CN111116585B - Compound with c-MET kinase inhibitory activity, preparation method, composition and application - Google Patents
Compound with c-MET kinase inhibitory activity, preparation method, composition and application Download PDFInfo
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Abstract
The invention belongs to the field of medicines, and particularly relates to a compound with c-MET kinase inhibitory activity, a preparation method, a composition and application thereof, wherein the compound is a compound with a structure shown in formula I or pharmaceutically acceptable salt, hydrate, solvate and isotope compound thereof, wherein R is1Is selected from substituted or unsubstituted phenyl or aromatic heterocyclic radical, and the substituent comprises F, Cl, Br, aminocarbonyl, and substituted or unsubstituted five-membered or six-membered aromatic heterocyclic radical; r2Represents a substituted or unsubstituted phenyl or phenylheterocyclyl group. The compound provided by the invention has better c-MET kinase inhibitory activity, can be used for treating cancers, and has the advantages of high specificity and low side effect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound with c-MET kinase inhibitory activity, a preparation method, a composition and application.
Background
Tumors are important diseases threatening human health, the current tumor treatment means mainly comprise surgical treatment, radiotherapy, chemotherapy and the like, but the traditional means have certain defects, and the research of targeted drugs becomes the hot spot of the current research.
The hepatocyte growth factor receptor (c-MET) is a key protein in a tumor signal pathway, is over-expressed in various cancers such as gastric cancer, lung cancer and the like, is abnormally activated and plays a role in various links such as tumor growth, invasion, metastasis and the like, the over-activation of the c-MET is a cross point of a plurality of pathways in tumor formation and metastasis, so the simultaneous interference of the plurality of pathways can be realized by taking the c-MET as a target, the abnormality of the Hepatocyte Growth Factor (HGF)/c-MET signal transduction pathway plays an important role in the generation and development of cancer and the generation of drug resistance, therefore, the HGF/c-MET signal transduction pathway becomes one of hot spots of the research of anti-tumor drugs and important targets of cancer treatment, wherein the c-MET kinase small molecule inhibitor is one of important means for regulating the HGF/c-MET signal transduction pathway, the development of a c-MET inhibitor with high specificity and low side effect has important significance for preventing and treating tumor diseases.
Disclosure of Invention
The invention provides a compound with c-MET kinase inhibitory activity, a preparation method, a composition and application thereof, and the compound has high specificity and low side effect and has important significance for preventing and treating tumor diseases.
In a first aspect, the present invention provides a compound, stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate, isotopic compound thereof, having the structure of formula i:
wherein R is1Is selected from substituted or unsubstituted phenyl or aromatic heterocyclic radical, and the substituent comprises F, Cl, Br, aminocarbonyl, and substituted or unsubstituted five-membered or six-membered aromatic heterocyclic radical;
R2represents a substituted or unsubstituted phenyl or phenylheterocyclyl group.
The compound provided by the invention takes 4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine as a mother nucleus, has better c-MET kinase inhibitory activity, can be used for treating cancers, and has the advantages of high specificity and low side effect.
In a second aspect, there is provided a method for preparing a compound, a stereoisomer, or a pharmaceutically acceptable salt, hydrate, solvate or isotopic compound thereof according to any one of the first aspects, comprising the steps of:
synthesis of intermediate IV:
heating the compound VI and the compound V in a reaction solvent under the action of alkali to react to obtain an intermediate IV;
synthesis of intermediate III:
heating the intermediate IV in a reaction solvent under the action of acid to react to obtain an intermediate III;
synthesis of Compound I:
and heating the intermediate III and the compound II in a reaction solvent under the action of a catalyst and a ligand to react to obtain a compound I.
The preparation method provided by the invention takes the compound VI and the compound V as starting raw materials, generates the intermediate IV under the action of alkali, generates the intermediate III under the action of acid, and reacts the intermediate III with the compound II to generate the compound I, and the generated compound I has better c-MET kinase inhibitory activity and is suitable for preventing and treating tumor diseases.
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of the compounds, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds of the first aspect, and optionally a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides a c-MET inhibitor comprising a therapeutically effective amount of a compound selected from the group consisting of the compounds, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds of the first aspect, and optionally a pharmaceutically acceptable carrier.
In a sixth aspect, the present invention provides the use of a compound, stereoisomer or a pharmaceutically acceptable salt, hydrate, solvate or isotopic compound according to the first aspect as an inhibitor of c-MET in the manufacture of a medicament for the prevention and/or treatment of a neoplastic disease associated with an abnormality of c-MET.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more clearly apparent, the present invention is further described in detail below with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In one aspect, the present embodiments provide a compound, stereoisomer, or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound having the structure of formula i:
wherein R is1Is selected from substituted or unsubstituted phenyl or aromatic heterocyclic radical, and the substituent comprises F, Cl, Br, aminocarbonyl, and substituted or unsubstituted five-membered or six-membered aromatic heterocyclic radical;
R2represents a substituted or unsubstituted phenyl or phenylheterocyclyl group.
The compound provided by the invention takes 4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine as a mother nucleus, has better c-MET kinase inhibitory activity, can be used for treating cancers, and has the advantages of high specificity and low side effect.
Further, when R is1And when the substituent is a substituted five-membered or six-membered aromatic heterocyclic group, the substituent of the five-membered or six-membered aromatic heterocyclic group comprises but is not limited to alkyl, carbonyl, F, Cl and Br.
Further, when said R is2When represents a substituted phenyl or phenylheterocyclyl group, said R2Substituents of (a) include, but are not limited to, cyano, carbonyl, or amido.
Further, when said R is2When substituted or unsubstituted, the phenylheterocyclyl group includes, but is not limited to, at least one nitrogen atom or oxygen atom, for example, the phenylheterocyclyl group includes one nitrogen atom, two nitrogen atoms, or one oxygen atom.
Further, said R1May be selected from, but is not limited to, the groups shown below:
further, said R2May be selected from, but is not limited to, the groups shown below:
further, the structure shown in formula I can be, but is not limited to, the following structure:
in a second aspect, a method for preparing a compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate, isotopic compound of any one of the first aspects, comprises the steps of:
step S10: synthesis of intermediate IV: heating the compound VI and the compound V in a reaction solvent under the action of alkali to react to obtain an intermediate IV;
step S20: synthesis of intermediate III: heating the intermediate IV in a reaction solvent under the action of acid to react to obtain an intermediate III;
step S30: synthesis of Compound I: and heating the intermediate III and the compound II in a reaction solvent under the action of a catalyst and a ligand to react to obtain a compound I.
The preparation method provided by this embodiment uses compound VI and compound V as starting materials, generates intermediate IV under the action of an alkali, generates intermediate III under the action of an acid, and reacts intermediate III with compound II to generate compound I, and the generated compound I has a good c-MET kinase inhibitory activity, and is suitable for a drug for preventing and treating a tumor disease.
Further, in step S10, the base includes one or more of triethylamine, diisopropylethylamine, morpholine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, and lithium hydroxide.
Further, in step S10, the reaction solvent includes one or more of acetonitrile, dichloromethane, tetrahydrofuran, dioxane, and toluene.
Further, in step S10, the reaction temperature includes 20 ℃ to 100 ℃, for example, the reaction temperature is 20 ℃, 30 ℃, 50 ℃, 80 ℃ or 100 ℃.
Further, in step S20, the acid includes trifluoroacetic acid, hydrochloric acid, or a mixed solution of trifluoroacetic acid and hydrochloric acid.
Further, in step S20, the reaction solvent includes one or more of dichloromethane, dioxane, acetone, and acetonitrile.
Further, in step S20, the reaction temperature includes 20 ℃ to 100 ℃, for example, the reaction temperature is 20 ℃, 30 ℃, 50 ℃, 80 ℃ or 100 ℃.
Further, in step S30, the catalyst includes one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone palladium), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex.
Further, in step S30, the ligand includes triphenylphosphine and tri-tert-butylphosphine.
Further, in step S30, the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, and cesium carbonate.
Further, in step S30, the reaction solvent includes one or more of toluene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and N-methylpyrrolidone.
Further, in step S30, the reaction temperature includes 20 ℃ to 120 ℃, for example, the reaction temperature is 20 ℃, 30 ℃, 50 ℃, 80 ℃, 100 ℃ or 120 ℃.
It is noted that "pharmaceutically acceptable salts" refer 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.
The compounds provided in this example can include one or more asymmetric centers and, thus, can exist in a variety of "stereoisomers," such as enantiomers and/or diastereomers.
It will be appreciated by those skilled in the art that many organic compounds may form complexes with a solvent in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of formula I.
In a third aspect, the present embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of the compounds, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds of the first aspect, and optionally a pharmaceutically acceptable carrier.
The compositions provided in this example can be administered to a patient in need of such treatment by oral, rectal, or parenteral administration. For oral administration, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc., or liquid preparations such as water or oil suspension, or other liquid preparations such as syrup, etc.; for parenteral administration, it can be formulated into solution for injection, aqueous or oily suspension, etc.
A therapeutically effective amount refers to an amount of a compound of the present invention sufficient to effect the intended use. The therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc., can be readily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the particular compound selected, the dosing regimen according to, whether to administer in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system carried.
Those skilled in the art will understand that: pharmaceutically acceptable carriers refer to pharmaceutical carriers conventional in the pharmaceutical art, such as: diluents such as water and the like; fillers, such as starch, sucrose, and the like; binders such as cellulose derivatives, alginates, gelatin, polyvinylpyrrolidone; humectants, such as glycerol; disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate and magnesium stearate, and polyethylene glycol, and the like. In addition, other adjuvants such as flavoring agent and sweetener can also be added into the above medicinal composition.
In a fourth aspect, the present example provides a c-MET inhibitor comprising a therapeutically effective amount of a compound selected from the group consisting of the compounds, stereoisomers, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds of the first aspect, and optionally a pharmaceutically acceptable carrier.
In a fifth aspect, the compound, stereoisomer or pharmaceutically acceptable salt, hydrate, solvate or isotopic compound of the first aspect is used as a c-MET inhibitor in the preparation of a medicament for preventing and/or treating tumor diseases related to c-MET abnormality.
Further, the cancer 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, uterine corpus cancer, endometrial cancer, testicular cancer, urinary cancer, melanoma, astrocytic cancer, meningioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute lymphatic leukemia, chronic lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia lymphoma, hepatocellular carcinoma, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, seminoma, rhabdomyosarcoma, chondrosarcoma, myosarcoma, fibrosarcoma.
The invention is described in further detail with reference to a part of the test results, which are described in detail below with reference to specific examples.
Example 1
Preparation of 2-fluoro-N-methyl-4- (1- (quinolin-6-ylsulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) benzamide
Synthesis of intermediate 1 c:
compound 1a (44.6g, 200.0mmol), compound 1b (45.4g, 200.0mmol), triethylamine (24.2g, 240.0mmol) were dissolved in acetonitrile (500ml), stirred at 30 ℃ for 8 hours, checked by TLC, quenched after the reaction with water (500ml), extracted with ethyl acetate (500ml x 2), the organic layers combined, dried, concentrated, and isolated by column chromatography to give 68.3g of a pale yellow solid in 82.5% yield.
Synthesis of intermediate 1 d:
dissolving the compound 1c (68.0g, 164.3mmol) in dichloromethane (300ml), adding trifluoroacetic acid (50ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust the pH to 8-9, standing, layering, extracting the aqueous phase with dichloromethane (300ml), combining the organic layers, concentrating, and separating by column chromatography to obtain an off-white solid 41.2g with the yield of 79.9%.
Synthesis of Compound 1:
compound 1d (1.6g, 5.0mmol), compound 1e (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C and stirred for 12 hours, checked by TLC, and directly concentrated by column chromatography to give 1.4g of off-white solid in 60.2% yield. Detecting the white solid: ESI (+) m/z 466.1.
Example 2
Preparation of N-methyl-5- (1- (quinolin-6-ylsulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -2-pyridinecarboxamide
The synthesis of intermediate 1c and intermediate 1d was performed as in example 1.
Synthesis of Compound 2:
compound 1d (1.6g, 5.0mmol), 5-bromo-N-methyl-2-pyridinecarboxamide (1.1g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, and directly concentrated by column chromatography to give 1.5g of off-white solid in 67.0% yield. Detecting the white solid: ESI (+) m/z 449.1.
Example 3
Preparation of 6- ((6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinoline
The synthesis of intermediate 1c and intermediate 1d was performed as in example 1.
Synthesis of Compound 3:
the compound 1d (1.6g, 5.0mmol), 4- (4-bromobenzene) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to obtain 1.1g of off-white solid with a yield of 46.8%. Detecting the white solid: ESI (+) m/z 471.1.
Example 4
Preparation of 6- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinoline
The synthesis of intermediate 1c and intermediate 1d was performed as in example 1.
Synthesis of Compound 4:
the compound 1d (1.6g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to obtain 1.6g of off-white solid with a yield of 67.5%. Detecting the white solid: ESI (+) m/z 475.1.
Example 5
Preparation of 1- (4- (1- (quinolin-6-ylsulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) benzoyl) pyrrolidin-3-one
The synthesis of intermediate 1c and intermediate 1d was performed as in example 1.
Synthesis of Compound 5:
dissolving compound 1d (1.6g, 5.0mmol), 1- (4-bromobenzoyl) pyrrolidin-3-one (1.3g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 deg.C, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.3g of off-white solid with a yield of 51.9%. Detecting the white solid: ESI (+) m/z 502.1.
Example 6
Preparation of 4- (1- ((4-aminocarbonylphenyl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -2-fluoro-N-methylbenzamide
Synthesis of intermediate 6 b:
compound 1a (44.6g, 200.0mmol), compound 6a (43.64g, 200.0mmol), triethylamine (24.2g, 240.0mmol) were dissolved in acetonitrile (500ml), the reaction was stirred at 20 ℃ for 8 hours, checked by TLC, after completion of the reaction, the reaction was quenched with water (500ml), extracted with ethyl acetate (500ml x 2), the organic layers were combined, dried, concentrated, and isolated by column chromatography to give 59.5g of a pale yellow solid in 73.3% yield.
Synthesis of intermediate 6 c:
dissolving compound 6b (59.0g, 145.3mmol) in dichloromethane (300ml), adding trifluoroacetic acid (50ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust pH to 8-9, standing, layering, extracting aqueous phase with dichloromethane (300ml), combining organic layers, concentrating, and separating by column chromatography to obtain off-white solid 38.2g, yield 85.9%.
Synthesis of Compound 6:
compound 6c (1.5g, 5.0mmol), compound 1e (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C and stirred for 12 hours, checked by TLC, and directly concentrated by column chromatography to give 1.2g of off-white solid in 52.5% yield. The yield thereof was found to be 51.9%. Detecting the white solid: ESI (+) m/z 458.1.
Example 7
Preparation of 5- (1- ((4-aminocarbonylphenyl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -N-methyl-2-pyridinecarboxamide
The synthesis of intermediate 6b and intermediate 6c was performed as in example 6.
Synthesis of compound 7:
compound 6c (1.5g, 5.0mmol), 5-bromo-N-methyl 2-pyridinecarboxamide (1.1g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C, stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to give 1.5g of off-white solid in 68.2% yield. Detecting the white solid: ESI (+) m/z 441.1.
Example 8
Preparation of 4- ((6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzamide
The synthesis of intermediate 6b and intermediate 6c was performed as in example 6.
Synthesis of compound 8:
the compound 6c (1.5g, 5.0mmol), 4- (4-bromophenyl) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to obtain 1.6g of off-white solid with a yield of 69.3%. Detecting the white solid: ESI (+) m/z 463.1.
Example 9
Preparation of 4- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzamide
The synthesis of intermediate 6b and intermediate 6c was performed as in example 6.
Synthesis of compound 9:
the compound 6c (1.5g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to obtain 1.3g of off-white solid with a yield of 55.8%. Detecting the white solid: ESI (+) m/z 467.1.
Example 10
Preparation of 4- ((6- (4- (3-oxopyrrolidine 1-carbonyl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzamide
The synthesis of intermediate 6b and intermediate 6c was performed as in example 6.
Synthesis of compound 10:
dissolving compound 6c (1.5g, 5.0mmol), 1- (4-bromobenzoyl) pyrrolidin-3-one (1.3g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 deg.C, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.4g of off-white solid with a yield of 56.8%. Detecting the white solid: ESI (+) m/z 494.1.
Example 11
Preparation of 4- (1- ((3-cyanophenyl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -2-fluoro-N-methylbenzamide
Synthesis of intermediate 11 b:
compound 1a (22.3g, 100.0mmol), compound 11a (20.1g, 100.0mmol), triethylamine (12.1g, 120.0mmol) were dissolved in acetonitrile (500ml), the reaction was stirred at 50 ℃ for 8 hours, checked by TLC, after completion of the reaction, the reaction was quenched with water (300ml), extracted with ethyl acetate (300ml x 2), the organic layers were combined, dried, concentrated, and isolated by column chromatography to give 31.2g of a pale yellow solid in 80.4% yield.
Synthesis of intermediate 11 c:
dissolving the compound 11b (31.0g, 79.9mmol) in dichloromethane (300ml), adding trifluoroacetic acid (30ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust the pH to 8-9, standing, layering, extracting the aqueous phase with dichloromethane (300ml), combining the organic layers, concentrating, and separating by column chromatography to obtain 15.3g of off-white solid with the yield of 66.5%.
Synthesis of compound 11:
compound 11c (1.4g, 5.0mmol), compound 1e (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C and stirred for 12 hours, checked by TLC, and directly concentrated by column chromatography to give 1.5g of off-white solid in 68.2% yield. Detecting the white solid: ESI (+) m/z 440.1.
Example 12
Preparation of 5- (1- ((3-cyanophenyl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -N-methyl-2-pyridinecarboxamide
The synthesis of intermediate 11b and intermediate 11c was performed as in example 11.
Synthesis of compound 12:
compound 11c (1.4g, 5.0mmol), 5-bromo-N-methyl 2-pyridinecarboxamide (1.1g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C, stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to give 1.2g of off-white solid in 56.9% yield. Detecting the white solid: ESI (+) m/z 423.1.
Example 13
Preparation of 3- ((6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzonitrile
The synthesis of intermediate 11b and intermediate 11c was performed as in example 11.
Synthesis of compound 13:
compound 11c (1.4g, 5.0mmol), 1- (4-bromophenyl) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to give 1.4g of off-white solid in 63.1% yield. Detecting the white solid: ESI (+) m/z 445.1.
Example 14
Preparation of 3- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzonitrile
The synthesis of intermediate 11b and intermediate 11c was performed as in example 11.
Synthesis of compound 14:
compound 11c (1.4g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 ℃ and stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to give 1.3g of off-white solid in 61.6% yield. Detecting the white solid: ESI (+) m/z 449.1.
Example 15
Preparation of 3- ((6- (4- (3-oxopyrrolidine-1-carbonyl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) benzonitrile
The synthesis of intermediate 11b and intermediate 11c was performed as in example 11.
Synthesis of compound 15:
dissolving compound 11c (1.4g, 5.0mmol), 1- (4-bromobenzoyl) pyrrolidin-3-one (1.3g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 deg.C, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.7g of off-white solid with a yield of 71.6%. Detecting the white solid: ESI (+) m/z 476.1.
Example 16
Preparation of 2-fluoro-N-methyl-4- (1- ((2-oxo-2H-benzopyran-7-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) benzamide
Synthesis of intermediate 16 b:
compound 1a (22.3g, 100.0mmol), compound 16a (24.4g, 100.0mmol), triethylamine (12.1g, 120.0mmol) were dissolved in acetonitrile (500ml), the reaction was stirred at 80 ℃ for 8 hours, checked by TLC, after completion of the reaction, the reaction was quenched with water (300ml), extracted with ethyl acetate (300ml x 2), the organic layers were combined, dried, concentrated, and isolated by column chromatography to give 30.7g of a pale yellow solid in 71.2% yield.
Synthesis of intermediate 16 c:
dissolving compound 16b (30.0g, 69.6mmol) in dichloromethane (300ml), adding trifluoroacetic acid (30ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust pH to 8-9, standing, layering, extracting aqueous phase with dichloromethane (300ml), combining organic layers, concentrating, and separating by column chromatography to obtain off-white solid 14.3g, yield 62.2%.
Synthesis of compound 16:
compound 16c (1.7g, 5.0mmol), compound 1e (1.2g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C and stirred for 12 hours, checked by TLC, and directly concentrated by column chromatography to give 1.3g of off-white solid in 53.9% yield. Detecting the white solid: ESI (+) m/z 483.1.
Example 17
Preparation of N-methyl-5- (1- ((2-oxo-2H-benzopyran-7-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -2-pyridinecarboxamide
The synthesis of intermediate 16b and intermediate 16c was performed as in example 16.
Synthesis of compound 17:
compound 16c (1.7g, 5.0mmol), 5-bromo-N-methyl 2-pyridinecarboxamide (1.1g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), and sodium tert-butoxide (576mg, 6.0mmol) were dissolved in toluene (50ml), heated to 100 deg.C, stirred for 12 hours, detected by TLC, directly concentrated by column chromatography to give 1.6g of off-white solid in 68.8% yield. Detecting the white solid: ESI (+) m/z 466.1.
Example 18
Preparation of 7- ((6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) -2H-benzopyran-2-one
The synthesis of intermediate 16b and intermediate 16c was performed as in example 16.
Synthesis of compound 18:
dissolving compound 16c (1.7g, 5.0mmol), 4- (4-bromophenyl) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.7g of off-white solid with yield of 69.8%, wherein the detection result shows that: ESI (+) m/z 488.1.
Example 19
Preparation of 7- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) -2H-benzopyran-2-one
The synthesis of intermediate 16b and intermediate 16c was performed as in example 16.
Synthesis of compound 19:
dissolving compound 16c (1.7g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain white-like solid 1.4g with yield of 57.0%, detecting the white-like solid: ESI (+) m/z 492.1.
Example 20
Preparation of 1- (4- (1- ((2-oxo-2H-benzopyran-7-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-ylbenzoyl) pyrrolidin-3-one
The synthesis of intermediate 16b and intermediate 16c was performed as in example 16.
Synthesis of compound 20:
dissolving compound 16c (1.7g, 5.0mmol), 1- (4-bromobenzoyl) pyrrolidin-3-one (1.3g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃ and stirring for 12 hours, detecting by TLC, directly concentrating and separating by column chromatography to obtain white solid 1.5g with yield of 57.9%, detecting the white solid: ESI (+) m/z 519.1.
Example 21
Preparation of 2-fluoro-N-methyl-4- (1- ((2-oxo-1, 2-dihydroquinolin-7-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) benzamide
Synthesis of intermediate 21 b:
compound 1a (22.3g, 100.0mmol), compound 21a (24.3g, 100.0mmol), and triethylamine (12.1g, 120.0mmol) were dissolved in acetonitrile (500ml), stirred at 30 ℃ for 8 hours, checked by TLC, quenched after the reaction with water (300ml), extracted with ethyl acetate (300ml x 2), the organic layers combined, dried, concentrated, and isolated by column chromatography to give 31.1g of a pale yellow solid in 72.2% yield.
Synthesis of intermediate 21 c:
dissolving the compound 21b (31.0g, 72.1mmol) in dichloromethane (300ml), adding trifluoroacetic acid (30ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust the pH to 8-9, standing, layering, extracting the aqueous phase with dichloromethane (300ml), combining the organic layers, concentrating, and separating by column chromatography to obtain 15.2g of off-white solid with the yield of 63.9%.
Synthesis of compound 21:
dissolving the compound 21c (1.7g, 5.0mmol), the compound 1e (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), the tri-tert-butylphosphine (101mg, 0.5mmol) and the sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring and reacting for 12 hours, detecting by TLC, directly concentrating and carrying out column chromatography to obtain 1.6g of off-white solid with the yield of 66.4%, and detecting the off-white solid: ESI (+) m/z 482.1.
Example 22
Preparation of N-methyl-5- (1- ((2-oxo-1, 2-dihydroquinolin-7-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) -2-pyridinecarboxamide
The synthesis of intermediate 21b and intermediate 21c was performed as in example 21.
Synthesis of compound 22:
dissolving the compound 21c (1.7g, 5.0mmol), 5-bromo-N-methyl-2-pyridinecarboxamide (1.1g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.0g of white-like solid with a yield of 43.1%, wherein the white-like solid is detected: ESI (+) m/z 465.1.
Example 23
Preparation of 7- ((6- (4- (1-methyl-1H-pyrazol-4-yl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinolin-2 (1H) -one
The synthesis of intermediate 21b and intermediate 21c was performed as in example 21.
Synthesis of compound 23:
dissolving the compound 21c (1.7g, 5.0mmol), 4- (4-bromophenyl) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.7g of off-white solid with yield of 69.7%, wherein the detection result shows that: ESI (+) m/z 487.1.
Example 24
Preparation of 7- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinolin-2 (1H) -one
The synthesis of intermediate 21b and intermediate 21c was performed as in example 21.
Synthesis of compound 24: dissolving the compound 21c (1.7g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), the catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.5g of off-white solid with yield of 61.2%, wherein the detection result shows that: ESI (+) m/z 491.1.
Example 25
Preparation of 7- ((6- (4- (3-oxopyrrolidine-1-carbonyl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinolin-2 (1H) -one
The synthesis of intermediate 21b and intermediate 21c was performed as in example 21.
Synthesis of compound 25: dissolving the compound 21c (1.7g, 5.0mmol), 1- (4-bromobenzoyl) pyrrolidin-3-one (1.3g, 5.0mmol), Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.8g of off-white solid with yield of 69.6%, detecting the off-white solid: ESI (+) m/z 518.1.
Example 26
Preparation of 2-fluoro-N-methyl-4- (1- ((3-oxo-3, 4-d-dihydroquinoxalin-6-yl) sulfonyl) -1,4,5, 7-tetrahydro-6H-pyrazolo [3,4-c ] pyridin-6-yl) benzamide
Synthesis of intermediate 26 b:
compound 1a (22.3g, 100.0mmol), compound 26a (24.4g, 100.0mmol), triethylamine (12.1g, 120.0mmol) were dissolved in acetonitrile (500ml), the reaction was stirred at 30 ℃ for 8 hours, checked by TLC, after completion of the reaction, the reaction was quenched with water (300ml), extracted with ethyl acetate (300ml x 2), the organic layers were combined, dried, concentrated, and isolated by column chromatography to give 29.6g of a pale yellow solid in 68.7% yield.
Synthesis of intermediate 26 c:
dissolving compound 26b (29.0g, 67.3mmol) in dichloromethane (300ml), adding trifluoroacetic acid (30ml) at 30 ℃, stirring for 4 hours, detecting by TLC, adding saturated sodium bicarbonate after the reaction to adjust pH to 8-9, standing, layering, extracting aqueous phase with dichloromethane (300ml), combining organic layers, concentrating, and separating by column chromatography to obtain off-white solid 15.5g, yield 69.6%.
Synthesis of compound 26:
dissolving compound 26c (1.7g, 5.0mmol), compound 1e (1.2g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol), sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 deg.C, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain white solid 1.2g with yield 49.9%, detecting the white solid: ESI (+) m/z 483.1.
Example 27
Preparation of 7- ((6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinoxalin-2 (1H) -one
The synthesis of intermediate 26b and intermediate 26c was performed according to example 26.
Synthesis of compound 27:
dissolving compound 26c (1.7g, 5.0mmol), 4- (4-bromophenyl) -1-methyl-1H-pyrazole (1.2g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain 1.7g of off-white solid with yield of 69.8%, wherein the detection result shows that: ESI (+) m/z 488.1.
Example 28
Preparation of 7- ((6- (4- (4-fluoro-1H-pyrazol-1-yl) phenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridin-1-yl) sulfonyl) quinoxalin-2 (1H) -one
The synthesis of intermediate 26b and intermediate 26c was performed according to example 26.
Synthesis of compound 28:
dissolving compound 26c (1.7g, 5.0mmol), 1- (4-bromophenyl) -4-fluoro-1H-pyrazole (1.2g, 5.0mmol), catalyst Pd (dba)2(144mg, 0.25mmol), tri-tert-butylphosphine (101mg, 0.5mmol) and sodium tert-butoxide (576mg, 6.0mmol) in toluene (50ml), heating to 100 ℃, stirring for 12 hours, detecting by TLC, directly concentrating, and separating by column chromatography to obtain white-like solid 1.4g with yield of 57.0%, detecting the white-like solid: ESI (+) m/z 492.1.
Biological evaluation
Assay for c-MET inhibitory Activity
Measuring the inhibitory activity of c-MET by Fluorescence Resonance Energy Transfer (FRET) method, wherein the c-MET is diluted with kinase to appropriate concentration, and the kinase reaction mixture comprises c-MET, substrate, HEPES (pH7.5), MgCl2And EDTA. c-MET and phosphate-peptide substrate are reacted for 1 hour at room temperature by using 100% phosphorylation control and using no ATP as 0% phosphorylation control, Development reagent A which is diluted moderately is added into the reaction system, the reaction is continued for 1 hour at room temperature, a termination reagent is added, the excitation wavelength is 400nm, the fluorescence intensity of 445nm and 520nm is detected, and the IC50 value of the compound is calculated.
A＜10nM，10nM≤B≤100nM，100nM≤C
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | A | 15 | C |
| 2 | C | 16 | A |
| 3 | B | 17 | B |
| 4 | B | 18 | B |
| 5 | B | 19 | C |
| 6 | C | 20 | A |
| 7 | C | 21 | A |
| 8 | A | 22 | C |
| 9 | A | 23 | C |
| 10 | B | 24 | B |
| 11 | A | 25 | A |
| 12 | C | 26 | C |
| 13 | B | 27 | A |
| 14 | A | 28 | B |
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 within the scope of the present invention.
Claims (10)
1. A compound, enantiomer or a pharmaceutically acceptable salt thereof, having the structure of formula i:
wherein, R is1Selected from the group shown below:
the R is2Selected from the group shown below:
2. the compound, enantiomer or pharmaceutically acceptable salt thereof of claim 1, wherein the structure of formula i is one of the following:
3. a process for the preparation of a compound, enantiomer or a pharmaceutically acceptable salt thereof, as claimed in any of claims 1-2, comprising the steps of:
synthesis of intermediate IV:
heating the compound VI and the compound V in a reaction solvent under the action of alkali to react to obtain an intermediate IV;
synthesis of intermediate III:
heating the intermediate IV in a reaction solvent under the action of acid to react to obtain an intermediate III;
synthesis of Compound I:
and heating the intermediate III and the compound II in a reaction solvent under the action of a catalyst and a ligand to react to obtain a compound I.
4. The process according to claim 3, characterized in that, in the step of synthesis of the intermediate IV:
the base comprises one or more of triethylamine, diisopropylethylamine, morpholine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate and lithium hydroxide;
the reaction solvent comprises one or more of acetonitrile, dichloromethane, tetrahydrofuran, dioxane and toluene;
the reaction temperature is 20-100 ℃.
5. The process according to claim 3, characterized in that, in the step of synthesis of the intermediate III:
the acid comprises trifluoroacetic acid, hydrochloric acid or a mixed solution of the trifluoroacetic acid and the hydrochloric acid;
the reaction solvent comprises one or more of dichloromethane, dioxane, acetone and acetonitrile;
the reaction temperature is 20-100 ℃.
6. The process according to claim 3, characterized in that, in the step of synthesis of compound I:
the catalyst comprises one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone palladium) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex;
the ligand comprises triphenylphosphine or tri-tert-butylphosphine;
the base comprises one or more of sodium tert-butoxide, potassium tert-butoxide and cesium carbonate;
the reaction solvent comprises one or more of toluene, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone;
the reaction temperature is 20-120 ℃.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from any one of claims 1-2, an enantiomer, or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier.
8. A c-MET inhibitor comprising a therapeutically effective amount of a compound selected from any one of claims 1-2, an enantiomer, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
9. Use of a compound, enantiomer or a pharmaceutically acceptable salt thereof according to any of claims 1-2, as an inhibitor of c-MET in the manufacture of a medicament for the prevention and/or treatment of a neoplastic disease associated with an abnormality of c-MET.
10. Use according to claim 9, wherein the neoplastic disease comprises skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, prostate cancer, colon cancer, lung cancer, brain cancer, rectal cancer, esophageal cancer, tongue cancer, kidney cancer, cervical cancer, endometrial cancer, testicular cancer, meningioma, hepatocellular carcinoma, chondrosarcoma, fibrosarcoma.
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Denomination of invention: Compounds with c-MET kinase inhibitory activity, preparation method, composition, and use Effective date of registration: 20230829 Granted publication date: 20210205 Pledgee: Industrial Bank Co.,Ltd. Beijing Pinggu Branch Pledgor: BEIJING XINKAIYUAN PHARMACEUTICAL TECHNOLOGY CO.,LTD. Registration number: Y2023110000364 |
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