS m/z:573.7[M-H]-.
Example 5 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6005)
Figure BDA0002835070820000102
Compound ZLF6005 was synthesized according to the procedure described in example 1, except that the starting material methanol in step one was replaced with deuterated methanol. The yield of the last reaction step was 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.06(s,3H),2.66(td,J＝15.7,4.2Hz,4H),2.39(s,4H),2.22(s,4H).
ESI-MS m/z:591.7[M-H]-.
Example 6 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (difluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6006)
Figure BDA0002835070820000111
Compound ZLF6006 was synthesized according to the procedure described in example 1, except that the starting material methanol in step one was replaced with deuterated methanol, and the starting material 1-fluoro-2-iodoethane was replaced with 1, 1-difluoro-2-iodoethane. The yield of the last reaction step was 71%.
1H NMR(400 MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2 Hz,1H),7.20(dd,J＝8.2,1.5 Hz,1H),7.13(d,J＝8.5 Hz,2H),6.89(d,J＝8.5 Hz,2H),5.83(d,J＝8.2 Hz,1H),3.20–3.01(m,5H),2.72(s,2H),2.48–2.39(s,4H),2.23(s,4H).
ESI-MS m/z:609.7[M-H]-.
Example 7 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (trifluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolinone-6-carboxylic acid methyl ester (ZLF6007)
Figure BDA0002835070820000112
Synthesis procedure the procedure described in example 1 was followed except that N-methyldp-nitroaniline was replaced with N-trideuteromethyl-p-nitroaniline in a final yield of 69%.
Wherein, the synthetic route of the N-tridedeuterium methyl paranitroaniline is shown as follows:
Figure BDA0002835070820000113
the synthetic route of N-trideuteromethyl p-nitroaniline is described in Ullmann amino reference J.org.chem.2011,76, 1180-1183.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.77(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H),2.31(s,4H),2.22(s,4H).
ESI-MS m/z:573.7[M-H]-.
Example 8 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6008)
Figure BDA0002835070820000121
Synthesis procedure the procedure described in example 1 was followed, except that N-methyldp-nitroaniline was replaced by N-Trideuteromethyl-p-nitroaniline and the starting material 1-fluoro-2-iodoethane was replaced by 1, 1-difluoro-2-iodoethane, resulting in a final yield of 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),2.66(td,J＝15.7,4.2Hz,4H),2.39(s,4H),2.22(s,4H).
ESI-MS m/z:591.7[M-H]-.
Example 9 preparation of methyl (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6009)
Figure BDA0002835070820000122
Synthesis procedure the procedure described in example 1 was followed, except that N-methyldp-nitroaniline was replaced with N-Trideuteromethyl-p-nitroaniline to synthesize the compound ZLF 6009. The yield of the last reaction step was 69%.
Wherein, the synthetic route of the N-tridedeuterium methyl paranitroaniline is shown as follows:
Figure BDA0002835070820000123
the synthetic route of N-trideuteromethyl p-nitroaniline is described in Ullmann amino reference J.org.chem.2011,76, 1180-1183.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.18–3.01(m,2H),2.72(s,2H),2.48–2.39(s,4H),2.23(s,4H).
ESI-MS m/z:609.7[M-H]-.
Example 10 preparation of methyl (Z) -3- (((4- (2- (4- (difluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6010)
Figure BDA0002835070820000131
Synthesis procedure the procedure described in example 1 was followed, except that N-methyldp-nitroaniline was replaced with N-trideuteromethyl-p-nitroaniline and 1-fluoro-2-iodoethane was replaced with 1, 1-difluoro-2-iodoethane as the starting material, to synthesize the compound ZLF 6010. The yield of the last reaction step was 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.77(s,3H),3.07(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H).
ESI-MS m/z:578.7[M-H]-.
EXAMPLE 11 preparation of methyl (Z) -3- (((4- (2- (4- (trifluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6011)
Figure BDA0002835070820000132
Synthesis procedure the procedure described in example 1 was followed, except that N-methyldp-nitroaniline was replaced with N-trideuteromethyl-p-nitroaniline and 1-fluoro-2-iodoethane was replaced with trifluoro-2-iodoethane, to synthesize the compound ZLF 6011. The yield of the last reaction step was 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.06(s,3H).
ESI-MS m/z:596.7[M-H]-.
EXAMPLE 12 preparation of methyl (Z) -3- (((4- (2- (4- (2- (2-methoxyethyl) ethyl) piperazine-1-substituted) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6012)
Figure BDA0002835070820000141
Synthesis procedure the procedure described in example 1 was followed, except that N-methyldp-nitroaniline was replaced with N-trideuteromethyl-p-nitroaniline and 1-iodo-2 (2-methoxyethyl ether) ethane was used instead of the starting material 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6012. The yield of the last reaction step was 69%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.20–3.01(m,5H),2.72(s,2H).
ESI-MS m/z:614.7[M-H]-.
Example 13 preparation of methyl (Z) -3- (((4- (2- (4- (fluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6013)
Figure BDA0002835070820000142
Synthesis procedure the procedure described in example 1 was followed except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used in place of the starting N-Boc-piperazine to synthesize the compound ZLF 6013. The yield of the last reaction step was 69%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.77(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H).
ESI-MS m/z:581.7[M-H]-.
Example 14 preparation of methyl- (Z) -3- (((4- (2- (4- (difluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6014)
Figure BDA0002835070820000151
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used in place of the starting material N-Boc-piperazine, and 1, 1-difluoro-2-iodoethane was used in place of the starting material 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6014. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),2.66(td,J＝15.7,4.2Hz,4H).
ESI-MS m/z:599.7[M-H]-.
Example 15 preparation of methyl- (Z) -3- (((4- (2- (4- (trifluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6015)
Figure BDA0002835070820000152
Synthesis procedure the procedure described in example 1 was followed, except that the starting material N-Boc-piperazine was replaced with N-Boc-2, 3,5, 6-octadeuteropiperazine and the starting material 1-fluoro-2-iodoethane was replaced with trifluoro-2-iodoethane, to synthesize the compound ZLF 6015. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.17–3.01(m,2H),2.72(s,2H).
ESI-MS m/z:617.7[M-H]-.
EXAMPLE 16 preparation of methyl (Z) -3- (((4- (2- (4- (2- (2-methoxyethylethyl) ethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6016)
Figure BDA0002835070820000161
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used instead of N-Boc-piperazine and 1-iodo-2 (2-methoxyethyl ether) ethane was used instead of 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6016. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.65–7.54(m,3H),7.53–7.47(m,2H),7.42(d,J＝1.3Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.53–3.44(m,4H),3.44–3.37(m,2H),3.23(s,3H),2.71(s,2H),2.42(s,2H).
ESI-MS m/z:637.8[M-H]-
Example 17 preparation of methyl (Z) -3- (((4- (fluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6017)
Figure BDA0002835070820000162
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used instead of N-Boc-piperazine and N-trideuteromethyl-p-nitroaniline was used instead of N-methyl-p-nitroaniline, to synthesize the compound ZLF 6017. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),3.07(s,3H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H).
ESI-MS m/z:581.7[M-H]-.
Example 18 preparation of methyl (Z) -3- (((4- (difluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6018)
Figure BDA0002835070820000171
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used instead of the starting material N-Boc-piperazine, difluoro-2-iodoethane was used instead of the starting material 1-fluoro-2-iodoethane, and N-trideuteromethyl-p-nitroaniline was used instead of N-methyl-p-nitroaniline, to synthesize the compound ZLF 6018. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is sold on the market.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.06(s,3H),2.66(td,J＝15.7,4.2Hz,4H).
ESI-MS m/z:599.7[M-H]-.
Example 19 preparation of methyl (Z) -3- (((4- (trifluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6019)
Figure BDA0002835070820000172
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used instead of N-Boc-piperazine, trifluoro-2-iodoethane was used instead of 1-fluoro-2-iodoethane, and N-trideuteromethyl-p-nitroaniline was used instead of N-methyl-p-nitroaniline, to synthesize Compound ZLF 6019. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.20–3.01(m,5H),2.72(s,2H).
ESI-MS m/z:617.7[M-H]-.
EXAMPLE 20 preparation of methyl (Z) -3- (((4- (2- (4- (2- (2-methoxyethylethyl) ethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N- (methyl-d 3) acetylamino) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6020)
Figure BDA0002835070820000181
Synthesis procedure the procedure described in example 1 was followed, except that N-Boc-2, 3,5, 6-octadeuteropiperazine was used instead of N-Boc-piperazine, 1-iodo-2 (2-methoxyethyl ether) ethane was used instead of 1-fluoro-2-iodoethane, and N-trideuterio-methyl-p-nitroaniline was used instead of N-methyl-p-nitroaniline, to synthesize the compound ZLF 6020. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.65–7.54(m,3H),7.53–7.47(m,2H),7.42(d,J＝1.3Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.53–3.44(m,4H),3.44–3.37(m,2H),3.06(s,3H),2.71(s,2H),2.42(s,2H).
ESI-MS m/z:637.8[M-H]-.
Example 21 preparation of methyl-d 3- (Z) -3- (((4- (fluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6021)
Figure BDA0002835070820000182
Synthesis procedure the procedure described in example 1 was followed except that the starting material methanol in step one was replaced with deuterated methanol and the starting material N-Boc-piperazine was replaced with N-Boc-2, 3,5, 6-octadeuteropiperazine to synthesize compound ZLF 6021. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H),2.31(s,4H),2.22(s,4H).
ESI-MS m/z:576.7[M-H]-.
Example 22 preparation of methyl-d 3- (Z) -3- (((4- (difluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6022)
Figure BDA0002835070820000191
Synthesis procedure the procedure described in example 1 was followed, except that the starting material methanol in step one was replaced with deuterated methanol, the starting material N-Boc-piperazine was replaced with N-Boc-2, 3,5, 6-octadeuteropiperazine, and the starting material 1-fluoro-2-iodoethane was replaced with difluoro-2-iodoethane, to synthesize the compound ZLF 6022. The yield of the last reaction step was 62%. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),3.06(s,3H),2.66(td,J＝15.7,4.2Hz,4H).
ESI-MS m/z:599.7[M-H]-.
Example 23 preparation of methyl-d 3- (Z) -3- (((4- (trifluoromethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6023)
Figure BDA0002835070820000192
Synthesis procedure the procedure described in example 1 was followed, except that the starting material methanol in step one was replaced with deuterated methanol, the starting material N-Boc-piperazine was replaced with N-Boc-2, 3,5, 6-octadeuteropiperazine, and the starting material 1-fluoro-2-iodoethane was replaced with trifluoro-2-iodoethane to synthesize the compound ZLF 6023. The yield of the last reaction step was 62%. . Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.20–3.01(m,5H),2.72(s,2H).
ESI-MS m/z:617.7[M-H]-.
Example 24 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (2- (2-methoxyethylethyl) ethyl) piperazine-1-substituted-2, 2,3,3,5,5,6,6-d8) -N-methylacetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6024)
Figure BDA0002835070820000201
Synthesis procedure the procedure described in example 1 was followed except that the starting material methanol in step one was replaced with deuterated methanol and the starting material N-Boc-piperazine was replaced with N-Boc-2, 3,5, 6-octadeuteropiperazine to synthesize compound ZLF 6024. The yield of the last step reaction was 62%, 1-fluoro-2-iodoethane was replaced with 1-iodo-2 (2-methoxyethyl ether) ethane. Wherein, N-Boc-2, 3,5, 6-octadeuteropiperazine is commercially available.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.65–7.54(m,3H),7.53–7.47(m,2H),7.42(d,J＝1.3Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.53–3.44(m,4H),3.44–3.37(m,2H),3.06(s,3H),2.71(s,2H),2.42(s,2H).
ESI-MS m/z:637.8[M-H]-.
Example 25 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (fluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetylamino) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6025)
Figure BDA0002835070820000202
Synthesis procedure the procedure described in example 1 was followed, except that the starting material methanol in step one was replaced with deuterated methanol and N-methyldi-nitroaniline was replaced with N-trideuteromethyl-p-nitroaniline to synthesize the compound ZLF 6025. The yield of the last reaction step was 62%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.50(d,J＝7.1Hz,2H),7.42(d,J＝1.3Hz,1H),7.20(d,J＝8.2Hz,1H),7.14(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.83(d,J＝8.2Hz,1H),4.55(t,J＝4.9Hz,1H),4.43(t,J＝4.9Hz,1H),2.71(s,2H),2.59(t,J＝4.8Hz,1H),2.53(s,1H),2.31(s,4H),2.22(s,4H).
ESI-MS m/z:576.7[M-H]-.
Example 26 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (difluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetylamino) anilino) (phenyl) methylene) -2-indolone-6-carboxylic acid methyl ester (ZLF6026)
Figure BDA0002835070820000211
Synthesis procedure the procedure described in example 1 was followed, except that the starting material methanol in step one was replaced with deuterated methanol, N-methyldiethyl-p-nitroaniline was replaced with N-methyl-p-nitroaniline, and difluoro-2-iodoethane was replaced with 1-fluoro-2-iodoethane, to synthesize the compound ZLF 6026. The yield of the last reaction step was 62%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.64–7.53(m,3H),7.52–7.47(m,2H),7.42(d,J＝1.4Hz,1H),7.20(dd,J＝8.2,1.6Hz,1H),7.14(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),6.09(tt,J＝55.8,4.3Hz,1H),5.83(d,J＝8.2Hz,1H),2.66(td,J＝15.7,4.2Hz,4H),2.39(s,4H),2.22(s,4H).
ESI-MS m/z:594.7[M-H]-.
Example 27 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (trifluoromethyl) piperazin-1-substituted) -N- (methyl-d 3) acetylamino) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6027)
Figure BDA0002835070820000212
Synthesis procedure the procedure described in example 1 was followed, except that the starting material methanol in step one was replaced with deuterated methanol, N-methyldi-nitrophenylamine was replaced with N-methyldi-nitrophenylamine, and 1-fluoro-2-iodoethane was replaced with trifluoro-2-iodoethane, to synthesize the compound ZLF 6027. The yield of the last reaction step was 62%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.63–7.54(m,3H),7.53–7.47(m,2H),7.43(d,J＝1.2Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),5.83(d,J＝8.2Hz,1H),3.18–3.01(m,2H),2.72(s,2H),2.48–2.39(s,4H),2.23(s,4H).
ESI-MS m/z:612.7[M-H]-.
Example 28 preparation of methyl-d 3- (Z) -3- (((4- (2- (4- (2- (2-methoxyethyl) ethyl) piperazine-1-substituted) -N- (methyl-d 3) acetamido) anilino) (phenyl) methylene) -2-indolone-6-carboxylate (ZLF6028)
Figure BDA0002835070820000221
Synthesis procedure the procedure described in example 1 was followed, except that in step one, the starting material methanol was replaced with deuterated methanol, N-methyldi-dinophenylamine was replaced with N-methyldi-phenylamine, and 1-iodo-2 (2-methoxyethyl ether) ethane was replaced with 1-fluoro-2-iodoethane, to synthesize Compound ZLF 6028. The yield of the last reaction step was 62%.
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),10.96(s,1H),7.65–7.54(m,3H),7.53–7.47(m,2H),7.42(d,J＝1.3Hz,1H),7.20(dd,J＝8.2,1.5Hz,1H),7.13(d,J＝8.5Hz,2H),6.89(d,J＝8.6Hz,2H),5.83(d,J＝8.2Hz,1H),3.77(s,3H),3.53–3.44(m,4H),3.44–3.37(m,2H),2.71(s,2H),2.42(s,2H),2.29(s,4H),2.21(s,4H).
ESI-MS m/z:632.8[M-H]-.
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 test for inhibitory Activity of the Compounds of the present invention on VEGFR2, FGFR1 and PDGFR α kinase
The purpose of this experiment was to test the inhibitory activity of the compounds of the invention on kinases in vitro,
1 materials of the experiment
20mM 3- (N-morpholinyl) propanesulfonic acid (MOPS); 1mM ethylenediaminetetraacetic acid (EDTA); 0.01% Brij 35 (Brij-35); 5% Glycerol (glycol); 0.1% mercaptoethanol (mercptoeethanol); 1mg/ml Bovine Serum Albumin (BSA); l0mM manganese dichloride solution (MnC 12); 10mM magnesium acetate and y-33p-ATP solution; stop buffer (3% phosphate buffer); wash buffer (75mM phosphate solution); methanol (methanol); a Filtermat A film; VEGFR2, FGFR1, and PDGFR α kinases, compounds made in the examples.
2 method of experiment
And respectively carrying out in-vitro activity inhibition tests on VEGFR2, FGFR1 and PDGFR alpha kinase crystal forms by adopting an isotope labeling method. Comprises the following steps:
in one reaction tube, buffer (8mM MOPS, pH 7.0,0.2mM EDTA,10mM MnC12), kinase to be tested (5-10mU), substrate for kinase to be tested, and 10mM magnesium acetate and gamma 33P-ATP solution, test compounds at various concentrations, were added in sequence. The reaction was initiated by adding MgATP ((final concentration of ATP is Km for kinase) and incubation at room temperature for 40 min. the reaction was finally stopped with 5. mu.L of 3% phosphate buffer, and 10. mu.L of the reaction was titrated onto a Filtermat A membrane, washed three times with 75mM phosphate solution, 5 min each, and once with methanol.
Median Inhibitory Concentration (IC) for kinase inhibitory Activity of test Compounds50) Represents, IC50Values were obtained by calculation of the inhibition rate of the test compound on kinase activity at different concentrations.
3 results of the experiment
Through the above experimental methods, the IC of the compounds obtained in the examples of the present invention against the inhibitory activities of VEGFR2, FGFR1 and PDGFR α kinase, respectively, was tested50The results are shown in Table 1.
IC of Table 1 Compounds for VEGFR2, FGFR1, and PDGFR α kinase inhibitory Activity50Value of
Figure BDA0002835070820000231
In Table 1, A is 1-100nM, B is 100-500nM, and C is >500 nM.
Experimental results show that the compound has strong inhibitory activity on VEGFR2, FGFR1 and PDGFR alpha.
Test example 2 in vivo antitumor test of Compound ZLF6004 of the present invention
1 test materials
Fetal bovine serum, Culture medium, pancreatin, etc. were purchased from Gibco BRL Corporation (Invitrogen Corporation, USA), Culture medium was purchased from ATCC (American Type Culture Collection), human pharyngeal squamous carcinoma cell line FaDu was purchased from American ATCC Corporation, and NOD-Balb/c mice were purchased from Beijing Huafukang animal Experimental center.
2 method of experiment
6-8 weeks of NOD-Balb/c mice were used at approximately 1X 107Concentration of individual/0.1 ml/mouse pharyngeal squamous cell carcinoma FaDu cell concentration was inoculated to mice subcutaneous posterior costal region, and after the tumor grew to a certain volume, mice were randomly grouped and oral administration by gavage was started.
FaDu experimental grouping: (1) low dose compound ZLF6004, 50mg/kg q.d; (2) high dose compound ZLF6004, 1000mg/kg q.d; (3) solvent control group. The solvent is a mixed solvent prepared from 12.5 percent of EL (castor oil polyoxyethylene ether), 12.5 percent of EtOH and 75 percent of water. Each group had 8 mice.
Observation indexes are as follows: the tumor length and the tumor neck were measured by weighing the mice every 3 days and the tumor volume (length x length) was calculated2X 0.52), calculating an average value; and observing the mice to have the reactions of diarrhea, cramp, rash, obvious weight reduction and the like.
3 results of the experiment
No adverse reactions such as weight loss, rash, diarrhea and the like of the mice are found in the administration process, which indicates that the compound ZLF6004 has low toxicity in the administration dosage range under the test dosage.
The experimental tumor growth curves of the groups are shown in figure 1. Experimental results show that the compound ZLF6004 has an obvious in-vivo growth inhibition effect on pharyngeal squamous carcinoma tumors.
Test example 3 pharmacokinetic experiment of Compound ZLF6004
1 method of experiment
Randomly dividing male SD rats into a BIBF1120 oral administration group and a 6004 oral administration group, wherein 8 rats in each group are administered with the dose of 50 mg/kg; blood samples are sequentially collected for 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h and 24h after administration, and are detected by LC/MS. The pharmacokinetic parameters of the blood concentration-time data obtained by detection and calculated by using Phoenix WinNonlin7.0 are shown in the following table 2.
2 results of the experiment
TABLE 2 pharmacokinetic Property test results
Figure BDA0002835070820000241
As can be seen from the results in Table 2, the half-life (T) of ZLF6004, a compound of the invention, is comparable to BIBF11201/2) Time to peak (T)max) Maximum blood concentration (C)max) And the area under the curve is obviously increased during drug administration, which shows that the compound ZLF6004 has obviously improved pharmacokinetic properties compared with BIBF 1120.
In summary, the present invention provides a compound represented by formula (a) and pharmaceutically acceptable salts thereof. Experimental results show that the compound provided by the invention has obviously improved pharmacokinetic properties compared with BIBF1120, has excellent inhibition effects on Vascular Endothelial Growth Factor Receptors (VEGFR), Fibroblast Growth Factor Receptors (FGFR) and platelet-derived growth factor receptors (PDGFR), can be used as VEGFR, FGFR and/or PDGFR inhibitors, can be used as angiogenesis inhibitors, and can be used as a medicament for preventing and/or treating various tumors including squamous cell carcinoma, and has wide application prospects.

Claims (7)

1. The following compounds or pharmaceutically acceptable salts thereof:
Figure DEST_PATH_IMAGE001
。
2. a process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the method comprises the steps of taking a compound (A-1) and a compound (A-2) as raw materials, and carrying out reaction to obtain a compound ZLF 6004;
Figure 125103DEST_PATH_IMAGE002
。
3. the method of claim 2, wherein: the molar ratio of the compound (A-1) to the compound (A-2) was 1: 1; the solvent for the reaction is methanol.
4. An antitumor agent characterized by: the compound or the pharmaceutically acceptable salt thereof as the active ingredient is added with the auxiliary materials commonly used in the pharmaceutical field to prepare the preparation.
5. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a VEGFR, FGFR and/or PDGFR inhibitor; the VEGFR is VEGFR2, the FGFR is FGFR1, and the PDGFR is PDGFR alpha.
6. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of an angiogenesis inhibitor; the angiogenesis inhibitor is an inhibitor related to VEGFR, FGFR and/or PDGFR inhibitors, the VEGFR is VEGFR2, the FGFR is FGFR1, and the PDGFR is PDGFR alpha.
7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of tumors, wherein the tumors are squamous cell carcinomas.
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