CN111039940A - Aurora A kinase inhibitor, preparation method, pharmaceutical composition and application thereof - Google Patents

Aurora A kinase inhibitor, preparation method, pharmaceutical composition and application thereof Download PDF

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CN111039940A
CN111039940A CN201911406150.1A CN201911406150A CN111039940A CN 111039940 A CN111039940 A CN 111039940A CN 201911406150 A CN201911406150 A CN 201911406150A CN 111039940 A CN111039940 A CN 111039940A
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cancer
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CN111039940B (en
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王永广
张佳琪
宋玉杰
苏小庭
戴信敏
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Beijing Xinkaiyuan Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an Aurora A kinase inhibitor, a preparation method, a pharmaceutical composition and application thereof. The compound is a compound having formula I or a pharmaceutically acceptable salt, hydrate, solvate thereofA solvate, an isotopic compound. The above compounds of the present invention can be used as the main ingredient of pharmaceutical compositions for the treatment of tumors by inhibiting Aurora a kinase activity, which can be treated by administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more of the compounds of the present invention or pharmaceutically acceptable salts, stereoisomers or tautomers thereof. The structure of formula I is:

Description

Aurora A kinase inhibitor, preparation method, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an Aurora A kinase inhibitor, a preparation method, a pharmaceutical composition and application thereof.
Background
Cancer is one of the major diseases threatening human health, and the main treatments at present are drug therapy, surgical therapy and radiation therapy, wherein drug therapy is the most common treatment mode. The traditional antitumor drugs can not distinguish tumor cells from normal cells, so that serious side effects are often caused, and the targeted drugs take the tumor cells as specific targets, can accurately act on tumors, greatly improve the treatment level and reduce the adverse reaction rate.
Aurora A is a member of Aurora protein kinase family, is a serine/threonine kinase which plays an important role in cell proliferation, participates in a plurality of processes of cell mitosis, including processes of cell G2/M conversion, mitotic spindle assembly, chromatid separation, cytoplasm division and the like, plays an important role in regulating and controlling the mitotic process of cells, and researches show that human Aurora A gene is located in a No. 20 chromosome Q13 region, the region is frequently amplified in breast cancer, is highly expressed in a plurality of types of tumors, and is always on a centrosome from the start of neutral replication to the end of mitosis. Abnormal expression of AuroraA leads to amplification of centrosomes, aneuploidy of the genome and chromosomal instability. Aurora a is a potential target for the treatment of tumors of interest, since it is aberrantly expressed in many types of tumors.
The Aurora protein kinase family plays an important role in the development process of various types of tumors, so that Aurora protein kinase inhibitors can play a role in killing tumor cells, wherein the inhibition of Aurora A kinase activity can cause cell cycle arrest at G2/M stage, lead to abnormal mitosis spindle and finally cause apoptosis, the mechanism of Aurora A and related tumor development is still unclear, and only few inhibitors are under study, such as ZM447439, VX-680 and the like
Aurora A kinase is a serine/threonine kinase which has important regulation and control functions in the cell growth cycle, participates in the regulation of spindle body formation, centrosome maturation, chromosome differentiation and cytokinesis processes, and has a key role in maintaining the stability of genome, researches show that the over-expression of Aurora A kinase easily causes abnormal cell mitosis and is closely related to the formation of tumor, the over-expression of Aurora A kinase in a plurality of cancer cells (such as lung cancer, breast cancer and pancreatic cancer), the inhibition of the activity of Aurora A kinase can cause the polyploid aggregation of tumor cells, the promotion of apoptosis and the blocking of cell proliferation, the treatment of antitumor drugs by taking Aurora A kinase as a target point is more and more emphasized, the Aurora A kinase is expressed and activated in the mitosis, the Aurora A kinase is ineffective to non-proliferative cells, but the proliferation speed of most normal cells in human body is not fast, therefore, the Aurora A kinase inhibitor belongs to targeted antitumor drugs.
The invention aims to improve the inhibition effect on Aurora A kinase, thereby solving the problem of drug resistance of the existing anticancer drugs and improving the targeting effect.
Disclosure of Invention
The researchers of the invention find that the derivative shown in the structural formula I has the function of improving the immune system capability and enhancing the anti-tumor activity. Therefore, the invention aims to provide an Aurora A kinase inhibitor, a preparation method, a pharmaceutical composition and application thereof. The compound represented by the formula I and various derivatives thereof have antitumor pharmacological activity.
One of the objects of the present invention is to provide compounds, stereoisomers or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds thereof, having the structure of formula I:
Figure BDA0002348680510000021
wherein R1 is selected from C1-C6Alkyl, substituted or unsubstituted phenyl or aromatic heterocyclic group, and R2 is selected from substituted or unsubstituted five-membered aromatic heterocyclic group and six-membered aromatic heterocyclic group.
The compound having the structure of formula I may be, but is not limited to, compounds of the following formulae (1) to (29):
Figure BDA0002348680510000022
Figure BDA0002348680510000031
the third purpose of the invention is to achieve the purpose of treating tumors by inhibiting Aurora A kinase activity, and provides a compound with a structure shown in formula I, a stereoisomer and non-toxic pharmaceutically acceptable salts, hydrates and solvates thereof, and a pharmaceutical composition containing the compound as an active ingredient, which is used as an Aurora A kinase inhibitor for treating tumors.
The tumor is selected from skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, fibrosarcoma.
The fourth object of the present invention is to provide a preparation method of the compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate and isotope thereof, which is characterized in that the preparation method comprises the following steps:
Figure BDA0002348680510000041
synthesis of intermediate VII:
compounds VIII and R2NH2Carrying out coupling reaction to obtain an intermediate VII; the reaction temperature is 60-150 ℃; the catalyst is cuprous iodide; the base comprises at least one of potassium carbonate, cesium carbonate and lithium hydroxide; the ligand comprises at least one of N, N' -dimethylethylenediamine and L-proline; the reaction solvent includes at least one of dioxane, dimethyl sulfoxide, and N, N-dimethylformamide.
Synthesis of intermediate VI:
under the action of acid, reacting the intermediate VII to obtain an intermediate VI; the reaction temperature is 20-100 ℃; the acid comprises at least one of trifluoroacetic acid and hydrochloric acid; the reaction solvent includes at least one of ethyl acetate, dichloromethane, toluene, and acetonitrile.
Synthesis of intermediate IV:
under the action of base catalysis, reacting the intermediate VI with the compound V to obtain an intermediate IV; the reaction temperature is 20-100 ℃; the base comprises at least one of triethylamine, diisopropylethylamine, morpholine and 1, 8-diazabicycloundec-7-ene; the reaction solvent includes at least one of dichloromethane, toluene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and N, N-dimethylformamide.
Synthesis of intermediate III:
carrying out hydrolysis reaction on the intermediate IV to obtain an intermediate III; the reaction temperature is 20-120 ℃; the alkali comprises at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the reaction solvent comprises at least one of methanol, a mixed solution of dioxane and water, a mixed solution of tetrahydrofuran and water, and ethanol.
Synthesis of Compound I:
under the action of base catalysis, the intermediate II and the compound II are subjected to condensation reaction to obtain a compound I; the reaction temperature is 20-120 ℃; the base comprises at least one of triethylamine, diisopropylethylamine, N-methylmorpholine and 4-dimethylaminopyridine; the condensing agent comprises at least one of 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide and bis (2-oxo-3-oxazolidinyl) phosphoryl chloride; the reaction solvent includes at least one of toluene, tetrahydrofuran, dichloromethane, N-dimethylformamide, and dimethyl sulfoxide.
Definition of
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. The salt comprises: acid addition salts obtained by reaction of the free base of the parent compound with an inorganic acid or with an organic acid; such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid, and the like; such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, malonic acid, or the like; preferably hydrochloric acid or (L) -malic acid; or when the acid proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion or aluminum ion, or coordinated with an organic base, a salt is formed; such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
"pharmaceutical composition" refers to a mixture of one or more of the compounds described herein or a physiologically acceptable salt thereof with other chemical ingredients such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
"carrier" when used herein refers to a carrier or diluent that does not produce a significant stimulus to an organism and does not abrogate the biological activity and properties of the administered compound.
"alkyl" refers to saturated aliphatic hydrocarbons, including straight or branched chain saturated aliphatic hydrocarbons.
"phenyl" refers to a group having a benzene ring as a functional group.
"aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. Preferably, the aryl group has 6 to 12 carbon atoms in the ring.
The compounds of the invention may have one or more asymmetric centers; the compounds can thus be prepared as individual (R) -stereoisomers or (S) -stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or designation of a particular compound in the specification and claims is intended to include the individual enantiomers as well as racemic or other mixtures thereof. Methods for determining stereochemical configuration and separating stereoisomers are well known in the art (see the discussion in chapter 4 of "Advanced Organic Chemistry", 4 th edition, j. march, John Wiley and Sons, new york, 1992). Thus, the present invention also encompasses any stereoisomeric form, its corresponding enantiomers (d-and l-or (+) and (-) isomers), and diastereomers thereof, and mixtures thereof, having the ability to modulate Aurora a kinase activity, and is not limited to any one stereoisomeric form.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples.
Example 1
N- (2-fluoro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Figure BDA0002348680510000071
The first step is as follows:
dissolving compound 1a (50.0g, 160.8mmol), compound 1b (16.8g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), and potassium carbonate (26.6g, 193.0mmol) in dioxane (500ml), heating to 100 ℃, incubating for 12 hours, detecting by TLC, cooling to room temperature after the reaction is completed, adding 300ml of water to quench the reaction, adding ethyl acetate (1000ml X2) to extract, combining the organic layers, drying the organic layers, concentrating, and separating by column chromatography to obtain off-white solid 40.3g, the off-white solid is compound 1c, with a yield of 75.7%.
The second step is that:
dissolving the compound 1c (40.0g, 120.8mmol) in dichloromethane (250ml), adding trifluoroacetic acid (30ml) at room temperature, stirring for reaction for 4 hours, detecting the reaction by TLC, adding 200ml of saturated sodium bicarbonate after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and performing column chromatography separation to obtain 21.3g of off-white solid, namely a compound 1d, wherein the yield is 76.3%.
The third step:
dissolving compound 1d (21.0g, 90.9mmol), compound 1e (13.3g, 109.1mmol) and triethylamine (11.0g, 109.1mmol) in dichloromethane (300ml), stirring at room temperature for reaction overnight, detecting by TLC, after the reaction is finished, adding diluted hydrochloric acid (100ml) to quench the reaction, drying the organic layer, concentrating, and separating by column chromatography to obtain a light yellow solid 24.6g, the light yellow solid is 1f, and the yield is 85.4%.
The fourth step:
dissolving the intermediate 1f (24.0g, 75.7mmol) in THF (100ml) and water (100ml), adding lithium hydroxide (6.4g, 151.4mmol) under stirring at room temperature, reacting for 2 hours, detecting by TLC, after the reaction is finished, adding diluted hydrochloric acid to adjust pH to 5-6, adding ethyl acetate (100ml X2) to extract, combining organic layers, then drying the organic layers, concentrating, and separating by column chromatography to obtain 18.3g of off-white solid, namely the intermediate 1g, with the yield of 79.8%.
The fifth step:
dissolving intermediate 1g (1.5g, 5.0mmol), 1H (775mg, 5.0mmol) and DIPEA (774mg, 6.0mmol) in DMF (20ml), adding HATU (72.3g, 6.0mmol) at room temperature, stirring for reaction for 3 hours, detecting by TLC, after the reaction is completed, adding water (20ml) to quench the reaction, adding ethyl acetate (50ml X2) to extract, combining the organic layers, drying the organic layers, concentrating, and separating by chromatography to obtain 1.4g of white-like solid which is N- (2-fluoro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, wherein the yield is 63.6%, and ESI (+) 441 m/z is 1.1.
Example 2
N- (2, 6-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the method of example 1, intermediate 1g (1.5g, 5.0mmol), (2, 6-difluorophenyl l) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, water (20ml) was added after the reaction was completed to quench the reaction, ethyl acetate (50mlX2) was added to extract, the organic layers were combined, then the organic layers were dried, concentrated, and column chromatography was performed to obtain 1.6g of off-white solid which was N- (2, 6-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide with a yield of 74.6%, ESI (+) m/z 429.1.
Figure BDA0002348680510000081
Example 3
N- (2-fluoro-4-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the method of reference example 1, intermediate 1g (1.5g, 5.0mmol), (2-fluoro-4-methoxyphenyl) methylamine (775mg, 5.0mmol), DIPEA (774mg, 6.0mmol) was dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml x2) was extracted, the organic layers were combined, dried, concentrated, and separated by column chromatography to obtain 1.3g of off-white solid which was N- (2-fluoro-4-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 59.0%, and ESI (+) m/z was 441.1.
Figure BDA0002348680510000091
Example 4
N- (2-chloro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the method of reference example 1, intermediate 1g (1.5g, 5.0mmol), (2-chloro-6-methoxyphenyl) methylamine (855mg, 5.0mmol), DIPEA (774mg, 6.0mmol) was dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of off-white solid which was N- (2-chloro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 61.3%, ESI (+) m/z 457.1.
Figure BDA0002348680510000092
Example 5
N- (2, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) was dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml x2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.8g of an off-white solid, which was N- (2, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield was 83.9%, ESI m/z was 429.1.
Figure BDA0002348680510000101
Example 6
N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (pyridin-4-yl) methylamine (540mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detecting reaction, after the reaction is finished, adding water (20ml) to quench the reaction, extracting with ethyl acetate (50mlX2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.2g, the off-white solid was N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in 60.9% yield and ESI (+) m/z ═ 394.1.
Figure BDA0002348680510000102
Example 7
N- ((6-methoxypyridin-3-yl) methyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (6-methoxypyridin-3-yl) methylamine (690mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml X2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to give 1.5g of a white-like solid which was N- ((6-methoxypyridin-3-yl) methyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 70.8%, and ESI (+) m/z was 424.1.
Figure BDA0002348680510000111
Example 8
N- (3-chloro-2-fluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (2-fluoro-3-chlorophenyl) methylamine (795mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, stirred for 3 hours, TLC detected, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml X2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.7g of a white-like solid which was N- (3-chloro-2-fluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide at a yield of 76.4%, ESI (+) m/z 445.1.
Figure BDA0002348680510000112
Example 9
N- (2, 6-dichlorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (2, 6-dichlorophenyl) methylamine (875mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detecting reaction, adding water (20ml) to quench reaction after the reaction is finished, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.4g, the off-white solid was N- (2, 6-dichlorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in 60.7% yield and ESI (+) m/z ═ 461.1.
Figure BDA0002348680510000121
Example 10
N- (2, 5-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (2, 5-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detecting reaction, adding water (20ml) to quench reaction after the reaction is finished, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.3g, the off-white solid was N- (2, 5-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield 60.6%, ESI (+) m/z 429.1.
Figure BDA0002348680510000131
Example 11
N- (2-fluoro-6-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Figure BDA0002348680510000132
The first step is as follows:
dissolving compound 1a (50.0g, 160.8mmol), compound 11a (31.7g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), and potassium carbonate (26.6g, 193.0mmol) in dioxane (500ml), heating to 100 ℃, incubating for 12 hours, detecting by TLC, cooling to room temperature after the reaction is completed, adding 300ml of water to quench the reaction, adding ethyl acetate (1000ml X2) to extract, combining organic layers, drying, concentrating, and chromatographically separating to obtain 57.3g of off-white solid, compound 11b, with an yield of 83.3%.
The second step is that:
dissolving the compound 11b (57.0g, 133.2mmol) in dichloromethane (250ml), adding trifluoroacetic acid (50ml) at room temperature, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate to adjust the pH to 5-6 after the reaction is finished, standing, layering, concentrating an organic layer, and performing column chromatography to obtain 20.4g of off-white solid which is the compound 11c, wherein the yield is 67.2%.
The third step:
after completion of the reaction, diluted hydrochloric acid (100ml) was added to quench the reaction, the organic layer was dried and concentrated, and column chromatography was performed to obtain 23.2g of a pale yellow solid, which was intermediate 1f, and the yield was 84.3%.
The fourth step:
dissolving intermediate 1f (23.0g, 73.2mmol) in THF (100ml) and water (100ml), adding lithium hydroxide (6.2g, 146.5mmol) under stirring at room temperature, reacting for 2 hours, detecting by TLC, adjusting pH to 5-6 with diluted hydrochloric acid after reaction, extracting with ethyl acetate (100ml X2), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 18.1g, off-white solid is intermediate 11e, yield is 82.4%.
The fifth step:
intermediate 11e (1.5g, 5.0mmol), 1h (775mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, stirred for reaction for 3 hours, TLC detecting reaction, adding water (20ml) to quench reaction after the reaction is finished, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.5g, the off-white solid was N- (2-fluoro-6-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, yield 68.6%, ESI (+) m/z ═ 438.1.
Example 12
N- (2, 6-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2, 6-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of a white-like solid, which was N- (2, 6-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 65.9%, and ESI (+) m/z was 426.2.
Figure BDA0002348680510000151
Example 13
N- (2-fluoro-4-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2-fluoro-3-methoxyphenyl) methylamine (775mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.6g of a white-like solid, which was N- (2-fluoro-4-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, yield 73.2%, ESI (+) m/z 438.2,
Figure BDA0002348680510000152
example 14
N- (2-chloro-6-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2-chloro-6-methoxyphenyl) methylamine (855mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.8g of a white-like solid, which was N- (2-chloro-6-methoxybenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, yield 79.5%, ESI (+) m/z 454.2.
Figure BDA0002348680510000161
Example 15
N- (2, 4-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.3g of a white-like solid, which was N- (2, 4-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 61.2%, and ESI (+) m/z was 426.2.
Figure BDA0002348680510000162
Example 16
N- (pyridin-4-ylmethyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (pyridin-4-yl) methylamine (540mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml X2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of a white-like solid which was N- (pyridin-4-ylmethyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 71.8%, and ESI (+) m/z was 391.2.
Figure BDA0002348680510000171
Example 17
N- ((6-methoxypyridin-3-yl) methyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (6-methoxypyridin-3-yl) methylamine (690mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml X2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to give 1.7g of a white-like solid which was N- ((6-methoxypyridin-3-yl) methyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, yield 80.9%, ESI (+) m/z 421.2.
Figure BDA0002348680510000172
Example 18
N- (3-chloro-2-fluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2-fluoro-3-chlorophenyl) methylamine (795mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.5g of a white-like solid, which was N- (3-chloro-2-fluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 68.0%, and ESI (+) m/z was 442.2.
Figure BDA0002348680510000181
Example 19
N- (2, 6-dichlorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2, 6-dichlorophenyl) methylamine (875mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml x2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.6g of a white-like solid, which was N- (2, 6-dichlorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 70.0%, and ESI (+) m/z was 458.1.
Figure BDA0002348680510000182
Example 20
N- (2, 5-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide
Referring to the procedure of example 11, intermediate 11e (1.5g, 5.0mmol), (2, 5-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of a white-like solid, which was N- (2, 5-difluorobenzyl) -2- (2- ((3-methyl-1H-pyrazol-5-yl) amino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) -2-oxoacetamide, the yield was 65.9%, and ESI (+) m/z was 426.2.
Figure BDA0002348680510000191
Example 21
N- (2-fluoro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Figure BDA0002348680510000192
The first step is as follows:
dissolving compound 1a (50.0g, 160.8mmol), compound 21a (16.8g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), and potassium carbonate (26.6g, 193.0mmol) in dioxane (500ml), heating to 100 ℃, incubating for 12 hours, detecting by TLC, cooling to room temperature after the reaction is completed, adding 300ml of water to quench the reaction, adding ethyl acetate (1000ml X2) to extract, combining organic layers, drying the organic layers, concentrating, and chromatographically separating to obtain off-white solid 38.1g, compound 21b, with a yield of 71.6%.
The second step is that:
dissolving the compound 21b (38.0g, 114.8mmol) in dichloromethane (250ml), adding trifluoroacetic acid (30ml) at room temperature, stirring for reaction for 4 hours, detecting the reaction by TLC, adding 200ml of saturated sodium bicarbonate after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and separating by column chromatography to obtain 22.5g of off-white solid which is the compound 21c, wherein the yield is 84.7%.
The third step:
the compound 21c (22.0g, 95.2mmol), the compound 1e (11.6g, 95.2mmol) and triethylamine (9.6g, 95.2mmol) were dissolved in dichloromethane (300ml), the reaction was stirred at room temperature overnight, the reaction was detected by TLC, after the reaction was completed, diluted hydrochloric acid (100ml) was added to quench the reaction, the organic layer was dried, concentrated, and separated by column chromatography to give 22.4g of a pale yellow solid, which was intermediate 21d, as a pale yellow solid, in 74.2% yield.
The fourth step:
dissolving intermediate 21d (22.0g, 69.4mmol) in THF (100ml) and water (100ml), adding lithium hydroxide (5.8g, 138.8mmol) under stirring at room temperature, reacting for 2 hours, detecting by TLC, after the reaction is finished, adding diluted hydrochloric acid to adjust pH to 5-6, extracting with ethyl acetate (100ml X2), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid 17.3g, which is intermediate 21e, with yield of 82.3%.
The fifth step:
dissolving intermediate 21e (1.5g, 5.0mmol), 1H (775mg, 5.0mmol) and DIPEA (774mg, 6.0mmol) in DMF (20ml), adding HATU (72.3g, 6.0mmol) at room temperature, stirring, reacting for 3 hours, detecting by TLC, adding water (20ml) after the reaction is finished, quenching, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, and separating by column chromatography to obtain 1.2g of white-like solid, wherein the white-like solid is N- (2-fluoro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield is 54.5%, and the ESIm/z is 441.1.
Example 22
N- (2, 6-difluorobenzyl) -2-2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 21, intermediate 21e (1.5g, 5.0mmol), (2, 6-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detecting reaction, adding water (20ml) to quench reaction after the reaction is finished, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.4g, the off-white solid was N- (2, 6-difluorobenzyl) -2-2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in 65.4% yield and ESI (+) m/z 429.1.
Figure BDA0002348680510000211
Example 23
N- (2-fluoro-4-methoxybenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 21, intermediate 21e (1.5g, 5.0mmol), (2-fluoro-4-methoxyphenyl) methylamine (775mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detected, after the reaction was completed, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.5g of a white-like solid, which was N- (2-fluoro-4-methoxybenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 68.2%, and ESI (+) m/z was 441.1.
Figure BDA0002348680510000212
Example 24
N- (2-chloro-6-methoxybenzyl) -2-2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 21, intermediate 21e (1.5g, 5.0mmol), (2-chloro-6-methoxyphenyl) methylamine (855mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml x2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.2g of a white-like solid, which was N- (2-chloro-6-methoxybenzyl) -2-2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 52.4%, ESI (+) m/z 457.1.
Figure BDA0002348680510000221
Example 25
N- (2, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 21, intermediate 21e (1.5g, 5.0mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detecting reaction, adding water (20ml) to quench reaction after the reaction is finished, extracting with ethyl acetate (50ml X2), combining organic layers, drying, concentrating, separating by column chromatography to obtain off-white solid 1.5g, the off-white solid was N- (2, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in 70.1% yield and ESI (+) m/z 429.1.
Figure BDA0002348680510000222
Example 26
N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Figure BDA0002348680510000231
The first step is as follows:
dissolving compound 1a (50.0g, 160.8mmol), compound 26b (15.1g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), and potassium carbonate (26.6g, 193.0mmol) in dioxane (500ml), heating to 100 ℃, incubating for 12 hours, detecting by TLC, cooling to room temperature after the reaction is completed, adding 300ml of water to quench the reaction, adding ethyl acetate (1000ml X2) to extract, combining organic layers, drying, concentrating, and chromatographically separating to obtain off-white solid 36.2g, the off-white solid is compound 26b, with a yield of 69.3%.
The second step is that:
dissolving the compound 26b (36.0g, 110.8mmol) in dichloromethane (250ml), adding trifluoroacetic acid (30ml) at room temperature, stirring for reaction for 4 hours, detecting by TLC, adding saturated sodium bicarbonate 200ml after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and separating by column chromatography to obtain off-white solid 22.3g which is a compound 26c with the yield of 89.5%.
The third step:
after completion of the reaction, diluted hydrochloric acid (100ml) was added to quench the reaction, the organic layer was dried and concentrated, and column chromatography was performed to obtain 21.7g of a pale yellow solid, which was intermediate 26d, and yield was 71.3%.
The fourth step:
dissolving intermediate 26d (21.0g, 67.5mmol) in THF (100ml) and water (100ml), adding lithium hydroxide (5.7g, 135.0mmol) under stirring at room temperature, reacting for 2 hours, detecting by TLC, after the reaction is finished, adding diluted hydrochloric acid to adjust pH to 5-6, extracting with ethyl acetate (100ml X2), combining organic layers, drying, concentrating, and separating by column chromatography to obtain off-white solid, namely intermediate 26e, with yield of 90.8%.
The fifth step:
intermediate 26e (1.5g, 5.0mmol), 1H (775mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred and reversed, 3 hours, TLC detected, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography separated to give 1.4g of an off-white solid, which was N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield 72.4%, ESI (+) m/z ═ 388.2.
Example 27
N- ((6-methoxypyridin-3-yl) methyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 26, intermediate 26e (1.5g, 5.0mmol), (6-methoxypyridin-3-yl) methylamine (690mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50ml X2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to give 1.1g of a white-like solid which was N- ((6-methoxypyridin-3-yl) methyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield 52.8%, ESI (+) m/z 418.2.
Figure BDA0002348680510000241
Example 28
N- (3-chloro-2-fluorobenzyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Referring to the procedure of example 26, intermediate 26e (1.5g, 5.0mmol), (3-chloro-2-fluorophenyl) methylamine (795mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after completion of the reaction, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.2g of a white-like solid, which was N- (3-chloro-2-fluorobenzyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield 54.8%, ESI (+) m/z 439.1.
Figure BDA0002348680510000251
Example 29
Acetamide
Referring to the procedure of example 26, intermediate 26e (1.5g, 5.0mmol), (2, 6-dichlorophenyl) methylamine (875mg, 5.0mmol), DIPEA (774mg, 6.0mmol) were dissolved in DMF (20ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detected, after the reaction was completed, water (20ml) was added to quench the reaction, ethyl acetate (50mlX2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.5g of off-white solid which was acetamide with a yield of 66.1%, ESI (+) m/z 455.1.
Figure BDA0002348680510000252
Example 30
Biological evaluation
Aurora A kinase in vitro Activity assay
The experimental method comprises the following steps:
adding 10 mu L of reaction solution, 10 mu L of Aurora A kinase, 10 mu L of substrate, 10 mu L of solution of compound to be detected and 10 mu L of LATP solution into a 96-well plate in sequence, mixing uniformly and incubating for 30 minutes; then 10 μ L of kinase reaction stop solution was added to each well plate, followed by 10 μ L of phospho-histone H3 antibody in each well plate, 100 μ L of LLHRP-antibody chelator solution after 60 minutes incubation at 25 ℃, followed by 100 μ L of TMB substrate at 25 ℃ for 10 minutes, and finally 100 μ L of ELISA stop solution in each well plate, 450nm readings were recorded with an ELISA detector, and IC50 was calculated using drug-free solvent as a blank, as shown in the following table:
A＜50nM，50nM≤B≤500nM，500nM＜C
examples IC50(Aurora A) Examples IC50(Aurora A)
Compound 1 B Compound 16 C
Compound 2 B Compound 17 A
Compound 3 A Compound 18 A
Compound 4 C Compound 19 B
Compound 5 A Compound 20 B
Compound 6 A Compound 21 C
Compound 7 B Compound 22 A
Compound 8 C Compound 23 B
Compound 9 C Compound 24 A
Compound 10 A Compound 25 A
Compound 11 A Compound 26 C
Compound 12 B Compound 27 C
Compound 13 B Compound 28 A
Compound 14 C Compound 29 B
Compound 15 A Compound 30
。
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included therein.

Claims (11)

1. A compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound having a structure of formula I:
Figure FDA0002348680500000011
wherein R1 is selected from C1-C6Alkyl, substituted or unsubstituted phenyl or an aromatic heterocyclic group;
r2 is selected from substituted or unsubstituted five-membered aromatic heterocyclic group and six-membered aromatic heterocyclic group.
2. The process for the preparation of a compound having the structure of formula I, a stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof according to claim 1, wherein the process comprises the steps of:
Figure FDA0002348680500000012
synthesis of intermediate VII:
compounds VIII and R2NH2Carrying out coupling reaction to obtain an intermediate VII;
synthesis of intermediate VI:
under the action of acid, reacting the intermediate VII to obtain an intermediate VI;
synthesis of intermediate IV:
under the action of base catalysis, reacting the intermediate VI with a compound V to obtain an intermediate IV;
synthesis of intermediate III:
the intermediate IV is subjected to hydrolysis reaction to obtain an intermediate III;
synthesis of Compound I:
and under the action of base catalysis, carrying out condensation reaction on the intermediate III and the compound II to obtain the compound I.
3. The method for preparing the compound, the stereoisomer or the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopic compound thereof with the structure shown in the formula I according to claim 2, wherein in the step of synthesizing the intermediate VII, the reaction temperature is 60-150 ℃;
and/or, the catalyst is cuprous iodide;
and/or the base comprises at least one of potassium carbonate, cesium carbonate and lithium hydroxide;
and/or, the ligand comprises at least one of N, N' -dimethylethylenediamine and L-proline;
and/or the reaction solvent comprises at least one of dioxane, dimethyl sulfoxide, and N, N-dimethylformamide.
4. The method for preparing the compound, the stereoisomer or the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopic compound thereof with the structure shown in the formula I in claim 2, wherein in the step of synthesizing the intermediate VI, the reaction temperature is 20-100 ℃;
and/or, the acid comprises at least one of trifluoroacetic acid and hydrochloric acid;
and/or the reaction solvent comprises at least one of ethyl acetate, dichloromethane, toluene and acetonitrile.
5. The method for preparing the compound, the stereoisomer or the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopic compound thereof with the structure shown in the formula I according to claim 2, wherein in the step of synthesizing the intermediate IV, the reaction temperature is 20-100 ℃;
and/or the base comprises at least one of triethylamine, diisopropylethylamine, morpholine, and 1, 8-diazabicycloundec-7-ene;
and/or the reaction solvent comprises at least one of dichloromethane, toluene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether and N, N-dimethylformamide.
6. The method for preparing the compound, the stereoisomer or the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopic compound thereof with the structure shown in the formula I according to claim 2, wherein in the step of synthesizing the intermediate III, the reaction temperature is 20-120 ℃;
and/or, the base comprises at least one of lithium hydroxide, sodium hydroxide, and potassium hydroxide;
and/or the reaction solvent comprises at least one of methanol, a mixed solution of dioxane and water, a mixed solution of tetrahydrofuran and water and ethanol.
7. The method for preparing the compound, the stereoisomer or the pharmaceutically acceptable salt, the hydrate, the solvate or the isotopic compound thereof with the structure shown in the formula I according to claim 2, wherein in the step of synthesizing the compound I, the reaction temperature is 20-120 ℃;
and/or the base comprises at least one of triethylamine, diisopropylethylamine, N-methylmorpholine and 4-dimethylaminopyridine;
and/or the condensing agent comprises at least one of 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide and bis (2-oxo-3-oxazolidinyl) phosphoryl chloride;
and/or the reaction solvent comprises at least one of toluene, tetrahydrofuran, dichloromethane, N-dimethylformamide, and dimethylsulfoxide.
8. A pharmaceutical composition comprising a compound having the structure of formula I, stereoisomers and non-toxic pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds, pharmaceutically acceptable carriers, diluents, as claimed in claim 1.
9. A compound having the structure of formula I, stereoisomers and non-toxic pharmaceutically acceptable salts, hydrates, solvates thereof, pharmaceutical compositions containing these compounds as active ingredient according to claim 1 for use as Aurora a kinase inhibitors for the treatment of tumors.
10. The use of claim 9, wherein the tumor is selected from the group consisting of skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, stomach cancer, kidney cancer, renal parenchymal cancer, cervical cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, fibrosarcoma.
11. The compound having the structure of formula I, stereoisomers and non-toxic pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds thereof according to claim 1, wherein said compound having the structure of formula I is a compound of formulae (1) - (29) below:
Figure FDA0002348680500000041
Figure FDA0002348680500000051
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101027290A (en) * 2004-09-24 2007-08-29 霍夫曼-拉罗奇有限公司 Novel 2,3-phthalazinone derivatives, as AURORA-A kinase inhibitors
WO2008025526A1 (en) * 2006-08-31 2008-03-06 F. Hoffmann-La Roche Ag Indole derivatives, their manufacture and use as pharmaceutical agents
CN101341145A (en) * 2005-12-19 2009-01-07 霍夫曼-拉罗奇有限公司 Isoquinoline aminopyrazole derivatives, their manufacture and use as pharmaceutical agents for the treatment of cancer
CN101405282A (en) * 2006-01-23 2009-04-08 安姆根有限公司 Aurora kinase modulators and method of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101027290A (en) * 2004-09-24 2007-08-29 霍夫曼-拉罗奇有限公司 Novel 2,3-phthalazinone derivatives, as AURORA-A kinase inhibitors
CN101341145A (en) * 2005-12-19 2009-01-07 霍夫曼-拉罗奇有限公司 Isoquinoline aminopyrazole derivatives, their manufacture and use as pharmaceutical agents for the treatment of cancer
CN101405282A (en) * 2006-01-23 2009-04-08 安姆根有限公司 Aurora kinase modulators and method of use
WO2008025526A1 (en) * 2006-08-31 2008-03-06 F. Hoffmann-La Roche Ag Indole derivatives, their manufacture and use as pharmaceutical agents

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