CN104987324A - Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor - Google Patents
Pyrimidine derivative used as anaplastic lymphoma kinase (ALK) inhibitor Download PDFInfo
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- CN104987324A CN104987324A CN201510304880.6A CN201510304880A CN104987324A CN 104987324 A CN104987324 A CN 104987324A CN 201510304880 A CN201510304880 A CN 201510304880A CN 104987324 A CN104987324 A CN 104987324A
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- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 title claims description 23
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The invention provides a pyrimidine derivative used as an ALK inhibitor. The pyrimidine derivative is a compound as shown in a formula I which is described in the specification or a pharmaceutical salt, hydrate, solvate, metabolite or prodrug thereof. R1, R2, R3 and R4 in the formula are as defined in the specification. The compound and a pharmaceutical composition thereof can be used as the ALK inhibitor and for preparation of an antineoplastic therapeutic capable of inhibiting ALK.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a novel compound, a method for preparing the compound, a pharmaceutical composition and application thereof, in particular to a novel pyrimidine derivative serving as an ALK inhibitor and application of the compound in preparation of medicines for treating and preventing cancers.
Background
Non-small cell lung cancer (Non-small-cell carcinoma, NSCLC) is synonymous with "Non-small cell carcinoma". Non-small cell lung cancers, including squamous cell carcinomas, adenocarcinomas, large cell carcinomas, have slower growth and division of cancer cells and relatively late metastatic spread as compared to small cell carcinomas. Non-small cell lung cancer accounts for approximately 80-85% of the total lung cancer. The data show that the lung cancer incidence rate in China is increased by 26.9% every year at present, and the number of lung cancer incidence in China is estimated to increase by 12 thousands of people from 2000 to 2005. Of these, men have increased from 26 to 33 million in 2000 to 2005, while women have increased from 12 to 17 million. In addition, lung cancer is the leading cause of "cancer of numerous" in many areas throughout the country. The incidence of lung cancer in Beijing city increases by 56% from 2001 to 2010. One fifth of the new cancer patients in Beijing is lung cancer patients in ten years; among the 2011 Zhejiang cancer "cancer spectra published by Zhejiang tumor hospitals, lung cancer is still the first ranked cancer; compared with the lung cancer in Guangzhou region before 30 years, the incidence rate of lung cancer is increased by 7 times.
With the progress of molecular medicine and the continuous emergence of targeted drugs, the treatment of advanced NSCLC has entered the age of individualized treatment. At present, the individual target therapy applied clinically mainly aims at the fusion genotype lung cancer of EGFR mutant and ALK (Anaplastic lymphoma kinase), and the two genetically modified lung cancers have definite molecular targets, target detection technology and targeted drugs on the market, so the clinical curative effect is obviously improved. ALK variation in lung cancer is mainly caused by ALK gene rearrangement and fusion with other genes. Genetic abnormalities at the ALK gene site have been reported to be associated with a variety of cancers. Echinoderm tubulin-like 4(EML4) -ALK fusions due to chromosomal rearrangements have been reported in non-small cell lung cancer (NSCLC) patient populations.
Although a large number of compounds having inhibitory activity against protein kinases have been studied and some protein kinase inhibitors such as crizotinib and the like have been marketed for the treatment of NSCLC, they are resistant and have some drawbacks. Patients who are therapeutically effective, e.g., crizotinib, typically develop resistance after 6 months to 1 year of administration. Moreover, the most common adverse reactions observed in two clinical studies of crizotinib are visual disturbance, nausea, diarrhea, vomiting, edema and constipation, and the incidence rate of the adverse reactions is more than or equal to 25 percent. Therefore, the development of a novel ALK inhibitor drug for treating cancer with higher safety and efficiency has great social value and economic benefit, and is also a research hotspot of various medical enterprises at present.
Thus, current ALK inhibitors remain to be improved.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems to at least some extent or to at least provide a useful commercial choice. To this end, it is an object of the present invention to propose a compound that can be used for the preparation of a medicament for the treatment of cancer.
According to one aspect of the invention, a compound is provided. According to an embodiment of the invention, the compound is a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite or prodrug of a compound of formula I,
wherein,
R1is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C, hydroxy, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl according to embodiments of the present invention1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1- 6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R3is selected from optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally thiomorpholinyl, or optionally substituted amino;
R4is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
According to an embodiment of the invention, R2Is selected from one of the following:
according to an embodiment of the invention, R3Is selected from one of the following:
it will be understood by those skilled in the art that, according to the convention used in the art, in the structural formulae of the present application,for delineating chemical bonds, which are the points at which moieties or substituents are attached to a core structure or a backbone structure. In addition, in the structural formula of the present application,the positions of the substituent groups on the benzene ring are described as two adjacent positions of the chemical bond with the substituent groups in the structural formula, namely the positions marked by the circular rings in the chemical formula
Thus, throughout this specification, the skilled person will be able to refer to the R in the compounds of formula I1～R7And substituents thereof, and p are selected to provide stable compounds of formula I or pharmaceutically acceptable salts, hydrates, solvates, metabolites or prodrugs thereof as described in the examples of the invention.
According to an embodiment of the present invention, the compound of formula I according to the present invention may be at least one selected from the group consisting of:
as used herein, the term "pharmaceutically acceptable salts" refers to the conventional non-toxic salts formed by the reaction of a compound of formula I with an inorganic or organic acid. For example, the conventional non-toxic salts can be prepared by reacting a compound of formula I with an inorganic or organic acid. Wherein, the inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, and the organic acid can be citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like. Or the "pharmaceutically acceptable salts" of the compounds of formula I may be sodium, potassium, calcium, aluminum or ammonium salts of the compounds of formula I, which are prepared by esterification of propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid with an inorganic base. Or methylamine salt, ethylamine salt or ethanolamine salt formed by the compound shown in the general formula I and organic base. Or the compound shown in the general formula I forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
As used herein, the term "prodrug" means that upon administration of the compound to a subject, the compound undergoes chemical transformation by metabolic or chemical processes to yield the compound of formula I and/or a salt and/or solvate thereof. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
It is also understood that hydrates, solvates (e.g., methanolate, ethanolate, DMSO) of the compounds of formula I of the present invention are also within the scope of the present invention. Methods of solvation are well known in the art.
According to a second aspect of the present invention, the present invention provides an intermediate, according to an embodiment of the present invention, the intermediate has a compound represented by formula 5, the compound represented by formula 5 is an intermediate for preparing the compound represented by formula I of the present invention, and the compound represented by formula 5 can be used for preparing the compound represented by formula I of the present invention.
Wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally each of said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroarylIndependently by one or more groups selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
preferably, R2Is selected from one of the following:
according to a third aspect of the present invention, the present invention provides an intermediate, according to a specific embodiment of the present invention, having a compound represented by formula 6, wherein the compound represented by formula 6 is an intermediate for preparing the compound represented by formula I of the present invention, and the compound represented by formula 6 can be used for preparing the compound represented by formula I of the present invention.
Wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, the 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
preferably, R2Is selected from one of the following:
according to a fourth aspect of the present invention, the present invention provides an intermediate, according to an embodiment of the present invention, the intermediate has a compound represented by formula 8, the compound represented by formula 8 is an intermediate for preparing the compound represented by formula I of the present invention, and the compound represented by formula 8 can be used for preparing the compound represented by formula I of the present invention.
Wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, the 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl radicals5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
preferably, R2Is selected from one of the following:
according to a specific embodiment of the present invention, among them, R in the compound represented by formula 5, the compound represented by formula 6, and the compound represented by formula 81、R2And R4As defined in the preceding description.
According to a fifth aspect of the present invention, the present invention provides a method for preparing the compound shown in formula I. According to the embodiment of the invention, the method for preparing the compound shown in formula I comprises the following steps:
(1) contacting the compound represented by the formula 1 with a compound represented by the formula 2 to obtain a compound represented by the formula 3;
(2) contacting the compound represented by the formula 3 with a compound represented by the formula 4 to obtain a compound represented by the formula 5;
(3) subjecting the compound represented by the formula 5 to a hydrogenation reaction to obtain a compound represented by the formula 6;
(4) contacting the compound represented by the formula 6 with a compound represented by the formula 7 to obtain a compound represented by the formula 8; and
(5) contacting the compound represented by the formula 8 with a compound represented by the formula 9 to obtain a compound represented by the formula I,
according to an embodiment of the present invention, in the compounds of the above-mentioned compounds of formulae 1 to 9 and formula I, R1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group; r2Is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, each of which is independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C, hydroxy, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl according to specific examples of the present invention1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2; r3Is selected from optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally thiomorpholinyl, or optionally substituted amino; r4Is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
According to a particular embodiment of the invention, R2One of the following may be preferred:
according to a particular embodiment of the invention, R3One of the following may be preferred:
the inventor finds that the compound shown in the formula I can be quickly and effectively prepared by the method disclosed by the embodiment of the invention, the synthetic route is short, the environment is friendly, the yield and purity of a target product are higher, the raw materials are easy to obtain, the operation and the post-treatment are simple, and the method is suitable for industrial production. In one embodiment of the present invention, the synthetic route for the compound of formula I is:
the following describes the general process for preparing compounds of formula I used in the examples of the present invention:
step (1): preparation of Compound (intermediate) represented by formula 3
According to a specific embodiment of the present invention, in step (1), the compound represented by formula 1 is contacted with the compound represented by formula 2 in the presence of NaH in a first organic solvent. According to a specific example of the present invention, the first organic solvent may be at least one selected from the group consisting of N-methylpyrrolidone, DMF, dimethyl sulfoxide, dimethylacetamide, and N, N-dimethylacetamide. DMF is preferred. Therefore, a good reaction environment can be provided for the compound shown in the formula 1 and the compound shown in the formula 2, and the yield of the compound shown in the formula 3 can be improved.
According to a specific example of the present invention, in the step (1), the compound represented by formula 1 is contacted with the compound represented by formula 2 at 0 ℃. By selecting an appropriate reaction temperature, the yield of the compound represented by formula 3 can be further improved. According to another specific example of the present invention, in the step (1), the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 may be (25 to 30): (15-30). According to a preferred embodiment of the present invention, the molar ratio of the compound represented by formula 1 to the compound represented by formula 2 may be (27 to 28): (20-26). Further, the yield of the compound represented by the formula 3 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound (intermediate) represented by formula 3 may be specifically carried out according to the following steps: dissolving the compound shown in the formula 2 in DMF, adding NaH in batches at 0 ℃, continuously stirring the reaction solution for half an hour at 0 ℃ after the addition is finished, dripping 2,5, 6-trichloropyrimidine (the compound shown in the formula 1) into the reaction solution at 0 ℃, and naturally heating the mixture to room temperature after the dripping is finished and stirring the mixture overnight. After the reaction is finished, ice water is dripped to quench, the mixture is extracted by ethyl acetate, organic phases are combined, the mixture is washed by saturated salt for three times, dried and concentrated under reduced pressure, and the obtained crude product is subjected to column chromatography to obtain the compound shown in the formula 3.
Step (2): preparation of Compound (intermediate) represented by formula 5
According to a specific embodiment of the present invention, in the step (2), the compound represented by formula 3 and the compound represented by formula 4 are contacted in n-butanol containing p-toluenesulfonic acid.
According to the embodiment of the present invention, in the step (2), the compound represented by formula 3 is contacted with the compound represented by formula 4 at 80 ℃ for 6 hours, so that the reaction efficiency can be improved, and the two are sufficiently reacted, thereby finally improving the yield of the compound represented by formula 5. According to a specific embodiment of the present invention, in the step (2), the molar ratio between the compound represented by formula 3, the compound represented by formula 4, and p-toluenesulfonic acid is (4-6): (5-7): (5-7). According to a particular embodiment of the invention, it is preferably (5-6): (5.5-6.5): (5.5-6.5). Further, the yield of the compound represented by the formula 5 can be improved, and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound (intermediate) represented by formula 5 may be specifically carried out according to the following steps: dissolving the compound represented by the formula 3 in n-butanol, adding the compound represented by the formula 4 and p-toluenesulfonic acid thereto, and reacting the mixture at 80 ℃ for 6 hours with stirring. After TLC detection reaction is finished, the solvent is evaporated under reduced pressure, the residual solid is dispersed in ethyl acetate, and then the mixture is washed by saturated sodium bicarbonate aqueous solution, water and saturated saline solution, dried by anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, and the product is separated by column chromatography to obtain the compound shown in the formula 5.
And (3): preparation of Compound (intermediate) represented by formula 6
According to a specific embodiment of the present invention, in the step (3), the hydrogenation reaction is performed in a hydrogen atmosphere using palladium/carbon as a catalyst. According to the specific embodiment of the invention, the palladium/carbon contains 5% of palladium, so that the reaction potential energy of the palladium/carbon and the reaction efficiency of the palladium/carbon can be effectively reduced. According to a specific embodiment of the present invention, the hydrogen atmosphere is 1 atm. Thereby further improving the hydrogenation reaction efficiency and further improving the yield of the compound represented by formula 6. According to the specific embodiment of the present invention, in the step (3), the ratio of the compound represented by the formula 5 to palladium/carbon is (0.5-1 mmol): (35-55mg), preferably (0.7-0.9 mmol): (40-50mg), whereby the yield of the compound represented by formula 6 can be improved and the cost of raw materials can be saved.
According to an embodiment of the present invention, the preparation of the compound (intermediate) represented by formula 6 may be specifically performed according to the following steps: putting the compound shown as the formula 5 into a hydrogenation bottle, adding methanol, replacing with nitrogen, adding palladium/carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring and reacting under the condition of hydrogen (1atm), monitoring by TLC (thin layer chromatography), filtering the reaction solution after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain the compound shown as the formula 6.
And (4): preparation of Compound (intermediate) represented by formula 8
According to a specific embodiment of the present invention, in the step (4), the contacting of the compound represented by formula 6 with the compound represented by formula 7 to obtain the compound represented by formula 8 is performed by the following steps:
(4-1) providing a first dichloromethane solution containing the compound represented by the formula 6 and triethylamine, and a second dichloromethane solution containing the compound represented by the formula 7;
(4-2) mixing the first dichloromethane solution with the second dichloromethane solution.
The compound shown in the formula 8 can be effectively prepared by the preparation method, and the yield of the compound shown in the formula 8 can be improved to the maximum extent.
According to an embodiment of the present invention, the mixing is performed by dropwise adding the second dichloromethane solution to the first dichloromethane solution, and thus the reaction efficiency of the compound represented by formula 6 and the compound represented by formula 7 can be further improved. According to the specific embodiment of the present invention, in the step (4), the dropwise addition is performed under the ice-water bath cooling condition, and the contact time is 2 to 5 hours, so that the reaction efficiency of the two can be effectively improved, and the yield of the compound represented by formula 8 can be improved. According to a specific embodiment of the present invention, in the step (4), the molar ratio of the compound represented by formula 6 to the compound represented by formula 7 is (0.5 to 1): (1-2), preferably (0.7-0.75): (1-1.2). Thereby, the yield of the compound represented by the formula 8 can be improved and the raw material cost can be saved.
According to one embodiment of the present invention, the preparation of the compound (intermediate) represented by formula 8 can be specifically carried out according to the following steps: dissolving the compound shown as the formula 6 in dichloromethane, adding triethylamine into the solution, stirring, and dropwise adding a dichloromethane solution of the compound shown as the formula 7 under the cooling condition of an ice-water bath. Stirring the reaction mixture at room temperature for 2 hours, quenching the reaction mixture by using a saturated sodium carbonate aqueous solution, extracting the reaction mixture by using dichloromethane, combining organic phases, washing the organic phases by using saturated salt water, drying the organic phases by using anhydrous magnesium sulfate, filtering the organic phases, and evaporating the organic solvents under reduced pressure to obtain a crude product of the compound shown in the formula 8, wherein the crude product is directly used for the next reaction without purification.
And (5): preparation of Compounds of formula I
According to a specific embodiment of the present invention, in the step (5), the compound represented by formula 8 is contacted with the compound represented by formula 9 to obtain the compound represented by formula I, by the following steps:
providing acetonitrile solution containing the compound shown in the formula 8 and triethylamine,
adding the compound represented by the formula 9 to the acetonitrile solution to contact the compound represented by the formula 8 with the compound represented by the formula 9. The compound shown in the formula I can be effectively prepared by adopting the method.
According to a specific embodiment of the present invention, in the step (5), the contacting is performed under a heating reflux condition for 3 to 5 hours. Therefore, the two can be fully reacted, and the yield of the compound shown in the formula I is improved.
According to a specific embodiment of the present invention, in the step (5), the molar ratio of the compound represented by formula 8 to the compound represented by formula 9 is (0.5 to 1.5): (1.5-2.5), preferably (0.8-1.2): (1.8-2.2). According to a specific embodiment of the present invention, in the step (5), the molar ratio of the compound represented by the formula 8 to triethylamine is (0.1 to 0.5): (0.5-1.5): preferably (0.2-0.25): (1-1.1). Therefore, the yield of the compound shown in the formula I can be improved, and the raw material cost is saved.
According to a specific embodiment of the present invention, the preparation of the compound of formula I can be specifically carried out according to the following steps: dissolving the crude product of the compound shown in the formula 8 in acetonitrile, sequentially adding triethylamine into the acetonitrile, dropwise adding the compound shown in the formula 9 under stirring at room temperature, heating and refluxing, after the reaction is finished, evaporating the solvent under reduced pressure, diluting the residue with water, extracting dichloromethane, combining organic phases, washing with saturated salt water, drying with anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain the crude product of the compound shown in the formula I, and separating by column chromatography to obtain the product of the compound shown in the formula I.
According to a sixth aspect of the invention, a pharmaceutical composition is proposed. According to a particular embodiment of the invention, the pharmaceutical composition comprises a compound as described above. According to a specific example of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
According to a particular embodiment of the invention, the pharmaceutical composition is in the form of a tablet, capsule, injection, powder, syrup, solution, suspension or aerosol. Thereby the applicability of the pharmaceutical composition can be remarkably improved. And the pharmaceutical compositions of the above embodiments of the invention may be presented in a suitable solid or liquid carrier or diluent and in a suitable sterile device for injection or instillation.
Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The compounds and pharmaceutical compositions of the present invention may be administered to mammals in clinical use, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes, among others. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment regimen. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found. The most preferred route of administration is oral.
According to a seventh aspect of the present invention, there is provided the use of a compound as hereinbefore described, a compound prepared by a process as hereinbefore described or a pharmaceutical composition as hereinbefore described in the manufacture of a medicament.
According to a particular embodiment of the invention, the medicament is for at least one of: useful as kinase inhibitors, inhibiting ALK kinase activity, treating or preventing cancer, and inhibiting proliferation of cancer cells. According to the specific example of the invention, the in vitro ALK kinase inhibitory activity assay experiment results of the compound show that the compounds shown in the formula I have good ALK kinase inhibitory activity, and the compounds can be used as ALK inhibitors and prepared into antitumor treatment medicines for inhibiting anaplastic lymphoma kinase.
Therefore, the medicine of the invention can be effectively used as an ALK inhibitor and is used for treating one or more tumor diseases related to ALK activity, wherein the tumor diseases include but are not limited to lung cancer. The pyrimidine derivative (compound shown in formula I) serving as the ALK inhibitor has good clinical application and medical application as the ALK inhibitor.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications.
In the specific examples described below, the compound structure was determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). Wherein NMR shift () is given in parts per million (ppm), NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and solvent is deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD3OD) with internal standard Tetramethylsilane (TMS); LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column)
The progress of the reaction in the following examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents: dichloromethane and methanol system, n-hexane/petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound. The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying compounds in the following examples include: a: dichloromethane and methanol system, B: the volume ratio of the n-hexane/petroleum ether and ethyl acetate system is adjusted according to the different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
The starting materials used in the examples below may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCRGmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
The embodiment of the invention provides a compound shown in formula I or a pharmaceutically acceptable salt, a hydrate, a solvate, a metabolite or a prodrug thereof, a method and an intermediate for preparing the compound shown in formula I or the pharmaceutically acceptable salt, the hydrate, the solvate or the prodrug thereof, a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparing medicines.
Example 1: preparation of the Compound represented by formula 2-1 (intermediate)
Placing a compound shown as a formula a (15g,106.31mmol) and potassium carbonate (29.38g,212.61mmol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.5g,111.62mmol) under stirring, stirring and heating the mixture to 80 ℃, reacting for 5 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula c (the yield is 19.5g, and the yield is 95%).
Placing a compound shown as a formula c (19.5g,98.86mmol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.2g, 348.84mmol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with saturated sodium sulfite aqueous solution, extracting with dichloromethane, washing with saturated potassium carbonate solution and saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula e (the yield is 20.4g and is 90 percent).
Placing the compound shown as the formula e (20.4g, 88.98mmol) in a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content 5%) in the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain the compound shown as the formula 2-1 (15.95 g, 90% yield).
Example 2: preparation of the Compound represented by formula 2-2 (intermediate)
Placing a compound shown as a formula f (14.2g,0.1mol) and potassium carbonate (27.6g,0.2mol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring and heating the mixture to 75 ℃, reacting for 6 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain the compound shown as the formula g (the yield is 17.9g, and the yield is 92.5%).
Placing a compound shown as a formula g (19.8g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.9g, 0.35mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula h (the yield is 21.1g, and the yield is 92%).
Putting the compound (23.0g,0.1mol) shown in the formula h into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain the compound shown in the formula 2-2 (the yield is 18.6g, and the yield is 93.5%).
Example 3: preparation of the Compound represented by formula 2-2 (intermediate)
Putting a compound shown as a formula j (15.9g,0.1mmol) and potassium carbonate (27.6g,0.2mmol) into a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring the mixture, heating to 80 ℃, reacting for 5 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula g (the yield is 18.1g, and the yield is 93%).
Placing a compound shown as a formula g (19.8g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (48.7g, 0.28mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula h (the yield is 21.5g, and the yield is 93.5%).
Putting a compound (23.0g,0.1mol) shown in the formula h into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1.5atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain the compound shown in the formula 2-2 (the yield is 18.4g, and the yield is 92%).
Example 4: preparation of Compounds represented by formula 2-3 (intermediates)
Placing a compound shown as a formula k (16.4g,0.1mol) and potassium carbonate (27.6g,0.2mol) in a 500mL round-bottom bottle, adding 150 mL of DMF, adding isopropylmercaptan (a compound shown as a formula b) (8.0g,0.105mol) under stirring, stirring and heating the mixture to 75 ℃, reacting for 6 hours, evaporating a reaction solvent under reduced pressure after the reaction is finished, washing the obtained crude product with water, extracting with ethyl acetate, drying, concentrating, and performing column chromatography to obtain a compound shown as a formula m (the yield is 18.3g, and the yield is 92%).
Placing a compound shown as a formula m (20.3g,0.1mol) and m-chloroperoxybenzoic acid (mCPBA, a compound shown as a formula d) (60.9g, 0.35mol) in a 1000mL round-bottomed bottle, adding 500mL of dichloromethane, stirring the mixture at room temperature overnight, quenching with a saturated sodium sulfite solution, extracting with dichloromethane, washing with a saturated potassium carbonate solution and a saturated common salt solution, drying, spin-drying, and performing column chromatography to obtain a compound shown as a formula n (the yield is 21.7g and 92.5 percent).
Putting a compound (23.5g,0.1mol) shown as a formula n into a 500mL hydrogenation bottle, adding 250 mL of methanol, replacing with nitrogen, adding 1000mg of palladium-carbon (Pd content is 5%) into the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and performing reduced pressure spin-drying on the filtrate to obtain a compound (18.9 g, 92% yield) shown as a formula 2-3.
Example 5: preparation of the Compound represented by the formula 6-1
Dissolving the compound shown in the formula 2-1 (5g,25.09mmol) in DMF (100mL), slowly adding NaH (1.1g,27.6mmol) at 0 ℃, continuing to stir the reaction liquid at 0 ℃ for half an hour after the addition is finished, dripping 2,5, 6-trichloropyrimidine (the compound shown in the formula 1) (5.06g,27.6mmol) into the reaction liquid at 0 ℃, and naturally heating the mixture to room temperature and stirring overnight after the dripping is finished. After the reaction, 300mL of ice water was added to quench, and extraction was performed with ethyl acetate (200 mL. times.3), the organic phases were combined, washed three times with saturated brine, dried, concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography to obtain the compound represented by formula 3-1 (yield 2.26g, yield 26%).
The compound represented by the formula 3-1 (2g,5.77mmol) was dissolved in 60mL of n-butanol, 3-nitroaniline (the compound represented by the formula 4-1) (798mg,5.77mmol) and p-toluenesulfonic acid (993mg,5.77mmol) were added thereto, and the mixture was stirred at 80 ℃ for 6 hours. After the completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the compound represented by the formula 5-1 (yield 1.24g, yield 48%).
Placing the compound shown as the formula 5-1 (400mg,0.893mmol) in a 100mL hydrogenation bottle, adding 50 mL of methanol, replacing with nitrogen, adding 40mg of palladium-carbon (Pd content 5%) in the bottle, replacing with hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring by TLC, filtering the reaction solution after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain the compound shown as the formula 6-1 (yield 316mg, yield 85%).
Example 6: preparation of the Compound represented by the formula 6-2
The compound represented by the formula 3-1 (2g,5.77mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-2 (798mg,5.77mmol) and p-toluenesulfonic acid (993mg,5.77mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for 6 hours. After the completion of the TLC detection reaction, the solvent was evaporated under reduced pressure, the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the compound represented by the formula 5-2 (yield 0.84g, yield 32.5%).
Placing the compound shown as the formula 5-2 (400mg,0.893mmol) in a 100mL hydrogenation bottle, adding 50 mL of methanol, replacing with nitrogen, adding 40mg of palladium-carbon (Pd content 5%) in the bottle, replacing with hydrogen balloon, stirring overnight under hydrogen (1atm) condition, monitoring by TLC, filtering the reaction solution after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain the compound shown as the formula 6-2 (279 mg, 75% yield).
Example 7: preparation of the Compound represented by formula 6-3
The compound represented by the formula 3-1 (2g,5.77mmol) was dissolved in 60mL of n-butanol, the compound represented by the formula 4-3 (1019mg,6.06mmol) and p-toluenesulfonic acid (1043mg,6.06mmol) were added thereto, and the mixture was stirred at 80 ℃ for reaction for 6 hours. After the completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was separated by column chromatography to give the compound represented by the formula 5-3 (yield: 1544mg, yield: 56%).
Placing the compound shown in the formula 5-3 (427mg,0.893mmol) in a 100mL hydrogenation bottle, adding 50 mL of methanol, replacing with nitrogen, adding 50mg of palladium-carbon (Pd content 5%) in the bottle, replacing with hydrogen balloon, stirring overnight under hydrogen (1atm) condition, monitoring by TLC, filtering the reaction solution after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula 6-3 (376 mg, 80% yield).
Example 8: preparation of the Compound represented by formula 6-4
The synthesis of example 8 is as in example 7.
LCMS:431(M+H+).
Example 9: preparation of the Compound represented by formula 6-5
The synthesis of example 9 is as in example 7.
LCMS:451(M+H+).
Example 10: preparation of the Compound represented by formula 6-6
The synthesis of example 10 is as in example 5.
LCMS:418(M+H+).
Example 11: preparation of Compounds represented by the formulae 6 to 7
The synthesis of example 11 is as in example 6.
LCMS:418(M+H+).
Example 12: preparation of Compounds represented by the formulae 6 to 8
In example 12, the synthesis method of the compound represented by the formula 2-2 was as described in example 5.
The compound represented by the formula 3-2 (2.0g,5.77mmol) was dissolved in 60mL of n-butanol, the compound represented by the formula 4-3 (1019mg,6.06mmol) and p-toluenesulfonic acid (1043mg,6.06mmol) were added thereto, and the mixture was stirred at 80 ℃ for 6 hours. After the completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was separated by column chromatography to give the compound represented by the formula 5-8 (yield 1.71g, yield 62%).
The compound represented by the formula 5-8 (428mg,0.893mmol) was placed in a 100mL hydrogenation flask, 50 mL of methanol was added, 50mg of palladium on charcoal (Pd content 5%) was added after replacement with nitrogen, the mixture was replaced with a hydrogen balloon, the mixture was stirred overnight under hydrogen (1.0atm) conditions, and the completion of the reaction was monitored by TLCAfter completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a compound represented by the formula 6-8 (yield 348mg, yield 74%). LCMS:418(M + H)+).
Example 13: preparation of Compounds represented by the formulae 6 to 9
The synthesis of example 13 is as in example 7.
LCMS:432(M+H+).
Example 14: preparation of Compounds represented by formulas 6 to 10
The synthesis of example 14 is as in example 7.
LCMS:452(M+H+).
Example 15: preparation of Compounds represented by formulas 6 to 11
The compound represented by the formula 2-3 (4.1g,20mmol) was dissolved in DMF (100mL), NaH (1.1g,27.6mmol) was slowly added at 0 ℃ and after the addition, the reaction mixture was stirred at 0 ℃ for half an hour, and then the compound represented by the formula 1 (5.06g,27.6mmol) was added dropwise to the reaction mixture at 0 ℃ and after the addition, the mixture was allowed to spontaneously warm to room temperature and stirred overnight. After the reaction, 300mL of water was added to quench, and extraction was performed with ethyl acetate (200 mL. times.3), the organic phases were combined, washed three times with saturated brine, dried, and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography to obtain the compound represented by formula 3-3 (amount 3.52g, yield 50%).
The compound represented by the formula 3-3 (2.03g,5.77mmol) was dissolved in 60mL of n-butanol, the compound represented by the formula 4-1 (798mg,5.77mmol) and p-toluenesulfonic acid (993mg,5.77mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for reaction for 6 hours. After the completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the compound represented by the formula 5-11 (yield: 2.1g, yield: 80%).
Placing the compound (363mg,0.8mmol) shown in the formula 5-11 in a 100mL hydrogenation bottle, adding 50 mL of methanol, replacing with nitrogen, adding 40mg of palladium-carbon (Pd content 5%) in the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula 6-11 (the obtained amount is 254mg, the yield is 75%). LCMS:423(M + H)+).
Example 16: preparation of Compounds represented by formulas 6 to 12
The compound represented by the formula 3-3 (2.03g,5.77mmol) was dissolved in 60mL of isopropanol, the compound represented by the formula 4-2 (798mg,5.77mmol) and p-toluenesulfonic acid (993mg,5.77mmol) were added thereto, and the mixture was stirred at a temperature of 70 ℃ for 6 hours. After the completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the residual solid was dispersed in 200mL of ethyl acetate, which was washed with saturated aqueous sodium bicarbonate, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was subjected to column chromatography to give the compound represented by formula 5-12 (yield 1.89g, yield 72%).
Placing the compound (363mg,0.8mmol) shown in the formula 5-12 in a 100mL hydrogenation bottle, adding 50 mL of methanol, replacing with nitrogen, adding 40mg of palladium-carbon (Pd content is 5%) in the bottle, replacing with a hydrogen balloon, stirring overnight under the condition of hydrogen (1atm), monitoring the reaction, filtering the reaction solution, and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula 6-12 (278 mg, 82% yield). LCMS:423(M + H)+).
Example 17: preparation of Compounds represented by formulas 6 to 13
The synthesis of example 17 is as in example 7.
LCMS:453(M+H+).
Example 18: preparation of Compounds represented by formulas 6 to 14
The synthesis of example 18 is as in example 7.
LCMS:437(M+H+).
Example 19: preparation of Compounds represented by formulas 6 to 15
The synthesis of example 19 is as in example 7.
LCMS:457(M+H+).
Example 20: preparation of the Compound represented by the formula 8-1
The compound represented by the formula 6-1 (300mg,0.717mmol) was dissolved in dry dichloromethane (15mL), triethylamine (289.67mg,399uL,2.868mmol) was added to the solution, and a solution of 2-chloroacetyl chloride (the compound represented by the formula 7-1) (85.1mg,0.753mmol) in dichloromethane (2mL) was added dropwise under stirring and cooling in an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium carbonate, extracted with dichloromethane (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the organic solvent was evaporated under reduced pressure to give 350mg of a crude product of the compound represented by formula 8-a, which was used directly in the next reaction without purification.
Example 21 to example 43: preparation of Compounds represented by formula 8-2 to formula 8-24
The structural formulas of the compounds represented by the formulas 8-2 to 8-24 are shown in the following table, and the synthesis methods of the compounds represented by the formulas 8-2 to 8-24 are all referred to in example 20.
Example 44: preparation of the Compound of formula I-11
Dissolving the compound represented by the formula 8-1 (100mg,0.202mmol) in dry acetonitrile (3mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding dicarbonylpiperazine (the compound represented by the formula 9-1) (40mg,0.404mmol) at room temperature with stirring, heating under reflux for 5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-11 (yield 68.8mg, 61% yield).
1H NMR(400MHz,cd3od)8.67(d,J＝8.3Hz,1H),8.16(s,1H),7.91–7.85(m,2H),7.67–7.59(m,1H),7.35–7.27(m,2H),7.22(dd,J＝5.0,1.6Hz,2H),3.41–3.34(m,2H),3.27(d,J＝5.1Hz,4H),3.20(q,J＝7.3Hz,1H),2.86–2.75(m,2H),1.28(d,6H).LCMS:t＝0.716min,558(M+H+).
Example 45: preparation of the Compound of formula I-33
Dissolving the compound represented by the formula 8-11 (100mg,0.200mmol) in dried acetonitrile (3mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-2 (19.2mg,0.22mmol) at room temperature with stirring, refluxing under heating for 4.5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-33 (yield 75mg, 68% yield).
1H NMR(400MHz,cd3od)8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.91(s,1H),7.87(d,J＝5.5Hz,1H),7.33–7.22(m,3H),3.81–3.68(m,4H),3.37(dd,J＝16.2,9.4Hz,1H),3.19(s,2H),2.67–2.54(m,4H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.667min,551.2(M+H+).
Example 46: preparation of the Compound of formula I-93
Dissolving the compound represented by the formula 8-5 (105mg,0.20mmol) in dried acetonitrile (5mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-3 (29mg,0.40mmol) while stirring at room temperature, heating under reflux for 4 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-93 (yield 60.5mg, yield 44%).
Example 47: preparation of the Compound of formula I-3
Mixing a compound represented by formula 8-4 (100mg,0.202 mmo)l) was dissolved in dried acetonitrile (4mL), and triethylamine (102mg,1.01mmol) was sequentially added thereto, a compound represented by formula 9-4 (25mg,0.404mmol) was added dropwise under stirring at room temperature, heating and refluxing were carried out for 4 hours, the solvent was distilled off under reduced pressure, the residue was diluted with water, dichloromethane was extracted (20mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, the organic solvent was distilled off under reduced pressure to obtain a crude product, and the compound represented by formula I-3 was isolated by column chromatography (yield 78.8mg, yield 75%).1H NMR(400MHz,cd3od)9.32(d,J＝8.6Hz,1H),8.35(dd,J＝4.4,1.4Hz,1H),8.18(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.32–7.19(m,4H),3.85(m,,1H),3.80-3.66(m,2H),3.44(s,2H),2.88–2.74(m,2H),1.31(d,J＝5.6Hz,6H).
LCMS:t＝0.654min,520.2(M+H+).
Example 48: preparation of the Compound of formula I-100
Dissolving a compound (105mg,0.2mmol) shown in the formula 8-10 in acetonitrile (3mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding a compound (40mg,0.404mmol) shown in the formula 9-1 at room temperature under stirring, heating and refluxing for 3 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated common salt water, drying with anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound (84.8 mg, 72% yield) shown in the formula I-100.
Example 49: preparation of the Compound of formula I-24
Dissolving the compound represented by the formula 8-10 (105mg,0.2mmol) in acetonitrile (3mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding the compound represented by the formula 9-5 (51mg,0.4mmol) at room temperature under stirring, heating and refluxing for 4.5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-156 (yield 74mg, yield 60%).
1H NMR(400MHz,cd3od)9.10(d,J＝8.4Hz,1H),8.36(d,J＝3.3Hz,1H),8.14(s,1H),7.76(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.3Hz,1H),7.45(d,J＝2.0Hz,1H),7.09(dd,J＝8.6,2.1Hz,1H),3.90–3.78(m,4H),3.24(d,J＝7.4Hz,2H),3.13(d,J＝11.9Hz,2H),2.87(s,6H),2.36(t,J＝11.3Hz,2H),2.08(d,J＝11.4Hz,2H),1.91(dd,J＝12.0,3.5Hz,2H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.611min,617.3(M+H+).
Example 50: preparation of the Compound of formula I-17
Dissolving the compound represented by the formula 8-1 (100mg,0.202mmol) in acetonitrile (3mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-4 (12.5mg,0.202mmol) at room temperature with stirring, heating under reflux for 3 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-17 (yield 57.7mg, yield 55%). Data:1H NMR(400MHz,cd3od)8.66(d,J＝8.4Hz,1H),8.15(s,1H),7.94–7.83(m,2H),7.68–7.56(m,1H),7.29(dt,J＝8.0,6.4Hz,2H),7.24–7.17(m,2H),3.70–3.61(m,2H),3.39(s,2H),3.35–3.31(m,1H),2.80–2.70(m,2H),1.26(d,J＝6.8Hz,6H).LCMS:t＝0.694min,519.2(M+H+)
example 51: preparation of the Compound of formula I-25
Dissolving a compound (105mg,0.2mmol) shown in the formula 8-10 in acetonitrile (3mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding a compound (20mg,0.201mmol) shown in the formula 9-6 under stirring at room temperature, heating and refluxing for 5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated common salt water, drying with anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound (68.3 mg, 64% yield) shown in the formula I-25.
1H NMR(400MHz,cd3od)9.09(d,J＝8.5Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.14(s,1H),7.73(d,J＝8.6Hz,1H),7.57(dd,J＝8.7,4.4Hz,1H),7.45(d,J＝2.2Hz,1H),7.08(dd,J＝8.6,2.2Hz,1H),3.89–3.77(m,4H),3.21(s,2H),2.42(s,6H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.641min,534.2(M+H+).
Example 52: preparation of the Compound of formula I-34
Dissolving the compound represented by the formula 8-11 (100mg,0.200mmol) in acetonitrile (3mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-7 (21mg,0.21mmol) while stirring at room temperature, heating under reflux for 5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated brine, and washing with anhydrous sulfuric acidDrying with magnesium, filtering, evaporating under reduced pressure to remove organic solvent to obtain crude product, and separating by column chromatography to obtain compound of formula I-34 (yield 88mg, yield 78%).1H NMR(400MHz,cd3od)8.42(d,J＝5.4Hz,1H),8.16(s,1H),7.94(s,1H),7.88(d,J＝5.5Hz,1H),7.27(q,J＝3.7Hz,3H),3.37(dd,J＝17.1,10.3Hz,1H),3.24(s,2H),2.82(b,8H),2.56(s,3H),1.34(dd,J＝11.1,6.8Hz,6H).LCMS:t＝0.683min,564.2(M+H+).
Example 53: preparation of the Compound of formula I-48
Dissolving the compound represented by the formula 8-19 (102mg,0.200mmol) in acetonitrile (3mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-8 (18.1mg,0.21mmol) at room temperature with stirring, heating under reflux for 3 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-48 (87.2 mg, 78% yield).
1H NMR(400MHz,cd3od)8.64(s,1H),8.53(d,J＝4.0Hz,1H),8.23(s,1H),7.74(d,J＝2.0Hz,1H),7.48(dd,J＝8.3,1.9Hz,2H),7.34(d,J＝8.4Hz,1H),4.15(d,J＝9.1Hz,2H),3.96(dt,J＝13.7,6.9Hz,1H),3.73–3.48(m,8H),2.23(s,3H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.661min,559.3(M+H+)
Example 54: preparation of the Compound of formula I-48
Dissolving a compound (99mg,0.200mmol) shown in the formula 8-9 in acetonitrile (3mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding a compound (341mg,0.200mmol) shown in the formula 9-8 under stirring at room temperature, heating and refluxing for 4 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated common salt water, drying with anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound (100.6 mg, 80% yield) shown in the formula I-50.
1H NMR(400MHz,cd3od)9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.16(s,1H),7.62(dd,J＝8.7,4.4Hz,1H),7.51(s,4H),3.84(dt,J＝13.7,6.9Hz,1H),3.78–3.64(m,4H),3.17(s,2H),3.04(d,J＝11.8Hz,2H),2.70–2.56(m,4H),2.33–2.18(m,3H),1.95(d,J＝12.7Hz,2H),1.66(td,J＝12.0,3.6Hz,2H),1.30(t,J＝9.2Hz,6H).LCMS:t＝0.639min,629.3(M+H+)
Example 55: preparation of the Compound of formula I-36
Dissolving a compound represented by the formula 8-5 (105mg,0.20mmol) in acetonitrile (4mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding a compound represented by the formula 9-4 (12.5mg,0.202mmol) at room temperature under stirring, heating and refluxing for 5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain a compound represented by the formula I-36 (yield 76mg, yield 69%).
Example 56: preparation of the Compound of formula I-42
Dissolving the compound represented by the formula 8-14 (100mg,0.20mmol) in acetonitrile (4mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-11 (15mg,0.205mmol) at room temperature under stirring, heating under reflux for 4.5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-42 (yield 82.7mg, 77% yield).
Example 57: preparation of the Compound of formula I-96
Dissolving the compound represented by the formula 8-22 (103mg,0.20mmol) in acetonitrile (4mL), sequentially adding triethylamine (102mg,1.01mmol), dropwise adding the compound represented by the formula 9-12 (12.4mg,0.21mmol) at room temperature under stirring, heating and refluxing for 3 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-96 (yield 85mg, yield 79%).
Example 58: preparation of the Compound of formula I-111
Dissolving the compound represented by the formula 8-24 (106mg,0.20mmol) in acetonitrile (4mL), adding triethylamine (102mg,1.01mmol) in this order, dropwise adding the compound represented by the formula 9-12 (15.4mg,0.21mmol) at room temperature with stirring, heating under reflux for 5 hours, evaporating the solvent under reduced pressure, diluting the residue with water, extracting with dichloromethane (20 mL. times.3), combining the organic phases, washing with saturated saline, drying over anhydrous magnesium sulfate, filtering, evaporating the organic solvent under reduced pressure to obtain a crude product, and separating by column chromatography to obtain the compound represented by the formula I-111 (93 mg, 82% yield).
Example 59:
synthetic preparation of the compound described in example 59 reference is made to example 49.
1H NMR(400MHz,cd3od)9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.16(s,1H),7.61(dd,J＝8.7,4.4Hz,1H),7.50(s,4H),3.80-3.87(m,,1H),3.15(s,2H),3.02(d,J＝11.8Hz,2H),2.31(s,6H),2.28–2.15(m,3H),1.90(d,J＝12.4Hz,2H),1.72–1.56(m,2H),1.31(d,J＝6.9Hz,6H).LCMS:t＝0.646min,587.3(M+H+).
Example 60:
synthetic preparation of the compound described in example 60 reference is made to example 44.
1H NMR(400MHz,cd3od)9.30(d,J＝8.6Hz,1H),8.38(d,J＝4.1Hz,1H),8.18(s,1H),7.63(dd,J＝8.6,4.3Hz,1H),7.51(s,3H),4.10(dd,J＝14.4,7.3Hz,1H),3.82-3.86(m,1H),3.42-3.40(m,2H),3.32-3.29(m,2H),2.83-2.86(m,2H),1.02–0.66(m,6H).LCMS:t＝0.679min,559.2(M+H+).
Example 61:
synthetic preparation of the compound described in example 61 reference was made to example 49.
1H NMR(400MHz,cd3od)9.33(d,J＝8.6Hz,1H),8.35(dd,J＝4.4,1.4Hz,1H),8.19(s,1H),7.90(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.33–7.21(m,3H),3.84-3.81(m,1H),3.12(s,2H),2.97(d,J＝11.8Hz,2H),2.30(s,6H),2.26–2.11(m,3H),1.94–1.81(m,2H),1.62-1.33(m,2H),1.32(d,J＝6.9Hz,6H).LCMS:t＝0.658min,587.3(M+H+).
Example 62:
synthetic preparation of the compound described in example 62 reference is made to example 44.
1H NMR(400MHz,cd3od)9.29(d,J＝8.4Hz,1H),8.37(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.62(dd,J＝8.7,4.4Hz,1H),7.57–7.44(m,3H),3.81-3.88(m,1H),3.74–3.63(m,2H),3.44-3.37(m,3H),2.82-2.79(m,2H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.696min,559.2(M+H+).
Example 63:
synthetic preparation of the compound described in example 63 reference is made to example 47.
1H NMR(400MHz,cd3od)9.29(d,J＝8.4Hz,1H),8.37(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.94(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.26-7.23(m,3H),3.87-3.80(m,1H),3.67-3.64(m,2H),3.43(s,2H),2.79-2.76(m,2H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.673min,520.2(M+H+).
Example 64:
synthetic preparation of the compound described in example 64 reference is made to example 51.
1H NMR(400MHz,cd3od)9.29(d,J＝8.7Hz,1H),8.37(dd,J＝4.4,1.4Hz,1H),8.17(s,1H),7.64-7.61(m,1H),7.53-7.48(m,4H),3.87-3.80(m,1H),3.14(s,2H),2.38(s,6H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.670min,504.2(M+H+).
Example 65:
synthetic preparation of the compound described in example 65 reference is made to example 51.
1H NMR(400MHz,cd3od)9.33(d,J＝8.7Hz,1H),8.36(dd,J＝4.4,1.4Hz,1H),8.19(s,1H),7.90(s,1H),7.55(dd,J＝8.7,4.4Hz,1H),7.32–7.20(m,3H),3.87-3.80(m,1H),3.11(s,2H),2.35(s,6H),1.32(d,J＝6.9Hz,6H).LCMS:t＝0.689min,504.1(M+H+).
Example 66:
synthetic preparation of the compound described in example 66 reference is made to example 44.
1H NMR(400MHz,CD3OD)8.62(d,J＝8.0Hz,1H),8.14(s,1H),7.94(d,J＝7.6Hz,1H),7.89(dd,J＝8.0,1.6Hz,1H),7.74–7.67(m,1H),7.50(dt,J＝6.7,5.9Hz,4H),7.34(dd,J＝11.2,4.1Hz,1H),4.49–4.44(m,1H),3.88–3.80(m,1H),3.44–3.37(m,2H),2.88–2.79(m,2H),1.24(d,J＝6.7Hz,6H).
LCMS:t＝0.695min,557(M),580.3(M+Na+).
Example 67:
synthetic preparation of the compound described in example 67 reference was made to example 56.
LCMS:561.2(M+H+).
Example 68:
synthetic preparation of the compound described in example 68 reference is made to example 51.
1H NMR(400MHz,CD3OD)8.62(d,J＝8.4Hz,1H),8.13(s,1H),7.88(dd,J＝8.0,1.6Hz,1H),7.74–7.65(m,1H),7.55–7.43(m,4H),7.37–7.27(m,1H),3.33(d,J＝5.7Hz,1H),3.15(s,2H),2.39(s,6H),1.28–1.21(m,6H).
LCMS:t＝0.685min,503.2(M+H+).
Example 69:
synthetic preparation of the compound described in example 69 reference example 49.
1H NMR(400MHz,CD3OD)8.62(d,J＝8.3Hz,1H),8.13(s,1H),7.88(dd,J＝8.0,1.5Hz,1H),7.75–7.65(m,1H),7.56–7.43(m,4H),7.32(dd,J＝11.2,4.1Hz,1H),3.33(m,1H),3.15(s,2H),3.03(d,J＝11.9Hz,2H),2.37(s,6H),2.27-2.22(m,2H),1.94-1.91(m,2H),1.68-1.65(m,2H),1.25(d,6H).
LCMS:t＝0.654min,586.3(M+H+).
Example 70:
synthetic preparation of the compound described in example 70 reference is made to example 49.
1H NMR(400MHz,cd3od)8.69(d,J＝8.3Hz,1H),8.15(s,1H),7.90–7.83(m,2H),7.67–7.58(m,1H),7.31(ddd,J＝12.1,5.7,1.6Hz,2H),7.25–7.14(m,2H),3.38–3.31(m,1H),3.13(s,2H),3.00(d,J＝11.9Hz,2H),2.50–2.31(m,7H),2.23(dd,J＝12.0,10.2Hz,2H),1.91(d,J＝13.0Hz,2H),1.65(td,J＝12.2,3.7Hz,2H),1.26(d,6H).
LCMS:t＝0.673min,586.3(M+H+).
Example 71:
synthetic preparation of the compound described in example 71 reference is made to example 47.
1H NMR(400MHz,cd3od)8.63(d,J＝8.5Hz,1H),8.14(s,1H),7.89(dd,J＝8.0,1.4Hz,1H),7.74–7.65(m,1H),7.50(q,J＝9.1Hz,4H),7.32(t,J＝7.2Hz,1H),3.77(dd,J＝17.8,12.7Hz,2H),3.69(s,2H),3.37–3.32(m,1H),3.03–2.90(m,2H),1.95(s,3H),1.25(d,6H).
LCMS:t＝0.673min,519.2(M+H+)
Example 72:
synthetic preparation of the compound described in example 72 reference example 53.
1H NMR(400MHz,cd3od)8.24-8.19(m,2H),7.98(d,J＝7.2Hz,1H),7.74(b,1H),7.67–7.49(m,3H),7.34(d,J＝8.6Hz,2H),4.26(s,2H),3.92–3.46(m,8H),3.42–3.34(m,1H),1.23(d,J＝6.8Hz,6H).
LCMS:t＝0.675min,544.3(M+H+)
Example 73:
synthetic preparation of the compound described in example 73 reference was made to example 53.
1H NMR(400MHz,cd3od)8.69(b,1H),8.58(d,J＝4.1Hz,1H),8.25(s,1H),7.73–7.53(m,3H),7.35(d,J＝8.5Hz,2H),4.31(s,2H),3.99-3.92(m,1H),3.85–3.57(m,8H),1.27(d,J＝6.8Hz,6H).
LCMS:t＝0.665min,545.3(M+H+)
Example 74:
synthetic preparation of the compound described in example 74 reference is made to example 53.
1H NMR(400MHz,cd3od)8.68(b,1H),8.60(dd,J＝4.5,1.2Hz,1H),8.28(s,1H),7.82(t,J＝1.9Hz,1H),7.61(dd,J＝8.3,4.4Hz,1H),7.47–7.31(m,2H),7.15(d,J＝8.5Hz,1H),4.27(s,2H),3.97(dt,J＝13.7,6.8Hz,1H),3.65(dd,J＝24.0,19.1Hz,8H),1.27(t,J＝14.4Hz,6H).
LCMS:t＝0.680min,545.3(M+H+)
Example 75:
synthetic preparation of the compound described in example 75 reference was made to example 45.
1H NMR(400MHz,cd3od)9.29(d,J＝8.5Hz,1H),8.36(dd,J＝4.3,1.2Hz,1H),8.16(s,1H),7.61(dt,J＝8.6,4.2Hz,1H),7.51(s,4H),3.86-3.84(m,1H),3.76(dd,J＝10.4,5.8Hz,4H),3.17(s,2H),2.62-2.60(m,4H),1.31(d,J＝6.9Hz,6H).
LCMS:t＝0.679min,546.2(M+H+)
Example 76:
synthetic preparation of the compound described in example 76 reference is made to example 45.
1H NMR(400MHz,cd3od)9.34(d,J＝8.6Hz,1H),8.36(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.92(s,1H),7.55(dd,J＝8.7,4.4Hz,1H),7.37–7.20(m,3H),3.86-2.83(m,1H),3.75–3.70(m,4H),3.15(s,2H),2.62–2.52(m,4H),1.32(d,J＝6.9Hz,6H).
LCMS:t＝0.698min,546.2(M+H+)
Example 77:
synthetic preparation of the compound described in example 77 reference is made to example 45.
1H NMR(400MHz,cd3od)8.62(d,J＝8.2Hz,1H),8.13(s,1H),7.88(d,J＝7.9Hz,1H),7.70(t,J＝7.9Hz,1H),7.50(q,J＝8.9Hz,4H),7.32(t,J＝7.6Hz,1H),3.82–3.68(m,4H),3.32-3.30(m,1H),3.17(s,2H),2.62-2.60(m,4H),1.24(d,J＝6.8Hz,6H).
LCMS:t＝0.698min,545.2(M+H+).
Example 78:
synthetic preparation of the compound described in example 78 reference example 53.
1H NMR(400MHz,cd3od)8.72(s,1H),8.59(dd,J＝4.4,1.1Hz,1H),8.23(s,1H),7.68(s,1H),7.57(s,1H),7.35(d,J＝8.6Hz,1H),7.18(s,1H),4.23(s,2H),3.98(dt,J＝13.6,6.8Hz,1H),3.78–3.49(m,8H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.636min,575.2(M+H+).
Example 79:
synthetic preparation of the compound described in example 79 reference was made to example 45.
1H NMR(400MHz,cd3od)9.07(d,J＝8.6Hz,1H),8.39(dd,J＝4.4,1.3Hz,1H),8.17(s,1H),7.74(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.4Hz,1H),7.45(d,J＝2.2Hz,1H),7.09(dd,J＝8.6,2.3Hz,1H),4.17(s,2H),3.99(s,4H),3.91–3.79(m,4H),3.47(s,4H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.646min,576.2(M+H+).
Example 80:
synthetic preparation of the compound described in example 80 reference is made to example 52.
1H NMR(400MHz,cd3od)9.33(d,J＝8.5Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.90(s,1H),7.54(dd,J＝8.7,4.4Hz,1H),7.27(ddd,J＝10.4,6.1,1.6Hz,3H),3.89-3.82(m,1H),3.18(s,2H),2.62(b,8H),2.34(s,3H),1.31(d,J＝6.5Hz,6H).
LCMS:t＝0.632min,559.2(M+H+).
Example 81:
synthetic preparation of the compound described in example 81 reference is made to example 52.
1H NMR(400MHz,cd3od)9.29(d,J＝8.4Hz,1H),8.36(d,J＝4.3Hz,1H),8.16(d,J＝1.0Hz,1H),7.61(dd,J＝8.7,4.3Hz,1H),7.50(s,4H),3.87-3.80(m,1H),3.21(s,2H),2.69(b,8H),2.40(s,3H),1.31(d,J＝6.9Hz,6H).LCMS:t＝0.638min,559.2(M+H+).
Example 82:
synthetic preparation of the compound described in example 82 reference is made to example 52.
1H NMR(400MHz,cd3od)9.11(d,J＝8.4Hz,1H),8.36(dd,J＝4.4,1.3Hz,1H),8.15(s,1H),7.75(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,4.4Hz,1H),7.44(d,J＝2.2Hz,1H),7.08(dd,J＝8.6,2.2Hz,1H),3.90–3.78(m,4H),3.27(s,2H),2.84(b,8H),2.56(s,3H),1.30(d,J＝6.9Hz,6H).LCMS:t＝0.650min,589.3(M+H+).
Example 83:
synthetic preparation of the compound described in example 83 reference is made to example 51.
1H NMR(400MHz,cd3od)8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.91(s,1H),7.88(d,J＝5.5Hz,1H),7.34–7.21(m,3H),3.42-3.34(m,1H),3.17(s,2H),2.38(d,J＝7.7Hz,6H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.673min,509.1(M+H+).
Example 84:
synthetic preparation of the compound described in example 84 reference is made to example 49.
1H NMR(400MHz,cd3od)8.41(d,J＝5.5Hz,1H),8.15(s,1H),7.95(s,1H),7.87(d,J＝5.5Hz,1H),7.27(td,J＝5.5,2.6Hz,3H),3.38(dd,J＝13.6,6.8Hz,1H),3.21(s,2H),3.17–3.00(m,3H),2.82(s,6H),2.31(dd,J＝11.9,10.3Hz,2H),2.03(d,J＝11.7Hz,2H),1.90–1.73(m,2H),1.33(d,J＝6.8Hz,6H).LCMS:t＝0.612min,592.3(M+H+).
Example 85:
synthetic preparation of the compound described in example 85 reference was made to example 53.
1H NMR(400MHz,cd3od)8.25(s,1H),8.02(b,1H),7.94(d,J＝5.4Hz,1H),7.86(s,1H),7.54(d,J＝8.3Hz,1H),7.45(t,J＝8.1Hz,1H),7.25(d,J＝7.9Hz,1H),4.19(d,J＝5.5Hz,2H),3.59(dd,J＝14.0,7.0Hz,8H),3.45(dt,J＝13.6,6.8Hz,2H),1.32(d,J＝6.8Hz,6H).
LCMS:t＝0.685min,549.1(M+H+)
Example 86:
synthetic preparation of the compound described in example 86 reference example 49.
1H NMR(400MHz,cd3od)9.02(d,J＝8.7Hz,1H),8.27(d,J＝3.4Hz,1H),8.13(s,1H),7.71(d,J＝2.0Hz,1H),7.44(dd,J＝8.2,2.0Hz,1H),7.34–7.22(m,2H),3.85(dt,J＝13.7,6.8Hz,1H),3.18(d,J＝8.2Hz,2H),3.05–2.96(m,2H),2.82(s,6H),2.34–2.15(m,5H),2.00(d,J＝11.4Hz,2H),1.77(dt,J＝12.1,8.5Hz,2H),1.29(t,J＝6.3Hz,6H).
LCMS:t＝0.647min,601.3(M+H+)
Example 87:
synthetic preparation of the compound described in example 87 reference is made to example 45.
1H NMR(400MHz,cd3od)9.01(d,J＝8.8Hz,1H),8.28–8.23(m,1H),8.12(s,1H),7.71(d,J＝2.2Hz,1H),7.40(dt,J＝7.3,3.7Hz,1H),7.30(dd,J＝8.8,4.3Hz,1H),7.24(d,J＝8.3Hz,1H),3.82(dt,J＝13.7,6.9Hz,1H),3.74–3.65(m,4H),3.14(s,2H),2.56-2.54(m,4H),2.21(s,3H),1.29(d,J＝6.9Hz,6H).
LCMS:t＝0.681min,560.2(M+H+)
Example 88:
synthetic preparation of the compound described in example 88 reference is made to example 52.
1H NMR(400MHz,cd3od)9.01(d,J＝8.7Hz,1H),8.27(dd,J＝4.3,1.1Hz,1H),8.12(s,1H),7.72(d,J＝2.1Hz,1H),7.41(dd,J＝8.2,2.2Hz,1H),7.33–7.22(m,2H),3.84(dt,J＝13.7,6.9Hz,1H),3.22(d,J＝7.3Hz,2H),2.99(s,4H),2.71(s,4H),2.64(s,3H),2.21(s,3H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.676min,573.3(M+H+)
Example 89:
synthetic preparation of the compound described in example 89 reference is made to example 52.
LCMS:598.6(M+H+).
Example 90:
synthetic preparation of the compound described in example 90 reference is made to example 54.
1H NMR(400MHz,cd3od)9.33(d,J＝8.2Hz,1H),8.35(dd,J＝4.4,1.3Hz,1H),8.19(s,1H),7.90(s,1H),7.53(dd,J＝8.7,4.4Hz,1H),7.34-7.18(m,3H),3.85(dt,J＝13.7,6.8Hz,1H),3.77-3.64(m,4H),3.14(s,2H),2.98(d,J＝11.5Hz,2H),2.61(d,J＝4.3Hz,4H),2.23(t,J＝11.2Hz,3H),1.92(d,J＝12.6Hz,2H),1.63-1.52(m,2H),1.30(d,J＝6.9Hz,6H).
LCMS:t＝0.646min,629.3(M+H+)
Example 91
Synthetic preparation of the compound described in example 91 reference was made to example 52.
LCMS:572.3(M+H+).
Example 92
Synthetic preparation of the compound described in example 92 reference example 52.
LCMS:592.5(M+H+).
Example 93
Synthetic preparation of the compound described in example 93 reference example 45.
LCMS:559.1(M+H+).
Example 94
Synthetic preparation of the compound described in example 94 reference is made to example 45.
LCMS:579.5(M+H+).
Example 95
Synthetic preparation of the compound described in example 95 reference is made to example 53.
LCMS:558(M+H+).
Example 96
Synthetic preparation of the compound described in example 96 reference is made to example 53. LCMS 577(M + H)+)
Example 97
Synthetic preparation of the compound described in example 97 reference is made to example 51.
LCMS:517.1(M+H+).
Example 98
Synthetic preparation of the compound described in example 98 reference example 49.
LCMS:600.2(M+H+).
Example 99
Synthetic preparation of the compound described in example 99 reference is made to example 49.
LCMS:620.1(M+H+).
Example 100
Synthetic preparation of the compound described in example 100 reference is made to example 51.
LCMS:509.1(M+H+).
Example 101
Synthetic preparation of the compound described in example 101 reference is made to example 46.
LCMS:531.1(M+H+).
Example 102
Synthetic preparation of the compound described in example 102 reference is made to example 44.
LCMS:588.1(M+H+).
Example 103
Synthetic preparation of the compound described in example 103 reference is made to example 47.
LCMS:549.1(M+H+).
Example 104
Synthetic preparation of the compound described in example 104 reference is made to example 49.
LCMS:616.2(M+H+).
Example 105
Synthetic preparation of the compound described in example 105 reference is made to example 44.
LCMS:610.1(M+H+).
Example 106
Synthetic preparation of the compound described in example 106 example 49 was referenced.
LCMS:586.2(M+H+).
Example 107
Synthetic preparation of the compound described in example 107 reference example 50.
LCMS:555.1(M+H+)
Example 108
Synthetic preparation of the compound described in example 108 reference is made to example 49.
LCMS:622.2(M+H+)
Example 109
Synthetic preparation of the compound described in example 109 reference is made to example 58.
LCMS:530.2(M+H+).
Example 110
Synthetic preparation of the compound described in example 110 reference was made to example 52.
LCMS:593.5(M+H+)
Example 111
Synthetic preparation of the compound described in example 111 reference example 45.
LCMS:580.5(M+H+)
Example 112
Synthetic preparation of the compound described in example 112 reference was made to example 53.
LCMS:578(M+H+)
Example 113
Synthetic preparation of the compound described in example 113 reference is made to example 51.
LCMS:518.1(M+H+)
Example 114
Synthetic preparation of the compound described in example 114 reference is made to example 51.
LCMS:538.5(M+H+)
Example 115
Synthetic preparation of the compound described in example 115 reference is made to example 49.
LCMS:621.6(M+H+)
Example 116
Synthetic preparation of the compound described in example 116 reference is made to example 51.
LCMS:539.1(M+H+)
Example 117
Synthetic preparation of the compound described in example 117 reference is made to example 50.
LCMS:550.1(M+H+)
Example 118
Synthetic preparation of the compound described in example 118 reference is made to example 58.
LCMS:544.2(M+H+).
Example 119
Synthetic preparation of the compound described in example 119 reference example 46.
LCMS:562.1(M+H+)
Example 120
Synthetic preparation of the compound described in example 120 reference is made to example 52.
LCMS:578.2(M+H+).
Example 121
Synthetic preparation of the compound described in example 121 reference is made to example 45.
LCMS:585.5(M+H+).
Example 122
Synthetic preparation of the compound described in example 122 example 45 was referenced.
LCMS:565.1(M+H+)
Example 123
Synthetic preparation of the compound described in example 123 reference was made to example 53.
LCMS:583(M+H+)
Example 124
Synthetic preparation of the compound described in example 124 reference example 53.
LCMS:563(M+H+)
Example 125
Synthetic preparation of the compound described in example 125 reference is made to example 51.
LCMS:543.5(M+H+)
Example 126
Synthetic preparation of the compound described in example 126 reference is made to example 51.
LCMS:523.1(M+H+)
Example 127
Synthetic preparation of the compound described in example 127 reference example 49.
LCMS:626.6(M+H+)
Example 128
Synthetic preparation of the compound described in example 128 reference is made to example 49.
LCMS:606.2(M+H+)
Example 129
Synthetic preparation of the compound described in example 129 reference is made to example 44.
LCMS:564.1(M+H+)
Example 130
Synthetic preparation of the compound described in example 130 reference is made to example 46.
LCMS:567.1(M+H+)
Example 131
Synthetic preparation of the compound described in example 131 reference is made to example 47.
LCMS:525.1(M+H+).
Example 132
Synthetic preparation of the compound described in example 132 reference example 47.
LCMS:525.1(M+H+).
Example 133
Synthetic preparation of the compound described in example 133 reference example 49.
LCMS:592.2(M+H+).
Example 134
Synthetic preparation of the compound described in example 134 reference is made to example 57.
LCMS:516.2(M+H+).
Example 135
Synthetic preparation of the compound described in example 135 reference is made to example 57.
LCMS:516.2(M+H+).
Example 136
Synthetic preparation of the compound described in example 136 reference is made to example 57.
LCMS:531.2(M+H+).
Example 137
Synthetic preparation of the compound described in example 137 reference example 57.
LCMS:531.2(M+H+).
Example 138: measurement of ALK kinase inhibitory Activity
The inhibitory activity of the compound of the present invention on ALK kinase in vitro was measured by the following method, and the inhibitory activity was expressed by IC50, which is an index, i.e., the concentration of the compound at which the activity of ALK kinase was inhibited by 50%.
Shorthand and definition
mg of
mL of
Microgram of μ g
Microliter of
mM millimole
EDTA Ethylenediaminetetraacetic acid
DMSO dimethyl sulfoxide
Standard deviation of SD
SOP Standard operating program
Experimental materials:
ALK(Carna,Cat.No 08-105,Lot.No.08CBS-0112)
ALK L1196M(Carna,Cat.No 08-529,Lot.No.11CBS-1134)
Peptide FAM-P22(GL Biochem,Cat.No.112393,Lot.No.P080401-XY112393)
ATP(Sigma,Cat.No.A7699-1G,CAS No.987-65-5)
DMSO(Sigma,Cat.No.D2650,Lot.No.474382)
EDTA(Sigma,Cat.No.E5134,CAS No.60-00-4)
96-well plate (Corning, Cat.No.3365, Lot.No.22008026)
384 well plates (Corning, Cat.No.3573, Lot.No.12608008)
Staurosporine(Sigma,Cat.No.S4400-1MG,Lot.No.046K4080)
The experimental method comprises the following steps:
1. preparing 1 time of kinase buffer solution and stop solution
1) 1-fold kinase buffer
50mM HEPES,pH 7.5
0.0015％Brij-35
10mM MgCl2
2mM DTT
2) Stopping liquid
100mM HEPES,pH 7.5
0.015％Brij-35
0.2％Coating Reagent#3
50mM EDTA
2. Compound preparation
1) Compounds were diluted 50-fold into 100% DMSO at the final desired maximum inhibitory concentration. Transfer 100 μ L of this compound dilution in 96-well plates. For example, if the highest inhibitor concentration of 1. mu.M is desired, a 50. mu.M DMSO solution is prepared at this step.
2) Compounds were diluted in 3-fold order to 10 concentrations.
3) 100 μ l of 100% DMSO was added to 2 empty identical 96-well plates without compound control and without enzyme control. The source plate is marked.
4) Preparation of intermediate plate
Transfer 10 μ L of compound from source plate to a new 96-well plate as an intermediate plate.
Add 90 μ L of 1 fold kinase buffer to the wells of each intermediate plate.
Mix the compound into the middle plate and shake for 10 minutes.
3. Preparing the test plate
Transfer 5 μ l from each well of the 96-well intermediate plate to 384-well plates as replicates. For example, a1 in a 96-well plate was transferred to a1 and a2 in a 384-well plate. A2 in 96-well plates was transferred to A3 and A4 in 384-well plates.
4. Kinase reaction
1) Preparing 2.5 times of enzyme solution
The kinase was added to 1 fold kinase buffer to form a 2.5 fold enzyme solution.
2) Preparing 2.5 times of substrate solution
FAM-labeled polypeptide and ATP were added to 1-fold kinase buffer to form a 2.5-fold substrate solution.
3) The assay plate already contains 5. mu.l of compound in 10% DMSO.
4) Transfer 2.5 times enzyme solution to assay plate.
5) Incubate at room temperature for 10 minutes
6) Transfer 2.5 fold peptide solution to assay plate.
7) Reaction and cessation of kinase
Incubate at 28 ℃ for 20 minutes. The reaction was stopped by adding 25. mu.l of stop solution.
Reading data by Caliper
Conversion data were read on the Caliper.
6. Fitting of curves
1) Conversion data was copied from the Caliper.
2) The conversion was converted to inhibition data. Wherein max refers to the conversion rate of a DMSO control, and min refers to the conversion rate of an enzyme-free control.
Percent inhibition＝(max-conversion)/(max-min)*100.
3) Data were imported into MS Excel and curve fitted using XLFit Excel add-in version 4.3.1.
The formula used is:
the following table shows the activity of the compounds of formulae I-1 to I-159 of the present invention in an in vitro ALK kinase inhibition assay. The results show that the compounds shown in the formula I have good ALK kinase inhibitory activity, and the compounds can be used as ALK inhibitors, used for treating one or more tumor diseases related to ALK activity, and used for preparing anti-tumor treatment medicines for inhibiting anaplastic lymphoma kinase.
| Compound numbering | IC50(nM) |
| I-1 | <100 |
| I-2 | <100 |
| I-3 | <100 |
| I-4 | <100 |
| I-5 | <100 |
| I-6 | <100 |
| I-7 | <100 |
| I-8 | <100 |
| I-10 | <10 |
| I-11 | <10 |
| I-12 | <10 |
| I-14 | <10 |
| I-15 | <10 |
| I-16 | <10 |
| I-17 | <10 |
| I-18 | <10 |
| I-19 | <100 |
| I-20 | <100 |
| I-21 | <100 |
| I-22 | 124 |
| I-23 | <10 |
| I-24 | <100 |
| I-25 | <100 |
| I-26 | <10 |
| I-27 | <100 |
| I-28 | <100 |
| I-29 | <100 |
| I-30 | <10 |
| I-31 | <10 |
| I-32 | <10 |
| I-33 | <10 |
| I-34 | <10 |
| I-35 | <10 |
| I-36 | <10 |
| I-42 | <100 |
| I-45 | <100 |
| I-46 | <100 |
| I-47 | <100 |
| I-48 | <100 |
| I-49 | <100 |
| I-50 | <100 |
| I-52 | <100 |
| I-53 | <100 |
| I-54 | <100 |
| I-55 | <10 |
| I-56 | <10 |
| I-57 | <10 |
| I-58 | <10 |
| I-59 | <100 |
| I-60 | <100 |
| I-61 | 138 |
| I-62 | <100 |
| I-63 | <100 |
| I-64 | <10 |
| I-65 | 124 |
| I-66 | <100 |
| I-67 | <100 |
| I-68 | <100 |
| I-69 | <100 |
| I-70 | <100 |
| I-71 | <100 |
| I-72 | <100 |
| I-73 | <100 |
| I-74 | <10 |
| I-75 | <10 |
| I-76 | <100 |
| I-77 | <10 |
| I-80 | <10 |
| I-81 | 100 |
| I-82 | <10 |
| I-83 | <10 |
| I-84 | <100 |
| I-86 | <100 |
| I-87 | <100 |
| I-90 | <100 |
| I-91 | <100 |
| I-93 | <100 |
| I-96 | <100 |
| I-97 | <100 |
| I-98 | <10 |
| I-99 | <10 |
| I-100 | <100 |
| I-107 | <100 |
| I-109 | <100 |
| I-110 | <100 |
| I-111 | <100 |
| I-113 | <100 |
| I-114 | <100 |
| I-115 | <100 |
| I-116 | <100 |
| I-119 | <100 |
| I-121 | <100 |
| I-122 | <100 |
| I-123 | <100 |
| I-129 | <100 |
| I-132 | <100 |
| I-144 | <100 |
| I-157 | <100 |
| I-158 | <100 |
| I-159 | <10 |
Example 139: tablets for oral administration, formulations as shown in the following table
| Composition (I) | Bulk drug (gram) |
| Active ingredient | 10 |
| Guar gum | 15 |
| Microcrystalline cellulose | 150 |
| Sodium carboxymethyl starch | 25 |
| Magnesium stearate | 2 |
| Is prepared into | 1000 tablets |
The active ingredients in the above table are sieved with a 100 mesh sieve, then uniformly mixed with guar gum, sodium carboxymethyl starch, microcrystalline cellulose and magnesium stearate sieved with a 100 mesh sieve, and formed into tablets by a suitable tablet press to prepare 1000 tablets in total, wherein each tablet contains 10mg of the active ingredient (the compound of the invention).
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.
Claims (14)
1. A compound that is a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, or prodrug of a compound of formula I,
wherein,
R1is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R3is optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally thiomorpholinyl, or optionally substituted amino;
R4is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
2. The compound of claim 1,
R2is one of the following:
optionally, R3Is one of the following:
3. a method for preparing a compound shown in formula I is characterized by comprising the following steps:
(1) contacting a compound represented by formula 1 with a compound represented by formula 2 to obtain a compound represented by formula 3;
(2) contacting the compound represented by the formula 3 with a compound represented by the formula 4 to obtain a compound represented by the formula 5;
(3) subjecting the compound represented by the formula 5 to a hydrogenation reaction to obtain a compound represented by the formula 6;
(4) contacting the compound represented by the formula 6 with a compound represented by the formula 7 to obtain a compound represented by the formula 8; and
(5) contacting the compound represented by the formula 8 with a compound represented by the formula 9 to obtain a compound represented by the formula I,
wherein,
R1is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, the 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R3is optionally substituted piperazinyl, optionally substituted piperidinyl, optionally substituted morpholinyl, optionally thiomorpholinyl, or optionally substituted amino;
R4is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
4. The method of claim 3, wherein R is2Is one of the following:
optionally, R3Is one of the following:
5. the method according to claim 3, wherein in step (1), the compound represented by formula 1 is contacted with the compound represented by formula 2 in a first organic solvent in the presence of NaH,
optionally, the first organic solvent is at least one selected from the group consisting of N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-dimethylacetamide, preferably N, N-dimethylformamide,
optionally, in step (1), contacting the compound of formula 1 with the compound of formula 2 at 0 ℃.
6. The method according to claim 3, wherein in step (2), the compound represented by formula 3 is contacted with the compound represented by formula 4 in n-butanol in the presence of p-toluenesulfonic acid,
optionally, in step (2), contacting the compound represented by formula 3 with the compound represented by formula 4 at 80 ℃.
7. The method according to claim 3, wherein in step (3), the hydrogenation reaction is carried out in a hydrogen atmosphere using palladium/carbon as a catalyst.
8. The method according to claim 3, wherein, in the step (4), the compound represented by the formula 6 is contacted with the compound represented by the formula 7 to obtain the compound represented by the formula 8, by the following steps:
(4-1) providing a first dichloromethane solution containing the compound represented by the formula 6 and triethylamine, and a second dichloromethane solution containing the compound represented by the formula 7;
(4-2) mixing the first dichloromethane solution with the second dichloromethane solution,
optionally, the mixing is performed by dropwise adding the second dichloromethane solution to the first dichloromethane solution,
optionally, in the step (4), the dropwise addition is carried out under the cooling condition of an ice-water bath,
optionally, in step (4), the contact time is 2 to 5 hours.
9. The method according to claim 3, wherein, in the step (5), the compound represented by the formula 8 is contacted with the compound represented by the formula 9 to obtain the compound represented by the formula I, by the following steps:
providing a solution containing the compound shown in the formula 8 and triethylamine acetonitrile,
adding the compound represented by the formula 9 to the acetonitrile solution to contact the compound represented by the formula 8 with the compound represented by the formula 9,
optionally, in step (5), the contacting is performed under heating reflux conditions for 3 to 5 hours.
10. An intermediate, which is a compound shown as a formula 5,
wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is a 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally said 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroarylAryl and 5-6 membered heteroaryl are each independently substituted by one or more groups selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
11. An intermediate, which is a compound shown as a formula 6,
wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, the 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
12. An intermediate, which is a compound shown as a formula 8,
wherein R is1Is hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group;
R2is 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, or 5-6 membered heteroaryl, optionally, the 5-6 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered aryl, and 5-6 membered heteroaryl are each independently substituted with one or more substituents selected from halogen, hydroxy, cyano, nitro, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C3-8Cycloalkyl, 3-8 membered heterocyclyl, C5-10Aryl, 5-10 membered heteroaryl, C1-6Alkoxy radical, C3-8Cycloalkoxy, -S (O) pR5、-C(O)R5、-C(O)OR5、-NR6R7or-C (O) NR7Wherein R is5、R6、R7Each independently is hydrogen, or Cl-4Alkyl, p is 0, 1 or 2;
R4is selected from hydrogen, halogen, C1-6Alkyl, or C1-6An alkoxy group.
13. Intermediate according to any one of claims 10 to 12, characterized in that R2Is one of the following:
14. use of a compound according to claim 1 or 2 in the manufacture of a medicament for inhibiting anaplastic lymphoma kinase.
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| CN201510304880.6A CN104987324B (en) | 2015-06-04 | 2015-06-04 | Pyrimidine derivatives as ALK inhibitor |
| PCT/CN2015/081487 WO2016192132A1 (en) | 2015-06-04 | 2015-06-15 | Pyrimidine derivative serving as alk inhibitor |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| CN107235931A (en) * | 2017-07-11 | 2017-10-10 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
| CN107586278A (en) * | 2016-07-08 | 2018-01-16 | 中国科学院上海药物研究所 | 2,4 2 amine pyrimidine compounds, its preparation method, pharmaceutical composition and the purposes of a kind of fragment containing phenol |
| CN108047204A (en) * | 2018-01-08 | 2018-05-18 | 沈阳药科大学 | 2,4- diarylamino pyrimidine derivatives and its preparation method and application |
| WO2018146472A1 (en) | 2017-02-07 | 2018-08-16 | Oblique Therapeutics Ab | Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| CN110294750A (en) * | 2018-03-21 | 2019-10-01 | 密执安州立大学董事会 | 5,6- dihydro -11H- indoles as ALK inhibitor simultaneously [2,3-B] quinoline -11- ketone compound |
| US10899710B2 (en) | 2015-08-07 | 2021-01-26 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Pyridines and their use in the treatment of cancer |
| US11028067B2 (en) | 2017-02-07 | 2021-06-08 | Oblique Therapeutics Ab | Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer |
| US11168069B2 (en) | 2017-02-07 | 2021-11-09 | Oblique Therapeutics Ab | Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109422733A (en) * | 2017-09-03 | 2019-03-05 | 上海美志医药科技有限公司 | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| US20110005947A1 (en) * | 2009-05-06 | 2011-01-13 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011140338A1 (en) * | 2010-05-05 | 2011-11-10 | Gatekeeper Pharmaceuticals, Inc. | Compounds that modulate egfr activity and methods for treating or preventing conditions therewith |
| WO2012125603A1 (en) * | 2011-03-16 | 2012-09-20 | Cephalon, Inc. | Macrocyclic compounds as alk, fak and jak2 inhibitors |
| CN105085483B (en) * | 2015-06-04 | 2019-01-01 | 湖北生物医药产业技术研究院有限公司 | Kinase inhibitor and its application |
-
2015
- 2015-06-04 CN CN201510304880.6A patent/CN104987324B/en not_active Expired - Fee Related
- 2015-06-15 WO PCT/CN2015/081487 patent/WO2016192132A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090306067A1 (en) * | 2006-04-10 | 2009-12-10 | Harald Engelhardt | 2, 4-diaminopyrimidide derivates and their use for the treatment of cancer |
| US20110005947A1 (en) * | 2009-05-06 | 2011-01-13 | Portola Pharmaceuticals, Inc. | Inhibitors of jak |
| WO2013169401A1 (en) * | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| CN104230954A (en) * | 2013-06-08 | 2014-12-24 | 中国科学院上海药物研究所 | 2,4-diaminopyrimidine compounds and medical applications thereof |
Non-Patent Citations (1)
| Title |
|---|
| SONG, ZILAN等: ""Discovery of Novel,4-Diarylaminopyrimidine Analogues(DAAPalogues) Showing Potent Inhibitory Activities against Both Wild-type and Mutant ALK Kinases"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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|---|---|---|---|---|
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| US10695347B2 (en) | 2015-11-05 | 2020-06-30 | Hubei Bio-Pharmaceutical Industrial Technological Institute, Inc. | Pyrimidine derivative and use thereof |
| CN106699743A (en) * | 2015-11-05 | 2017-05-24 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
| CN106699743B (en) * | 2015-11-05 | 2020-06-12 | 湖北生物医药产业技术研究院有限公司 | Pyrimidine derivative and application thereof |
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| CN107235931B (en) * | 2017-07-11 | 2019-09-24 | 大连医科大学 | New pyrimidine anti-tumor compounds and preparation method thereof and purposes |
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| CN108047204A (en) * | 2018-01-08 | 2018-05-18 | 沈阳药科大学 | 2,4- diarylamino pyrimidine derivatives and its preparation method and application |
| CN110294750A (en) * | 2018-03-21 | 2019-10-01 | 密执安州立大学董事会 | 5,6- dihydro -11H- indoles as ALK inhibitor simultaneously [2,3-B] quinoline -11- ketone compound |
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| CN104987324B (en) | 2018-05-04 |
| WO2016192132A1 (en) | 2016-12-08 |
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