CN111039940B - 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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CN111039940B
CN111039940B CN201911406150.1A CN201911406150A CN111039940B CN 111039940 B CN111039940 B CN 111039940B CN 201911406150 A CN201911406150 A CN 201911406150A CN 111039940 B CN111039940 B CN 111039940B
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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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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, isotopic compound thereof. 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 Aurora a 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 many 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 mitotic spindle and finally cause apoptosis, the mechanism of Aurora A and related tumor development is still unclear, and only few inhibitors are under research, such as ZM447439, VX-680 and the like
Aurora A kinase is a serine/threonine kinase which has important regulation and control effects in the cell growth cycle, participates in the processes of regulation of spindle body formation, centrosome maturation, chromosome differentiation and cytokinesis, and has a key effect on maintaining the stability of genome.
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 GDA0003609508780000031
wherein R1 is selected from C 1 -C 6 Alkyl, 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 GDA0003609508780000032
Figure GDA0003609508780000041
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 GDA0003609508780000051
synthesis of intermediate VII:
compounds VIII and R 2 NH 2 Carrying 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) carbodiimide 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.
By "pharmaceutical composition" is meant 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 irritation 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-isomers or (+) and (-) isomers) and diastereomers thereof and mixtures thereof and is not limited to any one stereoisomeric form, which has the ability to modulate Aurora a kinase activity.
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 GDA0003609508780000091
The first step is as follows:
compound 1a (50.0g, 160.8mmol), compound 1b (16.8g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), potassium carbonate (26.6g, 193.0mmol) were dissolved in dioxane (500 ml), the temperature was raised to 100 ℃ for 12 hours for incubation reaction, TLC detection reaction was performed, after the reaction, the temperature was lowered to room temperature, 300ml of water was added to quench the reaction, ethyl acetate (1000 ml X2) was added to extract, the organic layers were combined, the organic layers were dried, concentrated, and column chromatography was performed to give 40.3g of an off-white solid, which was compound 1c, with a yield of 75.7%.
The second step:
dissolving the compound 1c (40.0g, 120.8mmol) in dichloromethane (250 ml), adding trifluoroacetic acid (30 ml) at room temperature, stirring for reaction for 4 hours, detecting by TLC, adding 200ml of saturated sodium bicarbonate after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and carrying out column chromatography separation to obtain 21.3g of off-white solid, wherein the off-white solid is a compound 1d, and the yield is 76.3%.
The third step:
compound 1d (21.0g, 90.9mmol), compound 1e (13.3g, 109.1mmol) and triethylamine (11.0g, 109.1mmol) are dissolved in dichloromethane (300 ml), the mixture is stirred at room temperature for overnight reaction, TLC detection is carried out on the reaction, after the reaction is finished, diluted hydrochloric acid (100 ml) is added for quenching the reaction, an organic layer is dried and concentrated, column chromatography is carried out, and light yellow solid 24.6g, light yellow solid is obtained, the yield is 85.4%, and the concentration is 1 f.
The fourth step:
dissolving intermediate 1f (24.0g, 75.7mmol) in THF (100 ml) and water (100 ml), 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 the pH to 5-6, adding ethyl acetate (100 mlX 2) to extract, combining organic layers, drying the organic layers, concentrating, and performing column chromatography to obtain 18.3g of off-white solid, namely intermediate 1g, wherein the yield is 79.8%.
The fifth step:
dissolving intermediate 1g (1.5g, 5.0 mmol), 1H (775mg, 5.0 mmol) and DIPEA (774mg, 6.0 mmol) in DMF (20 ml), adding HATU (72.3g, 6.0 mmol) at room temperature, stirring for 3 hours, detecting by TLC, after the reaction is completed, adding water (20 ml) to quench the reaction, adding ethyl acetate (50 ml X2) to extract, combining the organic layers, drying the organic layers, concentrating, and separating by chromatography to obtain 1.4g of a 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 with a yield of 63.6% and ESIm/z =441.1.
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 procedure of example 1, intermediate 1g (1.5g, 5.0mmol), (2, 6-difluorophenyl l) methylamine (715mg, 5.0mmol), DIPEA (774mg, 6.0mmol) was dissolved in DMF (20 ml), 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 (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was added to extract, the organic layers were combined, and then the organic layers were dried, concentrated, and column chromatography was performed to obtain 1.6g of an 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% and ESI (+) m/z =429.1.
Figure GDA0003609508780000111
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 procedure 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 (20 ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, and after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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-fluoro-4-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, in a yield of 59.0%, ESI (+) m/z =441.1.
Figure GDA0003609508780000121
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 procedure 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 (20 ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, and after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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-chloro-6-methoxybenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide with a yield of 61.3% and ESI (+) m/z =457.1.
Figure GDA0003609508780000122
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, 5.0 mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 ml x 2) 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, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, yield 83.9%, ESI (+) m/z =429.1.
Figure GDA0003609508780000131
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) was dissolved in DMF (20 ml), 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 (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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- (pyridin-4-ylmethyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, the yield was 60.9%, and ESI (+) m/z =394.1.
Figure GDA0003609508780000132
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) was dissolved in DMF (20 ml), HATU (72.3g, 6.0mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, and after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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- ((6-methoxypyridin-3-yl) methyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in a yield of 70.8%, ESI (+) m/z =424.1.
Figure GDA0003609508780000141
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) was dissolved in DMF (20 ml), 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 (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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 in a yield of 76.4%, ESI (+) m/z =445.1.
Figure GDA0003609508780000151
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) was dissolved in DMF (20 ml), 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 (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of an off-white solid which 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, esim (+) z =461.1.
Figure GDA0003609508780000152
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) was dissolved in DMF (20 ml), 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 (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.3g of an off-white solid which was N- (2, 5-difluorobenzyl) -2-oxo-2- (2- (thiazol-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in 60.6% yield, esim (+) z =429.1.
Figure GDA0003609508780000161
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 GDA0003609508780000171
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 (500 ml), heating to 100 ℃, carrying out heat preservation reaction for 12 hours, carrying out TLC detection reaction, cooling to room temperature after the reaction is finished, adding 300ml of water for quenching reaction, adding ethyl acetate (1000 ml X2) for extraction, combining organic layers, drying the organic layers, concentrating, and carrying out chromatographic separation to obtain 57.3g of off-white solid, namely compound 11b, wherein the yield is 83.3%.
The second step:
dissolving the compound 11b (57.0g, 133.2mmol) in dichloromethane (250 ml), adding trifluoroacetic acid (50 ml) at room temperature, stirring for reacting for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust the pH to 5-6, standing, layering, concentrating an organic layer, and performing column chromatography to obtain 20.4g of off-white solid, namely the compound 11c, wherein the yield is 67.2%.
The third step:
compound 11c (21.0g, 87.7mmol), compound 1e (12.8g, 105.3mmol) and triethylamine (10.6g, 105.3mmol) were dissolved in dichloromethane (300 ml), the reaction was stirred at room temperature overnight, the reaction was detected by TLC, after completion of the reaction, diluted hydrochloric acid (100 ml) was added to quench the reaction, the organic layer was dried, concentrated, and column chromatography was carried out to give 23.2g of a pale yellow solid as intermediate 1f in 84.3% yield.
The fourth step:
dissolving the intermediate 1f (23.0g, 73.2mmol) in THF (100 ml) and water (100 ml), adding lithium hydroxide (6.2g, 146.5 mmol) while stirring at room temperature, reacting for 2 hours, detecting by TLC (thin layer chromatography), adjusting the pH to 5-6 by adding diluted hydrochloric acid after the reaction is finished, extracting by ethyl acetate (100 ml X2), combining organic layers, drying, concentrating, and carrying out column chromatography separation to obtain 18.1g of off-white solid, namely the intermediate 11e, wherein the yield is 82.4%.
The fifth step:
dissolving intermediate 11e (1.5g, 5.0mmol), 1H (775mg, 5.0mmol) and DIPEA (774mg, 6.0mmol) in DMF (20 ml), adding HATU (72.3g, 6.0mmol) at room temperature, stirring for reacting for 3 hours, detecting by TLC, adding water (20 ml) after the reaction is finished, quenching the reaction, extracting by ethyl acetate (50 ml X2), combining organic layers, drying, concentrating, and carrying out column chromatography to obtain 1.5g of white-like solid, wherein the white-like solid is 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, the yield is 68.6%, and the yield is (+) 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 (1.5 g,5.0 mmol), (2, 6-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of an off-white 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, yield 65.9%, ESI (+) m/z =426.2.
Figure GDA0003609508780000191
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, 5.0 mmol), (2-fluoro-3-methoxyphenyl) methylamine (775mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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 GDA0003609508780000201
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, 5.0 mmol), (2-chloro-6-methoxyphenyl) methylamine (855mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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 GDA0003609508780000202
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 (1.5 g,5.0 mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.3g of an off-white 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, yield 61.2%, ESI (+) m/z =426.2.
Figure GDA0003609508780000211
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 (1.5 g,5.0 mmol), (pyridin-4-yl) methylamine (540mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, yield 71.8%, ESI (+) m/z =391.2.
Figure GDA0003609508780000221
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, 5.0 mmol), (6-methoxypyridin-3-yl) methylamine (690mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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- ((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 GDA0003609508780000222
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 (1.5 g,5.0 mmol), (2-fluoro-3-chlorophenyl) methylamine (795 mg,5.0 mmol), DIPEA (774mg, 6.0 mmol) were dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, and after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, yield 68.0%, ESI (+) m/z =442.2.
Figure GDA0003609508780000231
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 (1.5 g,5.0 mmol), (2, 6-dichlorophenyl) methylamine (875mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, yield 70.0%, ESI (+) m/z =458.1.
Figure GDA0003609508780000241
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 (1.5 g,5.0 mmol), (2, 5-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of an off-white 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, yield 65.9%, ESI (+) m/z =426.2.
Figure GDA0003609508780000242
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 GDA0003609508780000251
The first step is as follows:
compound 1a (50.0g, 160.8mmol), compound 21a (16.8g, 160.8mmol), cuprous iodide (3.1g, 16.1mmol), N' -dimethylethylenediamine (2.8g, 32.2mmol), potassium carbonate (26.6g, 193.0mmol) were dissolved in dioxane (500 ml), the temperature was raised to 100 ℃ for 12 hours for incubation reaction, TLC detection reaction was performed, after the reaction was completed, the temperature was lowered to room temperature, 300ml of water was added to quench the reaction, ethyl acetate (1000 ml X2) was added to extract, the organic layers were combined, dried, and after concentration, chromatography was performed to obtain an off-white solid, 38.1g, and the off-white solid was compound 21b, with a yield of 71.6%.
The second step is that:
dissolving the compound 21b (38.0 g, 114.8mmol) in dichloromethane (250 ml), adding trifluoroacetic acid (30 ml) at room temperature, stirring for reaction for 4 hours, detecting the reaction by TLC, adding saturated sodium bicarbonate 200ml after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and performing column chromatography to obtain an off-white solid, namely the compound 21c, of which the yield is 84.7%.
The third step:
the compound 21c (22.0 g, 95.2mmol), the compound 1e (11.6 g, 95.2mmol) and triethylamine (9.6 g, 95.2mmol) were dissolved in dichloromethane (300 ml), stirred at room temperature for reaction overnight, detected by TLC, after the reaction was completed, diluted hydrochloric acid (100 ml) 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, in 74.2% yield.
The fourth step:
intermediate 21d (22.0g, 69.4mmol) was dissolved in THF (100 ml) and water (100 ml), and lithium hydroxide (5.8g, 138.8mmol) was added thereto under stirring at room temperature for 2 hours, followed by detection by TLC, after completion of the reaction, diluted hydrochloric acid was added to adjust the pH to 5-6, extraction was carried out with ethyl acetate (100 ml X2), and the organic layers were combined, dried, concentrated, and subjected to column chromatography to give 17.3g of an off-white solid as intermediate 21e in a yield of 82.3%.
The fifth step:
dissolving intermediate 21e (1.5 g,5.0 mmol), 1H (775mg, 5.0 mmol) and DIPEA (774mg, 6.0 mmol) in DMF (20 ml), adding HATU (72.3 g,6.0 mmol) at room temperature, stirring, reacting for 3 hours, detecting by TLC, adding water (20 ml) after the reaction is finished, quenching, extracting with ethyl acetate (50 ml 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 ESI (+) m/z =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 (1.5 g,5.0 mmol), (2, 6-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.4g of an off-white solid which 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, ESI (+) m/z =429.1.
Figure GDA0003609508780000271
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, 5.0 mmol), (2-fluoro-4-methoxyphenyl) methylamine (775mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, in a yield of 68.2%, ESI (+) m/z =441.1.
Figure GDA0003609508780000281
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, 5.0 mmol), (2-chloro-6-methoxyphenyl) methylamine (855mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, yield 52.4%, ESI (+) m/z =457.1.
Figure GDA0003609508780000282
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, 5.0 mmol), (2, 4-difluorophenyl) methylamine (715mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after the completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 1.5g of off-white solid which was N- (2, 4-difluorobenzyl) -2-oxo-2- (2- (thiazol-5-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide in a yield of 70.1%, esim (+) z =429.1.
Figure GDA0003609508780000291
Example 26
N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide
Figure GDA0003609508780000292
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 (500 ml), heating to 100 ℃, carrying out heat preservation reaction for 12 hours, carrying out TLC detection reaction, cooling to room temperature after the reaction is finished, adding 300ml of water to quench the reaction, adding ethyl acetate (1000 ml X2) to extract, combining organic layers, drying the organic layers, concentrating, and carrying out chromatographic separation to obtain 36.2g of off-white solid, wherein the off-white solid is compound 26b, and the yield is 69.3%.
The second step is that:
dissolving the compound 26b (36.0 g, 110.8mmol) in dichloromethane (250 ml), adding trifluoroacetic acid (30 ml) at room temperature, stirring for reaction for 4 hours, detecting the reaction by TLC, adding saturated sodium bicarbonate 200ml after the reaction is finished, quenching the reaction, standing, layering, concentrating an organic layer, and performing column chromatography to obtain an off-white solid, namely a compound 26c, of which the yield is 89.5%.
The third step:
compound 26c (22.0g, 97.8mmol), compound 1e (11.9g, 97.8mmol) and triethylamine (9.9g, 97.8mmol) were dissolved in dichloromethane (300 ml), the reaction was stirred at room temperature overnight, the reaction was detected by TLC, after the completion of the reaction, the reaction was quenched by addition of dilute hydrochloric acid (100 ml), the organic layer was dried, concentrated and isolated by column chromatography to give 21.7g of a pale yellow solid as intermediate 26d, which was isolated as a pale yellow solid in 71.3% yield.
The fourth step:
dissolving intermediate 26d (21.0g, 67.5mmol) in THF (100 ml) and water (100 ml), adding lithium hydroxide (5.7g, 135.0mmol) while stirring at room temperature, reacting for 2 hours, detecting by TLC, after the reaction is finished, adding diluted hydrochloric acid to adjust the pH value to 5-6, extracting by ethyl acetate (100 mlX 2), combining organic layers, drying, concentrating, and separating by column chromatography to obtain 18.2g of off-white solid, namely intermediate 26e, with the yield of 90.8%.
The fifth step:
dissolving intermediate 26e (1.5g, 5.0 mmol), 1H (775mg, 5.0 mmol) and DIPEA (774mg, 6.0 mmol) in DMF (20 ml), adding HATU (72.3g, 6.0 mmol) at room temperature, stirring, reacting for 3 hours, detecting by TLC, after the reaction is completed, adding water (20 ml) to quench the reaction, extracting with ethyl acetate (50 ml X2), combining the organic layers, drying, concentrating, and separating by column chromatography to obtain 1.4g of white-like solid, which is N- (pyridin-4-ylmethyl) -2-oxo-2- (2- (pyridin-2-ylamino) -5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl) acetamide, with a yield of 72.4% and 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, 5.0 mmol), (6-methoxypyridin-3-yl) methylamine (690mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) was extracted, the organic layers were combined, dried, concentrated, and column chromatography was performed to obtain 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, in a yield of 52.8%, ESI (+) m/z =418.2.
Figure GDA0003609508780000311
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 (1.5 g,5.0 mmol), (3-chloro-2-fluorophenyl) methylamine (795 mg,5.0 mmol), DIPEA (774mg, 6.0 mmol) were dissolved in DMF (20 ml), HATU (72.3 g,6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, the reaction was detected by TLC, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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 with a yield of 54.8%, ESI (+) m/z =439.1.
Figure GDA0003609508780000321
Example 29
Acetamide
Referring to the procedure of example 26, intermediate 26e (1.5g, 5.0 mmol), (2, 6-dichlorophenyl) methylamine (875mg, 5.0 mmol), DIPEA (774mg, 6.0 mmol) was dissolved in DMF (20 ml), HATU (72.3g, 6.0 mmol) was added at room temperature, the reaction was stirred for 3 hours, TLC detection was performed, after completion of the reaction, water (20 ml) was added to quench the reaction, ethyl acetate (50 mlX 2) 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, yield 66.1%, ESI (+) m/z =455.1.
Figure GDA0003609508780000331
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 incubation for 60 minutes at 25 ℃, followed by 100 μ L of TMB substrate for incubation for 10 minutes at 25 ℃, and finally 100 μ L of ELISA stop solution in each well plate, and the IC50 was calculated using an ELISA detector to record 450nm readings, with no drug added as a blank control, with the specific data shown in the following table:
A＜50nM，50nM≤B≤500nM，500nM＜C
Figure GDA0003609508780000332
Figure GDA0003609508780000341
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 (10)

1. A compound having a structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, an isotopic compound thereof:
Figure FDA0003794741340000011
when R is 2 Is composed of
Figure FDA0003794741340000012
When R is 1 Is selected from
Figure FDA0003794741340000013
Figure FDA0003794741340000014
When R is 2 Is composed of
Figure FDA0003794741340000015
When R is 1 Is selected from
Figure FDA0003794741340000016
Figure FDA0003794741340000021
When R is 2 Is composed of
Figure FDA0003794741340000022
When R is 1 Is selected from
Figure FDA0003794741340000023
Figure FDA0003794741340000024
When R is 2 Is composed of
Figure FDA0003794741340000025
When R is 1 Is selected from
Figure FDA0003794741340000026
Figure FDA0003794741340000027
The compound with the structure of formula I is selected from the following compounds of formulas (1) to (29):
Figure FDA0003794741340000031
Figure FDA0003794741340000041
2. the process for the preparation of a compound having the structure of formula I, a stereoisomer or a pharmaceutically acceptable salt, isotopic compound thereof, according to claim 1, comprising the steps of:
Figure FDA0003794741340000042
synthesis of intermediate VII:
compounds VIII and R 2 NH 2 Carrying 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;
and (3) synthesis of an 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 and the isotopic compound of 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 and the isotopic compound of the formula I according to 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 a compound, a stereoisomer or a pharmaceutically acceptable salt and an isotope thereof with a structure shown in 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 and the isotopic compound of 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 and the isotopic compound of 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 as claimed in claim 1, a stereoisomer thereof, a non-toxic pharmaceutically acceptable salt thereof, an isotopic compound, a pharmaceutically acceptable carrier, and a diluent.
9. Use of compounds having the structure of formula I, stereoisomers and non-toxic pharmaceutically acceptable salts thereof according to claim 1, pharmaceutical compositions containing these compounds as active ingredient for the manufacture of a medicament which is an Aurora a kinase inhibitor for the treatment of tumours.
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, kidney cancer, cervical cancer, uterine body 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, multiple myeloma, basal cell tumor, seminoma, chondrosarcoma, myosarcoma, fibrosarcoma.
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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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Denomination of invention: An Aurora A kinase inhibitor, preparation method, pharmaceutical composition, and its use

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