CN117362275A - Tyrosine protein kinase inhibitor and application thereof - Google Patents

Tyrosine protein kinase inhibitor and application thereof Download PDF

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CN117362275A
CN117362275A CN202210751111.0A CN202210751111A CN117362275A CN 117362275 A CN117362275 A CN 117362275A CN 202210751111 A CN202210751111 A CN 202210751111A CN 117362275 A CN117362275 A CN 117362275A
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compound
alkylene
protein kinase
alkyl
tyrosine protein
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徐伟
吴曙光
吴诺萍
陈海昌
何绮琪
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Guangzhou Baiting Medicine Technology Co ltd
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    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • 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

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Abstract

Compounds useful as tyrosine protein kinase inhibitors are disclosed which inhibit AXL, KDR and/or CSF-1R kinase. The invention also discloses application of the compound in preparing medicines for treating tumors and related diseases caused by the abnormality of AXL, KDR and/or CSF-1R.

Description

Tyrosine protein kinase inhibitor and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tyrosine protein kinase inhibitor, in particular to a compound for inhibiting AXL, KDR and CSF-1R kinase; also relates to the application of the inhibitor in medicaments for treating tumors and related diseases caused by abnormal AXL, KDR and CSF-1R kinase.
Background
Protein tyrosine kinases (protein tyrosine kinase, PTKs) are key kinases that catalyze the transfer of gamma phosphate groups of ATP to protein substrate tyrosine, and transduce extracellular signals into cells by phosphorylating tyrosine on the receptor itself and downstream signaling proteins, thus PTKs are important components of cellular signaling pathways. PTKs activate numerous signaling pathways within cells, leading to changes in cell proliferation, differentiation, migration, and metabolism.
Development of the vascular system is dependent on the synergistic effect of the PTK subfamily and its cognate ligands. Angiogenesis requires Vascular Endothelial Growth Factor (VEGF) and the receptor KDR acting in concert therewith. KDR is a key signaling protein involved in angiogenesis. Autophosphorylation of KDR, a key protein tyrosine kinase involved in cellular signal transduction processes, represents a key step in promoting angiogenesis.
Axl belongs to the TAM receptor tyrosine kinase family, which also contains the Tyro3, mer (TAM) subfamily. Ligands that activate the TAM receptor are growth retardation-specific gene 6 (Gas 6), protein S, tubby and tubby-like protein 1 (tubp 1). Gas6 has a sub-nanomolar affinity for Axl and is the only ligand that activates Axl; the binding affinity of Tyro, mer to Gas6 is reduced, while protein S preferentially binds to Tyro and Mer. TAM receptors have been demonstrated to be overexpressed in many solid tumors, such as breast, lung, brain, and gut tumors, etc., as detected by high Axl expression in acute leukemia patients; axl induces tumor cell proliferation and survival, and induces tolerance to apoptosis and chemotherapeutic drugs; furthermore, axl also plays a role in mediating cancer cell migration and invasion.
CSF-1R (colly-stimulating factor-1, CSF-1R) is the first hematopoietic growth factor isolated as a pure protein and acts through the colony growth factor receptor CSF-1R (CSF-1 receptor) of myeloid progenitor cells. Inhibition of CSF-1R may enhance the anti-tumor effects of other PTK inhibitors by enhancing tumor immune escape, and studying the combined inhibition of CSF-1/CSF-1R and related signaling pathways is a novel strategy for tumor therapy.
Although single-target PTK inhibitors show respective biological activity and anti-tumor effect through unique targets, more and more clinical results show that the curative effect is still limited, so that the development of new PTK multi-target combined application inhibitors can have unique and potential superiority for treating tumors.
Disclosure of Invention
In order to solve the technical problems, the invention provides a novel tyrosine protein kinase inhibitor which can inhibit kinase activity and tumor cell proliferation in vitro and can show excellent anti-tumor activity in animal models.
In a first aspect, the present invention provides a compound of formula (I), an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated product thereof:
wherein,
R 1 is C 1 -C 6 Alkyl, R 2 Is that(D is an isotope of hydrogen); or R is 2 Is C 1 -C 6 Alkyl, R 1 Is->(D is an isotope of hydrogen);
y is selected from C 1 -C 10 Alkylene, C 1 -C 10 Alkylene amino group, C 1 -C 10 Alkylene oxide, C 1 -C 10 Halogenated alkylene, piperidylene, C 1 -C 10 Alkylene piperidinyl, piperazinyl or C 1 -C 10 An alkylene piperazinyl group;
G 1 and G 2 Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxy group;
w is selected from the following groups:
in some preferred embodiments of the invention, in formula (I), R 1 Is C 1 -C 3 Alkyl, R 2 Is that Or R is 2 Is C 1 -C 3 Alkyl, R 1 Is->
Y is selected from C 3 -C 6 Alkylene, C 3 -C 6 Alkylene amino group, C 3 -C 6 Alkylene oxide, C 3 -C 6 A halogenated alkylene group.
In some preferred embodiments of the invention, in formula (I), R 1 Is C 1 -C 3 Alkyl, R 2 Is that Y is selected from C 3 -C 5 Alkylene or C 3 -C 5 A halogenated alkylene group.
In some preferred embodiments of the invention, in formula (I), G 1 And G 2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
In some preferred embodiments of the invention, in formula (I), W is selected from the following groups:
in some preferred embodiments of the invention, the invention also provides compounds including, but not limited to, the following:
in a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated compound thereof, and a pharmaceutically acceptable excipient.
In some preferred embodiments of the invention, the compounds of the invention (including racemates, enantiomers, stereoisomers, deuterides) or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and pharmaceutically acceptable carriers or excipients thereof are prepared into pharmaceutical compositions useful for administration.
The route of administration of the pharmaceutical composition of the invention may be: (1) oral administration: such as tablets, capsules, etc.; (2) injection: such as intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, etc.; (3) intrarectal: such as suppositories, gels, and the like; (4) nostril inhalation: such as sprays, aerosols, and the like; (5) The drug is administrated by a drug release system such as liposome, a slow release technology, a controlled release technology and the like.
The term "pharmaceutically acceptable salt" refers to salts that maintain the biological activity possessed by the compounds of the invention without exhibiting undesirable toxicological effects. Illustrative examples thereof include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, and the like, and salts with organic acids such as acetic acid, malic acid, tartaric acid, oxalic acid, succinic acid, benzoic acid, tannic acid, alginic acid, polyglutamic acid, and the like; the compounds of the present invention may also be administered as pharmaceutically acceptable quaternary ammonium salts.
In a third aspect, the present invention provides the use of said compound, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated product thereof or said pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of a disease caused by an abnormality of tyrosine protein kinase.
Preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R).
Preferably, the disease caused by tyrosine protein kinase abnormality includes neoplastic diseases such as solid tumors, such as gastric cancer, lung cancer, breast cancer, hematological tumors such as leukemia; and non-neoplastic diseases, such as inflammatory diseases, autoimmune diseases.
In a fourth aspect, the invention provides the use of said compound, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated compound thereof or said pharmaceutical composition in the manufacture of a medicament for inhibiting tyrosine protein kinase.
Preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R).
In a fifth aspect, the present invention provides a method for preventing or treating a disease caused by abnormal tyrosine protein kinase, comprising administering to a subject in need thereof an effective amount of the compound of the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated compound thereof or the pharmaceutical composition.
Preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R).
Preferably, the disease caused by tyrosine protein kinase abnormality includes neoplastic diseases such as solid tumors, such as gastric cancer, lung cancer, breast cancer, hematological tumors such as leukemia; and non-neoplastic diseases, such as inflammatory diseases, autoimmune diseases.
The tyrosine protein kinase inhibitor provided by the invention can inhibit kinase activity and tumor cell proliferation in vitro and has excellent anti-tumor activity in animal models, so that the tyrosine protein kinase inhibitor can be used as a novel PTK multi-target combined inhibitor and has unique and potential superiority for treating tumors.
Drawings
FIG. 1 shows the antitumor effect of the compounds of the examples on human leukemia MOLM-13 cell nude mice transplantation tumors.
Figure 2 shows the body weight change before and after administration of tumor-transplanted nude mice.
Detailed Description
The following examples are intended to further illustrate the invention and are not intended to limit the scope of the invention.
Definition of the definition
The terms and techniques used herein have the same meaning as understood by those skilled in the art.
The term "AXL" refers to a receptor tyrosine kinase in the TAM (Tyro 3, AXL, merTK) family.
The term "KDR" refers to vascular endothelial growth factor receptor 2 (VEGFR 2).
The term "CSF-1R" refers to colony stimulating factor-1receptor (CSF-1R).
The term "alkyl" refers to straight and branched chain aliphatic groups containing 1,2, 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms, and optionally substituted with one or more substituents; alkyl groups as defined include, but are not limited to, methyl, substituted methyl, ethyl, substituted ethyl, propyl, substituted propyl, isopropyl, substituted isopropyl, butyl, substituted butyl, isobutyl, substituted isobutyl, pentyl, substituted pentyl, hexyl, substituted hexyl, and the like.
The term "alkylene" refers to the-CH located between and linking two chemical groups 2 -a group; exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
The term "haloalkyl" refers to an alkyl chain in which one or more hydrogens are replaced with a halogen.
The term "halogen" includes fluorine, chlorine, bromine and iodine.
The term "alkoxy" refers to-O alkyl groups, e.g., O-C 1 -C 6 An alkyl group.
The term "cycloalkyl" refers to saturated or partially saturated cyclic groups having 3, 4, 5, 6 carbon compositions, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "heteroaryl" refers to a monocyclic or bicyclic group consisting of 5, 6, 7, 8, 9, 10 ring atoms; among the atoms constituting the ring, 1 or more hetero atoms selected from N, O and S, for example, 1,2, 3, 4, 5, 6, 7, 8, 9 are contained in addition to the carbon atoms.
The term "aralkyl" refers to an aryl group attached to an alkyl group, which may be independently optionally substituted.
The term "heteroalkyl" refers to an alkyl group in which one or more, for example 1,2, 3, 4, 5 carbon atoms in the alkyl group are replaced with O, S or N atoms.
The term "aryl" refers to a group consisting of 1,2, 3 aromatic rings, optionally substituted; the aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
The term "heterocyclyl" refers to a group of a 3, 4, 5, 6, 7, 8, 9, 10 membered ring containing one or more (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9) nitrogen, oxygen or sulfur atoms in addition to carbon atoms in the ring-forming atom, which may be monocyclic, bicyclic, spiro or bridged; the term "heterocyclylalkyl" refers to a group that is attached to the remainder of the molecule through an alkyl group attached to a heterocyclyl.
Compounds of formula (I)
The present invention provides a compound represented by the general formula (I):
wherein,
R 1 is C 1 -C 6 Alkyl, R 2 Is that(D is an isotope of hydrogen); or R is 2 Is C 1 -C 6 Alkyl, R 1 Is->(D is an isotope of hydrogen);
y is selected from C 1 -C 10 Alkylene, C 1 -C 10 Alkylene amino group, C 1 -C 10 Alkylene oxide, C 1 -C 10 Halogenated alkylene, piperidylene, C 1 -C 10 Alkylene piperidinyl, piperazinyl or C 1 -C 10 An alkylene piperazinyl group;
G 1 and G 2 Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxy group;
w is selected from the following groups:
in some preferred embodiments of the invention, in formula (I), R 1 Is C 1 -C 3 Alkyl, R 2 Is that Or R is 2 Is C 1 -C 3 Alkyl, R 1 Is->
Y is selected from C 3 -C 6 Alkylene, C 3 -C 6 Alkylene amino group, C 3 -C 6 Alkylene oxide, C 3 -C 6 A halogenated alkylene group.
In some preferred embodiments of the invention, in formula (I), R 1 Is C 1 -C 3 Alkyl, R 2 Is that Y is selected from C 3 -C 5 Alkylene or C 3 -C 5 A halogenated alkylene group.
In some preferred embodiments of the invention, in formula (I), G 1 And G 2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
In some preferred embodiments of the invention, in formula (I), W is selected from the following groups:
the present invention also provides compounds including, but not limited to, the following:
examples and embodiments
The embodiments and examples are intended to be illustrative of the practice of the invention in detail and are not intended to limit the scope of the invention. The compounds described in this invention may be prepared by a variety of methods known to those skilled in the art, including but not limited to the methods employed in this example and other alternatives. On the premise of the design thought of the invention, the modification or replacement of the technical scheme of the invention belongs to the protection scope of the invention.
The compounds of the general formula (I) according to the invention can be synthesized by the process of the following general formula route:
the main synthetic reaction process is as follows:
step 1, taking a compound 2, namely 7- (benzyloxy) -4-chloro-6-alkoxyquinoline, as a starting material, and carrying out an ether formation reaction with a nitrophenol compound 3 in DIPEA to generate an intermediate 4;
step 2, hydrolyzing the intermediate 4 in hydrochloric acid to remove benzyl to generate an intermediate 5;
step 3, reacting the intermediate 5 with a bromomethyl ester compound 6 under an alkaline condition to generate an intermediate 7;
step 4, reducing amino on the nitro group of the intermediate 7 to generate an intermediate 8;
step 5, performing condensation reaction on the intermediate 8 and the carboxylic acid compound 9 to generate an amide intermediate 10;
step 6, the intermediate 10 undergoes hydrolysis reaction to produce the final product I.
Example 1.4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
Step 1:
n, N-diisopropylethylamine (6.25 mL,35.86mmol,2.15 eq) was added to a mixture of 7-benzyloxy-4-chloro-6-methoxyquinoline (5.00 g,16.68mmol,1.00 eq) and 2-fluoro-4-nitrophenol (3.67 g,23.35mmol,1.40 eq) in chlorobenzene (25 mL). Oil bath at 140 ℃ and reflux overnight. The reaction was completed. Cooled to room temperature. 1M aqueous sodium hydroxide (50 mL) was added to precipitate a solid. And (5) decompressing and filtering, and leaching the filter cake with water for three times to obtain a yellow-green filter cake. The filter cake was stirred with ethanol four times to give 7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline (4.52 g,64.46%, brown solid).
Step 2:
7- (benzyloxy) -4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinoline (5.80 g,13.80 mmol) and 6M aqueous hydrochloric acid (60 mL) were mixed and the reaction was completed under reflux at 120℃for two hours. Cooled to room temperature. The reaction solution was diluted with water. Filtering under reduced pressure, washing the filter cake with water for three times, and drying. 4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinolin-7-ol (3.70 g,81.20% gray solid) was obtained.
Step 3:
potassium carbonate (1.85 g,13.35mmol,3.00 eq) and methyl 4-bromobutyrate (1.61 g,8.90mmol,2.00 eq) were added to a solution of 4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinolin-7-ol (1.47 g,4.45mmol,1.00 eq) in N, N-dimethylformamide (15 mL) and reacted in an oil bath at 90℃for four and half hours. The reaction was completed and cooled to room temperature. The reaction solution was poured into water to precipitate a large amount of solids. And (5) decompressing and filtering, leaching the filter cake for three times, and drying. Methyl 4- ((4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (1.43 g, yield 74.9% as yellow solid) was obtained.
Step 4:
methyl 4- ((4- (2-fluoro-4-nitrophenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (2.65 g,6.22mmol,1.00 eq), ammonium formate (1.18 g,18.65mmol,3.00 eq), 10% palladium on carbon (992.37 mg) and methanol (30 mL) were mixed. The reaction was carried out at room temperature (27 ℃ C.) for four hours. The reaction was completed. The mixture was filtered through celite and concentrated under reduced pressure to give a brown solid. After dissolution of ethyl acetate, the mixture was washed three times with water and twice with saturated sodium chloride. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. And (5) drying. Methyl 4- ((4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (2.05 g, 82.2% yield) was obtained as a brown solid.
Step 5:
methyl 4- ((4- (4-amino-2-fluorophenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (0.93 g,2.33mmol,1.00 eq), 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid (816.41 mg,3.50mmol,1.50 eq), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (1.77 g,4.67mmol,2.00 eq), 4-dimethylaminopyridine (142.57 mg,1.17mmol,0.50 eq) and N, N-diisopropylethylamine (1.63 mL,9.34mmol,4.00 eq) were dissolved in N, N-dimethylformamide (10 mL). The reaction was carried out at room temperature (20 ℃ C.) overnight. The reaction was completed. The reaction solution was poured into water to precipitate a solid, which was filtered under reduced pressure. The filter cake was washed three times with water. Column chromatography purification (DCM: meoh=30:1) afforded methyl 4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (1.19 g, yield 81.9% brown solid).
Step 6:
methyl 4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butyrate (521 mg, 847.1. Mu. Mol,1.00 eq) was dissolved in tetrahydrofuran (5 mL). A solution of lithium hydroxide monohydrate (142.12 mg,3.39mmol,4.00 eq) in water (5 mL) was added. The reaction was carried out at room temperature for one hour. The reaction was completed. The reaction solution was diluted with water, and the pH was adjusted to about 1 with 4M aqueous hydrochloric acid to precipitate a gum, which was filtered. Column chromatography (DCM: meoh=20:1) was purified and concentrated under reduced pressure. Stirring and washing with dichloromethane and tetrahydrofuran successively, and filtering to obtain white filter cake. Oven drying to give 4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butyric acid (332.9 mg, yield 65.4% as white solid).
1 H NMR(400MHz,DMSO)δ12.20(s,1H),8.80(d,J＝6.2Hz,1H),8.60(d,J＝7.1Hz,1H),8.24(t,J＝8.8Hz,2H),7.68(s,2H),7.60-7.54(m,4H),7.32(t,J＝6.8Hz,2H),6.80(d,J＝7.1Hz,1H),6.72(t,J＝7.1Hz,1H),4.15(t,J＝6.2Hz,2H),3.90(s,3H),3.64–3.56(m,1H),2.21(t,J＝7.1Hz,2H),1.62–1.50(m,2H)MS:m/z(ESI+)602.7[M+H] + 。
Example 2.5- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 2 was carried out according to the synthesis method of example 1, and in step 3, methyl 4-bromobutyrate was replaced with methyl 5-bromovalerate as an intermediate material.
1 H NMR(400MHz,DMSO)δ12.16(s,1H),8.74(d,J＝6.8Hz,1H),8.54(d,J＝7.0Hz,1H),8.14(t,J＝7.6Hz,2H),7.70(s,2H),7.68-7.59(m,4H),7.38(t,J＝7.1Hz,2H),6.84(d,J＝7.0Hz,1H),6.62(t,J＝6.9Hz,1H),4.19(t,J＝6.6Hz,2H),3.87(s,3H),3.60–3.52(m,1H),2.26(t,J＝7.1Hz,2H),1.72–1.69(m,2H),1.62–1.54(m,2H)MS:m/z(ESI+)616.4[M+H] + 。
Example 3.6- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 3 was carried out according to the synthesis method of example 1, and in step 3, methyl 4-bromobutyrate was replaced with methyl 6-bromohexanoate as an intermediate material.
1 H NMR(400MHz,DMSO)δ12.19(s,1H),8.81(d,J＝6.4Hz,1H),8.59(d,J＝7.1Hz,1H),8.14(t,J＝9.0Hz,2H),7.74(s,2H),7.632-7.561(m,4H),7.43(t,J＝8.6Hz,2H),6.97(d,J＝6.4Hz,1H),6.74(t,J＝6.9Hz,1H),4.22(t,J＝6.0Hz,2H),4.04(s,3H),3.65–3.55(m,1H),2.26(t,J＝7.1Hz,2H),1.93–1.81(m,2H),1.66–1.56(m,2H),1.54–1.42(m,2H)。MS:m/z(ESI+)630.8[M+H] + 。
Example 4.4- ((4- (4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
The synthesis of example 4 was performed with reference to the synthesis method of example 1. In the step 1 reaction, the intermediate raw material 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol.
1 H NMR(400MHz,DMSO)δ12.19(s,1H),8.81(d,J＝6.4Hz,1H),8.59(d,J＝7.1Hz,1H),8.14(t,J＝9.0Hz,2H),7.74(s,2H),7.632-7.561(m,4H),7.43(t,J＝8.6Hz,2H),6.97(d,J＝6.4Hz,1H),6.74(t,J＝6.9Hz,1H),4.22(t,J＝6.0Hz,2H),4.04(s,3H),3.65–3.55(m,1H),2.26(t,J＝7.1Hz,2H),1.93–1.81(m,2H),1.66–1.56(m,2H),1.54–1.42(m,2H),MS:m/z(ESI+)583.57[M+H] + 。
Example 5.5- ((4- (4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 5 was performed with reference to the synthesis method of example 1. In the step 1 reaction, the intermediate raw material 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3 reaction, the intermediate raw material methyl 5-bromopentanoate is used for replacing methyl 4-bromobutyrate.
1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.74(d,J＝7.1Hz,1H),8.54(d,J＝6.8Hz,1H),8.18(t,J＝7.1Hz,2H),7.68(s,2H),7.58-7.42(m,4H),7.30(t,J＝7.0Hz,2H),6.83(t,J＝7.6Hz,2H),6.62(d,J＝6.8Hz,1H),3.98(t,J＝6.8Hz,2H),3.72(s,3H),3.48–3.32(m,1H),2.21(t,J＝7.2Hz,2H),1.58–1.50(m,2H)1.48–1.40(m,2H)MS:m/z(ESI+)598.5[M+H] + 。
Example 6.6- ((4- (4- (1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 6 was performed with reference to the synthesis method of example 1. In the step 1 reaction, the intermediate raw material 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3 reaction, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate.
1 H NMR(400MHz,DMSO)δ11.89(s,1H),8.74(d,J＝7.1Hz,1H),8.54(d,J＝6.8Hz,1H),8.18(t,J＝7.1Hz,2H),7.68(s,2H),7.58-7.42(m,4H),7.30(t,J＝7.0Hz,2H),6.83(t,J＝7.6Hz,2H),6.62(d,J＝6.8Hz,1H),3.98(t,J＝6.8Hz,2H),3.72(s,3H),3.48–3.32(m,1H),2.21(t,J＝7.2Hz,2H),1.58–1.50(m,2H)1.48–1.40(m,2H)MS:m/z(ESI+)611.63[M+H] + 。
Example 7.4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopiperidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
The synthesis of example 7 was performed with reference to the synthesis method of example 1. In step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.17(s,1H),8.50(d,J＝7.1Hz,1H),8.36(t,J＝8.2Hz,2H),7.68(s,2H),7.60-7.54(m,3H),7.32(t,J＝6.8Hz,2H),6.80(d,J＝7.1Hz,1H),4.20(t,J＝7.4Hz,2H),3.80(s,3H),3.72–3.42(m,5H),2.19(t,J＝8.2Hz,2H),1.94–1.70(m,3H)1.60–1.52(m,2H)MS:m/z(ESI+)606.4[M+H] + 。
Example 8.5- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopiperidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 8 was performed with reference to the synthesis method of example 1. In the step 3, the intermediate raw material of 5-bromovalerate is used for replacing 4-bromobutyric acid methyl ester; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.22(s,1H),8.68(d,J＝6.8Hz,1H),8.28(t,J＝7.2Hz,2H),7.60(s,2H),7.70-7.58(m,3H),7.46(t,J＝7.1Hz,2H),6.72(d,J＝6.8Hz,1H),4.08(t,J＝7.1Hz,2H),3.60(s,3H),3.52–3.36(m,5H),2.18(t,J＝8.0Hz,2H),1.90–1.71(m,3H),1.70–1.62(m,2H)1.60–1.50(m,2H)1.42–1.36(m,2H)MS:m/z(ESI+)620.8[M+H] + 。
Example 9.6- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopiperidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 9 was performed with reference to the synthesis method of example 1. In the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.12(s,1H),8.54(d,J＝7.2Hz,1H),8.18(t,J＝6.8Hz,2H),7.66(s,2H),7.58-7.48(m,3H),7.38(t,J＝6.8Hz,2H),6.64(d,J＝6.8Hz,1H),4.02(t,J＝9.1Hz,2H),3.60(s,3H),3.50–3.38(m,5H),2.20(t,J＝8.0Hz,2H),2.06–1.81(m,3H),1.66–1.52(m,2H)1.48–1.30(m,2H)MS:m/z(ESI+)634.7[M+H] + 。
Example 10.4- ((4- (4- (1- (4-fluorophenyl) -2-oxopiperidin-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
The synthesis of example 10 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.20(s,1H),8.52(d,J＝7.1Hz,1H),8.36(t,J＝6.8Hz,2H),7.68(s,2H),7.62-7.52(m,4H),7.30(t,J＝7.1Hz,2H),6.80(d,J＝6.8Hz,1H),4.18(t,J＝7.2Hz,2H),3.76(s,3H),3.70–3.40(m,5H),2.20(t,J＝9.0Hz,2H),1.94–1.70(m,3H)1.64–1.56(m,2H)MS:m/z(ESI+)588.6[M+H] + 。
Example 11.5- ((4- (4- (1- (4-fluorophenyl) -2-oxopiperidin-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 11 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3, the intermediate raw material of 5-bromovalerate is used for replacing 4-bromobutyric acid methyl ester; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.26(s,1H),8.74(d,J＝8.2Hz,1H),8.37(t,J＝7.1Hz,2H),7.72(s,2H),7.66-7.48(m,4H),7.36(t,J＝6.8Hz,2H),6.68(d,J＝7.1Hz,1H),4.02(t,J＝7.2Hz,2H),3.54(s,3H),3.48–3.42(m,5H),2.28(t,J＝8.0Hz,2H),2.00–1.71(m,3H),1.66–1.60(m,2H)1.58–1.42(m,2H)MS:m/z(ESI+)602.5[M+H] + 。
Example 12.6- ((4- (4- (1- (4-fluorophenyl) -2-oxopiperidin-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 12 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopiperidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.26(s,1H),8.74(d,J＝8.2Hz,1H),8.37(t,J＝7.1Hz,2H),7.72(s,2H),7.66-7.48(m,4H),7.36(t,J＝6.8Hz,2H),6.68(d,J＝7.1Hz,1H),4.02(t,J＝7.2Hz,2H),3.54(s,3H),3.48–3.42(m,5H),2.28(t,J＝8.0Hz,2H),2.00–1.71(m,3H),1.66–1.60(m,2H)1.58–1.42(m,2H)MS:m/z(ESI+)615.66[M+H] + 。
Example 13.5- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 13 was performed according to the method of example 1. In the step 3, the intermediate raw material of 5-bromovalerate is used for replacing 4-bromobutyric acid methyl ester; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid was used in place of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.17(s,1H),8.70(d,J＝7.1Hz,1H),8.35(t,J＝7.2Hz,2H),7.70(s,2H),7.64-7.52(m,3H),7.32(t,J＝6.8Hz,2H),7.02(t,J＝2.4Hz,1H)6.64(d,J＝6.8Hz,1H),4.22(t,J＝1.6Hz,2H),4.08(t,J＝7.2Hz,2H),3.54(s,3H),3.50–3.36(m,5H),2.22(t,J＝8.0Hz,2H),MS:m/z(ESI+)604.6[M+H] + 。
Example 14.6- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 14 was performed with reference to the synthesis method of example 1. In the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid was used in place of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.21(s,1H),8.65(d,J＝6.4Hz,1H),8.24(t,J＝7.1Hz,2H),7.62(s,2H),7.56-7.46(m,3H),7.36(t,J＝7.4Hz,2H),7.14(t,J＝2.1Hz,1H)6.56(d,J＝6.8Hz,1H),4.30(t,J＝2.1Hz,2H),4.08(t,J＝6.8Hz,2H),3.64(s,3H),3.52–3.34(m,5H),2.28(t,J＝7.4Hz,2H),2.00–1.71(m,2H),MS:m/z(ESI+)618.6[M+H] + 。
Example 15.6- ((4- (4- (1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 15 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxylic acid was used in place of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.16(s,1H),8.70(d,J＝7.1Hz,1H),8.45(t,J＝6.6Hz,2H),7.80(s,2H),7.74-7.62(m,4H),7.30(t,J＝7.1Hz,2H),7.12(t,J＝2.1Hz,1H)6.70(d,J＝7.8Hz,1H),4.22(t,J＝2.2Hz,2H),4.13(t,J＝9.0Hz,2H),3.60(s,3H),3.56–3.40(m,5H),2.22(t,J＝7.4Hz,2H),1.82–1.68(m,2H),MS:m/z(ESI+)600.5[M+H] + 。
EXAMPLE 16.4- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
The synthesis of example 16 was performed with reference to the synthesis method of example 1. In step 5, the intermediate 1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.10(s,1H),8.63(d,J＝7.4Hz,1H),8.40(t,J＝6.8Hz,2H),7.50(s,2H),7.48-7.36(m,3H),7.24(t,J＝7.1Hz,2H),7.12(d,J＝4.2Hz,1H),4.30(t,J＝2.1Hz,2H),4.20-4.12(m,2H),3.66(s,3H),3.58(t,J＝1.7Hz,1H)3.56–3.32(m,3H),,2.10–1.81(m,2H),MS:m/z(ESI+)592.6[M+H] + 。
Example-17.5- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 17 was performed according to the method of example 1. In the step 3, the intermediate raw material of 5-bromovalerate is used for replacing 4-methyl butyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ12.18(s,1H),8.70(d,J＝7.1Hz,1H),8.53(t,J＝7.1Hz,2H),7.54(s,2H),7.50-7.38(m,3H),7.22(t,J＝7.2Hz,2H),7.16(d,J＝3.6Hz,1H),4.34(t,J＝2.1Hz,2H),4.28-4.16(m,2H),3.72(s,3H),3.64(t,J＝1.7Hz,1H)3.60–3.38(m,3H),,2.08–1.80(m,2H),1.76–1.68(m,2H),MS:m/z(ESI+)606.7[M+H] + 。
EXAMPLE 18.6- ((4- (2-fluoro-4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 18 was performed with reference to the synthesis method of example 1. In the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-butyrate; in step 5, the intermediate 1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ11.98(s,1H),8.64(d,J＝7.2Hz,1H),8.57(t,J＝6.8Hz,2H),7.66(s,2H),7.52-7.36(m,3H),7.18(t,J＝7.1Hz,2H),7.08(d,J＝4.2Hz,1H),4.52(t,J＝2.0Hz,2H),4.35-4.22(m,2H),3.86(s,3H),3.68(t,J＝2.1Hz,1H)3.64–3.40(m,3H),,2.32–2.08(m,2H),1.88–1.64(m,2H),1.50–1.44(m,2H)MS:m/z(ESI+)620.8[M+H] + 。
Example 19.4- ((4- (4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) butanoic acid
The synthesis of example 19 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in step 5, the intermediate 1- (phenyl) -2-oxopyrrolidine-3-carboxylic acid was used instead of 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ11.86(s,1H),8.70(d,J＝7.2Hz,1H),8.48(t,J＝6.8Hz,2H),7.62(s,2H),7.58-7.44(m,4H),7.36(t,J＝6.8Hz,2H),7.22(d,J＝3.2Hz,1H),4.42(t,J＝1.7Hz,2H),4.34-4.38(m,2H),3.72(s,3H),3.64(t,J＝2.1Hz,1H)3.60–3.44(m,3H),,1.93–1.76(m,2H),MS:m/z(ESI+)573.58,[M+H] + 。
Example 20.5- ((4- (4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) pentanoic acid
The synthesis of example 20 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3, the intermediate raw material of 5-bromovalerate is used for replacing 4-bromobutyric acid methyl ester; in the 5 th reaction step, 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid was replaced with the intermediate 1-phenyl-2-oxopyrrolidine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ11.86(s,1H),8.70(d,J＝7.2Hz,1H),8.48(t,J＝6.8Hz,2H),7.62(s,2H),7.58-7.44(m,4H),7.36(t,J＝6.8Hz,2H),7.22(d,J＝3.2Hz,1H),4.42(t,J＝1.7Hz,2H),4.34-4.38(m,2H),3.72(s,3H),3.64(t,J＝2.1Hz,1H)3.60–3.44(m,3H),,1.93–1.76(m,2H),MS:m/z(ESI+)587.60[M+H] + 。
EXAMPLE 21.6- ((4- (4- (1- (4-fluorophenyl) -2-oxopyrrolidine-3-carboxamide) phenoxy) -6-methoxyquinolin-7-yl) oxy) hexanoic acid
The synthesis of example 21 was performed with reference to the synthesis method of example 1. In the step 1 reaction, 4-nitrophenol is used for replacing 2-fluoro-4-nitrophenol; in the step 3, the intermediate raw material methyl 6-bromohexanoate is used for replacing methyl 4-bromobutyrate; in the 5 th step, 1- (4-fluorophenyl) -2-oxo-1, 2-dihydropyridine-3-carboxylic acid was replaced with the intermediate 1-phenyl-2-oxopyrrolidine-3-carboxylic acid.
1 H NMR(400MHz,DMSO)δ11.72(s,1H),8.62(d,J＝7.2Hz,1H),8.40(t,J＝8.6Hz,2H),7.60(s,2H),7.44-7.32(m,4H),7.30(t,J＝7.1Hz,2H),7.04(d,J＝4.1Hz,1H),4.32(t,J＝2.1Hz,2H),4.26-4.12(m,2H),3.76(s,3H),3.60(t,J＝4.6Hz,1H)3.46–3.34(m,4H),2.38–2.26(m,2H),1.86–1.64(m,2H),1.52–1.38(m,2H)MS:m/z(ESI+)602.9[M+H] + 。
Evaluation of biological Activity of Compounds of examples
Inhibition of the biochemical Activity of AXL, KDR and CSF-1R kinases by the Compounds of the examples
The biochemical activity of three kinases AXL, KDR and CSF-1R was determined by phosphorylation of a fluorescein-labeled tyrosine kinase substrate.
Reagent: AXL, KDR and CSF-1R tyrosine kinase (available from Carna Inc.),KinEASE-TK kit and 96 microwell plates (from Cisbio), ATP (from Sigma), dithiothreitol (DTT) (from Sigma), manganese chloride and magnesium chloride (from Sigma), XL-184 (as positive control) (from Shanghai Han Xiang Biotechnology Co., ltd.), a full wavelength multifunctional microplate reader (TECAN->M1000)。
The method comprises the following steps:
according to the kit instructions, AXL, KDR, CSF-1R tyrosine kinase buffer (1×), catalytic substrate solution (5×,5 μm), ATP solution (500 μm) were prepared, and the reaction solution was stopped (4×). When in test, three kinases are respectively and independently carried out, 2 mu L of AXL or KDR or CSF-1R kinase solution is respectively added into the test holes of the three 96 micro-well plates, and two holes are repeatedly arranged at each concentration; control wells were added with 2 μl (1×) of kinase buffer solution as control. The assay wells and control wells were each filled with kinase buffer (4. Mu.L), substrate solution (2. Mu.L), ATP solution (2. Mu.L). The reaction mixtures were incubated at 37℃for 0min, 10min, 20min, 30min, 40min, 50min, 60min, respectively, and 10. Mu.L of stop reaction solution was added thereto, followed by further incubation for 1 hour. Detecting fluorescence signal intensities at 665nm and 620nm with a full-wavelength multifunctional enzyme-labeled instrument at 317nm as excitation light wavelength, and calculating concentration (IC) of the compound at 50% inhibition according to ratio of 665nm fluorescence signal intensity/620 nm fluorescence signal intensity 50 Values), the results are shown in table 1.AXL, KDR and CSF-1R excitationEnzyme activity inhibition rate calculation: percentage inhibition = (F DMSO control -F Sample of )/(F DMSO control -F Negative control ) X 100%, DMSO added value was used as solvent control, and kinase-free negative control.
TABLE 1 inhibition of the biochemical Activity of the AXL, KDR and CSF-1R kinases by the example compounds (IC 50 ，nM)
Experimental results:
the results in table 1 show that: the compounds of the examples significantly inhibit the biochemical activity of AXL, KDR and CSF-1R kinases.
Inhibiting effect of example Compounds on proliferation of human leukemia MOLM-13 and human gastric cancer MKN-45 cells
1. Tumor cells: the MOLM-13 acute leukemia cell strain resistant to vascular endothelial growth factor, and the human gastric cancer cell MKN-45 cells were obtained from the university of medical science, southern university of medical science center.
2. The method comprises the following steps: the antiproliferative activity of the compounds of the examples on MOLM-13 acute leukemia cell lines was determined by Luminometer luminescence.
3. Instrument: promega microplate detector (CellTiter-Glo Luminescent Cell Viability Assay, promega).
4. Reagents and kits: RPMI1640 medium, fetal calf serum, dimethyl sulfoxide, penicillin-streptomycin, cell Titer-Gio detection kit. Cell culture bottle, CO 2 Incubator, cell culture microplate (96 well plate).
5. Tumor cell culture: resuscitates MOLM-13 tumor cells frozen in liquid nitrogen, and cultures the cells in RPMI cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin; when the cells grow to an exponential growth phase, the culture medium is sucked by a pipetting gun to be gently blown andcollecting cells, and re-suspending the cells in a culture solution; inoculating 5000-10000 cells in each hole, and uniformly distributing the cells; cells were incubated at 37℃with 5% CO 2 The culture was continued for 72 hours in a saturated humidity carbon dioxide incubator.
6. Example compounds and activity assays: the compound of the example was dissolved in dimethyl sulfoxide to prepare 10 concentration gradients, and different concentrations of the compound were added to the test wells according to the experimental design for further incubation for 72h. After the completion of the incubation, the 96-well plate was taken out and left at room temperature for 30 minutes, followed by detection of CTG. mu.L of CTG was added to the microwells, mixed well for 2 minutes, and left at room temperature for 10 minutes. Detecting and recording luminous signal value by using a microplate luminometer to observe cell activity, and calculating IC 50 Values, results are shown in Table 2.
TABLE 2 inhibition of proliferation of human leukemia MOLM-13 and human gastric cancer MKN-45 by example compounds
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The results in table 2 show that: the compound of the embodiment can obviously inhibit the proliferation of human leukemia MOLM-13 cells and the proliferation of human gastric cancer MKN-45 cells.
Anti-tumor effect of the Compounds of examples on human leukemia MOLM-13 cells in vivo
1. Cell culture: human leukemia MOLM-13 cells were cultured in DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin and 100. Mu.g/mL streptomycin, with the flask placed at 37deg.C and 5% CO 2 Culturing in a saturated humidity carbon dioxide incubator.
2. Experimental animals: BALB/C-nu mice were purchased from Guangdong Kangdong Biotechnology Co., ltd, 40, 28-34 days old. License number: SCXK (cantonese) 2020-0054, experiment unit use license number: SYXK (Guangdong) 2018-0131.5 mice were housed in a cage and animals were kept in SPF animal houses and used for tumor cell inoculation experiments after one week of examination.
Molm-13 cell nude mouse engraftment model: when the number of MOLM-13 cells reaches the exponential growth phase, lightly blowing off the agglomerated suspension cells by a liquid-transferring gun, collecting the suspension cells into a centrifuge tube, centrifuging at 1000r/min for 5min, collecting the cells at the bottom of the centrifuge tube, re-suspending the cells by a serum-free culture medium, and adjusting the cell concentration to 2X 10 7 /mL. Sucking the cell suspension with 1mL syringe, inoculating under the right anterior axilla of nude mice, inoculating 0.1mL each nude mice, and inoculating cell number 2×10 6 /only. After tumor cell inoculation, the tumor growth of the nude mice inoculation part is observed daily or periodically, the size of the tumor of each animal is measured by a vernier caliper, and when the tumor growth volume reaches 100mm 3 In the above cases, experiments may be optionally performed. Of 40 nude mice vaccinated with tumor cells, 30 met the inclusion criteria.
4. Experimental grouping and dosing: the experiment was randomly divided into 4 groups including a solvent control group, a positive compound control group and two dose groups of 2.5mg/kg and 5mg/kg of the compound of example. Compound 3 was dissolved in 50% PEG400 and 50% distilled water (the total amount of PEG400 administered daily to mice was controlled below 0.5%) and the drug administered once daily, 0.1mL each time, for 7 consecutive days. Animal weights were measured daily, tumor size was measured every two days, and changes in the mice' diet, drinking water, body weight, hair, etc. were observed.
5. Method for evaluating antitumor effect of compound: after the end of the administration, tumor-bearing mice were anesthetized, photographed as a whole, and tumors were removed and weighed (tumor weights are expressed as mean ± SD), and tumor inhibition rates were calculated.
Calculation of Tumor Volume (TV):
TV＝1/2×a×b 2
wherein a is the long diameter of the tumor, and b is the short diameter of the tumor.
Calculation of tumor inhibition (Tumor Growth Inhibition, TGI):
5-2. Calculation of percent body weight change before and after dosing of nude mice:
BW is the Weight of nude mice (Body Weight), BW Last day For the body weight of nude mice at the end of the experiment, BW First day The weight of nude mice at the time of group administration was calculated.
5-3 experimental results
As shown in FIG. 1, the compound of example 3 showed very remarkable antitumor effect and fast onset of action after continuous gastric lavage administration for 7 days in MOLM-13 cell-transplanted tumor nude mice.
As shown in fig. 2, the weight change before and after administration was compared, and no decrease in animal weight was observed in the 2.5mg/kg administration group during the administration period; weight gain of the 5mg/kg dosing group showed low toxicity of the compound.
The other compounds of this application were tested in the same manner and the results were similar to those of example 3.

Claims (10)

1.A compound of formula (I), an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated compound thereof:
wherein,
R 1 is C 1 -C 6 Alkyl, R 2 Is thatOr R is 2 Is C 1 -C 6 Alkyl, R 1 Is that
Y is selected from C 1 -C 10 Alkylene, C 1 -C 10 Alkylene amino group, C 1 -C 10 Alkylene oxide, C 1 -C 10 Halogenated alkylene, piperidylene, C 1 -C 10 Alkylene piperidinyl, piperazinyl or C 1 -C 10 An alkylene piperazinyl group;
G 1 and G 2 Are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 An alkoxy group;
w is selected from the following groups:
2. the compound of claim 1, wherein R 1 Is C 1 -C 3 Alkyl, R 2 Is that Or R is 2 Is C 1 -C 3 Alkyl, R 1 Is->
Y is selected from C 3 -C 6 Alkylene, C 3 -C 6 Alkylene amino group, C 3 -C 6 Alkylene oxide, C 3 -C 6 A halogenated alkylene group.
3. The compound of claim 2, wherein R 1 Is C 1 -C 3 Alkyl, R 2 Is that Y is selected from C 3 -C 5 Alkylene or C 3 -C 5 A halogenated alkylene group.
4. The compound of claim 1, wherein G 1 And G 2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or iodine.
5. The compound of claim 1, wherein W is selected from the group consisting of:
6. a compound according to any one of claims 1 to 5, wherein the compound is selected from:
7. a pharmaceutical composition comprising a compound of any one of claims 1-6, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated thereof, and a pharmaceutically acceptable excipient.
8. Use of a compound according to any one of claims 1-6, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated product thereof or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the prevention or treatment of a disease caused by tyrosine protein kinase abnormality;
preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R);
preferably, the diseases caused by tyrosine protein kinase abnormality include solid tumors such as gastric cancer, lung cancer, breast cancer, hematological tumors, inflammatory diseases and autoimmune diseases.
9. Use of a compound of any one of claims 1-6, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated thereof or a pharmaceutical composition of claim 7 in the manufacture of a medicament for inhibiting a tyrosine protein kinase;
preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R).
10. A method of preventing or treating a disease caused by an abnormality in tyrosine protein kinase comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-6, an isomer thereof, a pharmaceutically acceptable salt thereof or a deuterated thereof or a pharmaceutical composition of claim 7;
preferably, the tyrosine protein kinase is selected from one or more of receptor tyrosine kinase (AXL), vascular endothelial growth factor receptor 2 (KDR) and colony stimulating factor-1receptor (CSF-1R);
preferably, the diseases caused by tyrosine protein kinase abnormality include solid tumors such as gastric cancer, lung cancer, breast cancer, hematological tumors, inflammatory diseases and autoimmune diseases.
CN202210751111.0A 2022-06-29 2022-06-29 Tyrosine protein kinase inhibitor and application thereof Pending CN117362275A (en)

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CA2655128A1 (en) * 2006-06-08 2007-12-21 Array Biopharma Inc. Quinoline compounds and methods of use
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