CN106565612A - Diphenyl vinyl pyridine compound, composition and application thereof - Google Patents

Diphenyl vinyl pyridine compound, composition and application thereof Download PDF

Info

Publication number
CN106565612A
CN106565612A CN201610938467.XA CN201610938467A CN106565612A CN 106565612 A CN106565612 A CN 106565612A CN 201610938467 A CN201610938467 A CN 201610938467A CN 106565612 A CN106565612 A CN 106565612A
Authority
CN
China
Prior art keywords
phenyl
amine
compound
pharmaceutically acceptable
ethenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201610938467.XA
Other languages
Chinese (zh)
Other versions
CN106565612B (en
Inventor
马晓东
宋安然
王璐红
刘贺
张宝璟
王长远
孟强
舒晓宏
甄宇红
刘克辛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dalian Medical University
Original Assignee
Dalian Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dalian Medical University filed Critical Dalian Medical University
Priority to CN201610938467.XA priority Critical patent/CN106565612B/en
Publication of CN106565612A publication Critical patent/CN106565612A/en
Application granted granted Critical
Publication of CN106565612B publication Critical patent/CN106565612B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—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
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a diphenyl vinyl pyridine compound, a composition and application thereof. The diphenyl vinyl pyridine compound is specifically a compound shown by a general formula (I); and each substituent group of the general formula (I) is as shown by the definition in the specification. The invention also relates to application of the compound as shown in the general formula (I), pharmaceutically acceptable salts thereof or the pharmaceutical composition containing the same. The compound, the pharmaceutically acceptable salts thereof or the pharmaceutical composition containing the same is used for suppressing epidermal growth factor receptor (EGFR) protein tyrosine kinase to further treat tumor diseases, in particular, to treat non-small cell lung cancers, small cell lung cancers, squamous-cell carcinoma or pancreatic cancers.

Description

Distyryl pyrimidine compound, composition and application thereof
Technical Field
The invention relates to a distyryl pyrimidine compound, a composition and application thereof, belonging to the technical field of medicines.
Background
Protein Tyrosine Kinases (PTKs) regulate a series of physiological and biochemical processes such as growth, differentiation and apoptosis of cells by controlling signal transduction pathways of the cells. Receptor-type tyrosine kinases are a class of relatively large kinases that span the cell membrane, having a ligand-binding extracellular domain, a transmembrane domain, and an intracellular domain that functions as a kinase-phosphorylating specific tyrosine residues and thereby affecting cell proliferation. Abnormal expression of the kinase has been found in common human cancers (e.g., lung, breast, stomach, ovarian, lymphoma). Protein tyrosine kinase has become one of the important targets for research and development of antitumor drugs.
Epidermal growth factor receptor tyrosine kinase (EGFR) is one of the earliest discovered protein tyrosine kinases, the intracellular domain of EGFR has an ATP binding site, and an EGFR inhibitor can competitively bind with the ATP binding site, so as to inhibit the phosphorylation process of EGFR, block the conduction of downstream signals, and further inhibit the growth, differentiation and metastasis of tumor cells (Yun, et al. cancer Cell 2007,11, 217-227). The biochemical process of EGFR as an anti-tumor target has been elucidated, the crystal structure and active site thereof have been clarified, and the drugs gefitinib (gefitinib), erlotinib (erlotinib), afatinib (afatinib) and the like targeting this have been applied clinically, and with the intensive study of the structure and activity relationship of EGFR, many EGFR inhibitors having more excellent effects (EP 0566226, WO9961428, WO0051587, WO0375947, WO0132651, WO9633980, WO9630347, US7709479, US6716847, US6593333, US6251912, CN201080060451.4, CN201110191525.4 and the like) have been discovered. However, these drugs inevitably have a problem of poor resistance to drugs. The research shows that: the mutation of The amino acid from The790 to Met790 (T790M) is The major cause of resistance in this class of drugs. There are clinical case data showing that approximately 60% of patients have acquired resistance due to mutation at the T790M site. Therefore, the development of novel EGFR inhibitors with stronger drug resistance, less toxicity and stronger activity has very important practical value.
Osimetinib (AZD9291) is an orally irreversible, T790M mutation selective EGFR inhibitor, EGFR inhibitor deleted for Exon 19 in LoVo cellsL858R/T790MAnd EGFRWTIC of5011.44 and 493.8nM, respectively, were approved by the US FDA for marketing (WO 2013014448) at 2015 12 for treatment of EGFRT790MDrug-resistant lung cancer. Rociletinib (CO-1686, AVL-301) is another irreversibleOf (2) mutation-selective EGFRT790MInhibitors acting on EGFR in cell-free assaysT790MAnd EGFRWTK ofi21.5nM and 303.3nM, respectively, are currently in phase III studies (WO 2012061299). Others such as HM61713, EGF816, PF-06747775, Avitinib, ASP8273 are also novel inhibitors of egfr t entering clinical research (Ma et al, j.med.chem.,2016, DOI: 10.1021/acs.jmedchem.5b00840), referred to patents such as: US20120157426, US8563568B2, CN102740847, CN102083800, CN 102146076.
In view of the urgent need for cancer treatment, there is a need in the art to develop new drugs with better efficacy.
Disclosure of Invention
One of the purposes of the invention is to provide a distyryl pyrimidine compound or pharmaceutically acceptable salt thereof, wherein the distyryl pyrimidine compound has good antitumor activity.
The invention also aims to provide a pharmaceutical composition containing the distyryl pyrimidine compound or the pharmaceutically acceptable salt thereof.
The invention further aims to provide the distyryl pyrimidine compound or the pharmaceutically acceptable salt thereof, or the application of the composition.
To this end, in one aspect, the present invention provides a compound of formula (i) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (i) has the following structure:
R1selected from chlorine, fluorine, trifluoromethyl or nitro;
R2selected from hydrogen, methyl, methoxy or cyano; preferably, R2Selected from hydrogen;
(R3)nin each R3Independently selected from hydrogen, methyl, methoxy, hydroxy, fluoro, chloro or bromo;
n = an integer between 1 and 4; preferably, n =1 or 2;
x is selected from NH or O.
As a specific embodiment of the present invention, the compound represented by the general formula (I) of the present invention has the structure represented by I-1 to I-44:
the structural compound shown above is a distyryl pyrimidine compound. The screening of the anti-tumor activity shows that the compounds have stronger capacity of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells. As a molecule with novel structure, the compound has the potential of being developed into a novel high-efficiency EGFR inhibitor, and has great application value in treating related tumor diseases, particularly non-small cell lung cancer, squamous cell carcinoma or pancreatic cancer.
The structures represented by the foregoing I-1 to I-44 have the following names, respectively:
(i-1) N- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-2) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-3) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-4) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-5) N- [3- [ [ 5-chloro-2- [ [4- [2-3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-6) N- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-7) N- [3- [ [ 5-chloro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-8) N- [3- [ [ 5-chloro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-9) N- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-10) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-11) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-12) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-13) N- [3- [ [ 5-nitro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-14) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-15) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-16) N- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-17) O- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-18) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-19) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-20) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-21) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-22) O- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-23) O- [3- [ [ 5-chloro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-24) O- [3- [ [ 5-chloro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-25) O- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-26) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-27) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-28) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dihydroxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-29) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-30) O- [3- [ [ 5-fluoro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-31) O- [3- [ [ 5-fluoro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-32) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-33) O- [3- [ [ 5-nitro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-34) O- [3- [ [ 5-nitro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl;
(i-35) O- [3- [ [ 5-nitro-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-36) O- [3- [ [ 5-nitro-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-37) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-38) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-39) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (4-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-40) O- [3- [ [ 5-trifluoromethyl-2- [ [4- [2- (3-fluoro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-41) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl-3-methyl-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-42) O- [3- [ [ 5-chloro-2- [ [4- [2- (2-fluoro-4-chloro-1-phenyl-3-methoxy-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(i-43) N- [3- [ [ 5-fluoro-2- [ [4- [2- (4-fluoro-1-phenyl-3-cyano-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide;
(I-44) O- [3- [ [ 5-fluoro-2- [ [4- [2- (3-fluoro-1-phenyl-2-methyl-2-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide.
In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound represented by the general formula (i) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts, because of their potential use in medicine. The compounds of the present invention are bases, wherein the desired salt form can be prepared by suitable methods known in the art, including treatment of the free base with a mineral acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or treating the free base with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid (pyranosidyl 1 acid), such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and the like. Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propionate, oxalate, malonate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutyrates (phenylbutyrates), citrates, lactates, gamma-hydroxybutyrates, hydroxyacetates, tartrates, mandelates and sulfonates, such as xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonate and naphthalene-2-sulfonate.
The pharmaceutical compositions of the invention will generally contain one compound of the invention. However, in some embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In addition, the pharmaceutical compositions of the present invention may optionally further comprise one or more other pharmaceutically active compounds.
The invention also provides the distyryl pyrimidine compounds or pharmaceutically acceptable carriers thereof, and the pharmaceutical composition can inhibit the tumor proliferation by inhibiting EGFR (epidermal growth factor receptor) tyrosine kinase. In particular to the application of the compound in preparing a medicament for treating non-small cell lung cancer, squamous cell carcinoma or pancreatic cancer.
The invention provides an application of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition in preparation of an EGFR (epidermal growth factor receptor) protein tyrosine kinase inhibitor.
The invention provides a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof, or application of a pharmaceutical composition in preparing a medicament for treating tumors. Preferably, the tumor is selected from one or more of non-small cell lung cancer, squamous cell carcinoma and pancreatic cancer, further preferably non-small cell lung cancer or pancreatic cancer. More preferably, the use is primarily by inhibiting EGFR epidermal factor receptor protein tyrosine kinase.
Detailed Description
The present invention is further described and explained below in conjunction with specific examples, which are not intended to limit the scope of the present invention.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
EXAMPLE 1 preparation of target molecules
The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the silica-amine plate used in Thin Layer Chromatography (TLC) is 0.15-0.2 mm, and the thin layer chromatography separation and purification product is 0.4-0.5 mm.
The raw materials used in the present invention are mainly purchased from chemical reagents of national medicine group, Beijing coupled technology, Inc., Aladdin chemical reagents, Inc., Darriy Chemicals, etc.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The route adopted by the invention synthesizes the compound of the invention:
the synthetic route, reagent and condition of compound (I) are (a) acryloyl chloride and NaHCO3Acetonitrile, rt, 0.5h, 98%; (b) Fe-NH4Cl，EtOH-H2O (v: v =1:1), 50 ℃ to rt, 3h, 90%; (c)2, 4-dichloropyrimidine, diisopropylethylamine, 1, 4-dioxane, 60 ℃, 24h and 85 percent; (d) m-nitrophenol, K2CO3，DMF，rt，2h，97%；(e)Fe-NH4Cl，EtOH-H2O (v: v =1:1), 70 ℃, 2h, 90%; (a) acryloyl chloride, NaHCO3Acetonitrile, rt, 0.5h, 95%; (g) trifluoroacetic acid, 2-BuOH, 100 ℃, overnight, 61%. R1、R2And (R)3）nAs defined above.
Synthesis of Compound 2
Taking m-nitroaniline (5.525 g,40 mmol) and NaHCO3(5.04 g,60 mmol) in 20mL acetonitrile, slowly adding 1 (4.345 g,48 mmol), reacting at room temperature for 0.5h, cooling after the reaction is finished, adding 100mL water, precipitating off-white solid, filtering, drying to obtain white solid, and directly reacting in the next step without purification.
Synthesis of Compound 3
Take 2 (40 mmol) and NH4Cl (5.4 g,100 mmol) in 40mL EtOH-H2And (v: v =1:1), slowly adding Fe powder (4.48 g,80 mmol), heating to 50 ℃, reacting for 3 hours, filtering while the reaction is finished, washing filter residues with a small amount of DMF (dimethyl formamide), collecting filtrate, extracting the filtrate for 3-5 times by using DCM (DCM), combining organic phases, washing the organic phases with supersaturated salt water, taking the organic phases out, drying by anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain brown semisolid.
Synthesis of intermediate M4
Taking 2, 4-dichloro-5-R1Adding pyrimidine (32 mmol) into dioxane (10 mL), adding DIPEA (6.45 g,48 mmol) under stirring, dissolving c (5.185 g,32 mmol) in dioxane (10 mL), slowly adding into a reaction bottle, heating to 60 ℃ for reacting overnight, adding water after reaction, stirring, standing, precipitating, and filtering to obtain light yellow brown solid M4.
Synthesis of Compound 6
5 (40 mmol) was placed in a reaction flask, DMF (10 mL) was added and K was added with stirring2CO3(8.34 g,60 mmol), dissolving m-nitrophenol (40 mmol) in DMF (10 mL), slowly adding into a reaction bottle, reacting at normal temperature for 2h, adding 100mL of water after reaction, separating out off-white solid, filtering, drying to obtain white solid, and directly reacting in the next step without purification.
Synthesis of Compound 7
Take 6 (40 mmol) and NH4Cl (5.4 g,100 mmol) in 40mL EtOH-H2And (v: v =1:1), slowly adding Fe powder (4.48 g,80 mmol), heating to 70 ℃, reacting for 2 hours, filtering while the reaction is finished, washing filter residues with a small amount of DMF (dimethyl formamide), collecting filtrate, extracting the filtrate with ethyl acetate for 3-5 times, combining organic phases, washing with supersaturated salt solution, taking the organic phase, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain the product which is not purified and directly reacted in the next step.
Synthesis of intermediate M8
7 (36 mmol) was placed in a reaction flask, acetonitrile (20 mL) was added, NaHCO was added with stirring3(4.54 g,54 mmol), slowly dripping acryloyl chloride (45 mmol) into a reaction bottle, reacting at normal temperature for 0.5h, adding water, stirring after the reaction is finished, standing, precipitating, and filtering to obtain a solid M8.
Synthesis of object (I)
Dissolving M4 or M8 (2 mmol) and substituted stilbene arylamine (2 mmol) in 10mL 2-butanol respectively, slowly dropwise adding 5 drops of trifluoroacetic acid, heating to 100 ℃, refluxing and reacting overnight, cooling after the reaction is finished, pouring into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, washing with water, drying, and performing silica gel column chromatography separation to obtain the solid (I).
The target molecule was synthesized according to the above method, and the physicochemical data of the synthesized target molecule were as follows:
(I-1) N- [3- [ [ 5-chloro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):2.26(s,3H),2.36(s,3H),6.25-6.30(m,1H),5.70-5.73(m,1H),6.22-6.27(m,1H),6.42-6.49(m,1H),6.89-6.93(d,J=16,1H),7.00(s,2H),7.13-7.17(d,J=16,1H),7.33-7.35(m,4H),7.48-7.50(d,J=8,1H),7.55-7.56(d,J=4,1H),7.62-7.64（d,J=8,2H),7.89(s,1H),8.17(s,1H),9.01(s,1H),9.49(s,1H),10.21(s,1H).MS(ESI),m/z:496[M+H]+.
(I-2) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):2.28(s,6H),5.73-5.76(m,1H),6.25-6.30(m,1H),6.50-6.57(m,1H),6.89(s,1H),6.96-7.11(m,2H),7.17(s,1H),7.35-7.41(m,3H),7.53-7.41(m,4H),7.98(s,1H),8.30(s,1H),9.73(s,1H),10.18(s,1H),10.46(s,1H).MS(ESI),m/z:496[M+H]+.
(I-3) N- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):3.78(s,6H),5.72-5.75(m,1H),6.25-6.19(m,1H),6.39(s,1H),6.47-6.53(m,1H),6.72-6.73(d,1H,J=4),6.94-7.15(m,2H),7.28-7.38(m,4H),7.59-7.64(m,3H),7.93(s,1H),8.20(s,1H),9.19(s,1H),9.68(s,1H),10.33(s,1H).MS(ESI),m/z:528[M+H]+.
(I-5) N- [3- [ [ 5-chloro-2- [ [4- [2-3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):5.72-5.75(m,1H),6.23-6.28(m,1H),6.43-6.50(m,1H),6.99-7.30(d,1H,J=16),7.30(s,1H),7.34-7.40(m,4H),7.44(s,1H),7.57-7.62(m,5H),7.88(s,1H),8.23(s,1H),9.39(s,1H),9.79(s,1H),10.27(s,1H).MS(ESI),m/z:536[M+H]+.
(I-9) N- [3- [ [ 5-fluoro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):2.26(s,3H),2.36(s,3H),5.70-5.77(m,1H),6.23-6.29(m,1H),6.97-6.99(d,J=8,2H),7.15-7.19(d,J=16,1H),7.29-7.34(m,2H),7.40-7.42(m,4H),7.50-7.60(m,2H),7.76-7.78(d,J=8,2H),8.13-8.14(d,J=4,1H),9.46(s,1H),9.54(s,1H),10.52(s,1H),10.52(s,1H).MS(ESI),m/z:480[M+H]+.
(I-10) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):2.28(s,6H),5.73-5.76(m,1H),6.25-6.30(m,1H),6.45-6.52(m,1H),6.87(s,1H),6.93-7.10(m,2H),7.15(s,1H),7.31-7.39(m,3H),7.49-7.51(d,2H,J=8),7.69-7.71(d,2H,J=8),7.96(s,1H),8.13-8.14(d,1H,J=4),9.35(s,1H),9.49(s,1H),10.20(s,1H).MS(ESI),m/z:480[M+H]+.
(I-11) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dimethoxy-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):3.78(s,6H),5.72-5.75(m,1H),6.25-6.19(m,1H),6.39(s,1H),6.47-6.53(m,1H),6.72-6.73(d,1H,J=4),6.94-7.15(m,2H),7.28-7.38(m,4H),7.59-7.64(m,3H),7.93(s,1H),8.20(s,1H),9.19(s,1H),9.68(s,1H),10.33(s,1H).MS(ESI),m/z:512[M+H]+.
(I-12) N- [3- [ [ 5-fluoro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):5.73-5.76(d,1H,J=12),6.24-6.29(d,1H,J=20),6.46-6.53(m,1H),7.03-7.07(d,1H,J=16),7.33-7.37(m,2H),7.44-7.46(d,4H,J=8),7.50-7.52(d,1H,J=8),7.60-7.63(d,4H,J=12),7.99(s,1H),8.23-8.24(d,1H,J=4),9.90(s,1H),10.19(s,1H),10.29(s,1H).MS(ESI),m/z:520[M+H]+.
I-13N- [3- [ [ 5-nitro-2- [ [4- [2- (2, 4-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):2.26(s,3H),2.37(s,3H),5.69-5.72(d,1H,J=12),6.21-6.25(d,1H,J=16),7.00-7.02(d,1H,J=8),7.17-7.25(m,2H),7.28-7.37(m,4H),7.39-7.42(m,1H),7.50-7.58(m,3H),7.70-7.72(d,1H,J=8),7.87(s,1H),9.10(s,1H),10.39(s,1H),10.44(s,1H),10.56(s,1H).MS(ESI),m/z:507[M+H]+.
(I-18) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dimethyl-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenoyl
1H NMR(DMSO-d6):2.28(s,6H),5.76-5.79(d,1H,J=12),6.26-6.30(d,1H,J=16),6.43-6.50(m,1H),6.87-7.08(m,4H),7.16(s,2H),7.25-7.27(d,2H,J=8),7.40-7.51(m,3H),7.65-7.69(m,2H),8.05(s,1H),9.90(s,1H),10.46(s,1H).MS(ESI),m/z:497[M+H]+.
(I-21) O- [3- [ [ 5-chloro-2- [ [4- [2- (3, 5-dichloro-1-phenyl) ethenyl ] phenyl ] amine ] -4-pyrimidinyl ] amine ] phenyl ] -2-propenamide
1H NMR(DMSO-d6):5.77-5.80(m,1H),6.25-6.30(m,1H),6.43-6.50(m,2H),6.98-7.06(m,2H),7.29-7.33(m,2H),7.42-7.53(m,4H),7.62-7.63(d,1H,J=4),7.66-7.70(m,1H),7.76(s,1H),8.51(s,1H),8.83(s,1H),9.96(s,1H),10.48(s,1H).MS(ESI),m/z:537[M+H]+.
Method for salifying target molecule
The preparation method of the organic acid salt comprises the following steps: dissolving a target molecule (1 mmol) in 10mL of anhydrous methanol, slowly dropwise adding a 5mL of anhydrous methanol solution of organic acid (1 mmol) in ice bath, stirring for 30 minutes at the temperature after dropwise adding, and then evaporating methanol at normal temperature to obtain the organic acid salt of the target molecule. By the method, hydrochloride (I-1-1), hydrobromide (I-1-2), sulfate (I-1-3) and hydrobromide (I-1-4) of the compound I-1 are prepared;
the preparation method of the inorganic acid salt comprises the following steps: dissolving a target molecule (1 mmol) in 10mL of anhydrous methanol, slowly dropwise adding 5mL of dry ether of inorganic acid (1 mmol) in ice bath, stirring for 30 minutes at the temperature after dropwise adding, and then evaporating the solvent at normal temperature to obtain the inorganic acid salt of the target molecule. By this method, maleate salt (I-1-5), succinate salt (I-1-6) and fumarate salt (I-1-7) of compound I-1 were prepared.
Preparation of a mixture of target molecules
And (3) putting the two target molecules with equal molar weight (1 mmol) into anhydrous methanol (5 mL), stirring for 10 minutes at room temperature, and evaporating the solvent at room temperature to obtain a mixture of the target molecules. Three mixtures of (I-1) - (I-3), (I-2) - (I-9), (I-9) - (I-10) were prepared by this method.
Example 2 evaluation of biological Activity of target molecule
1. Method for testing in vitro inhibitory activity of receptor tyrosine kinase
Preparation of kinase assay buffer
First, a Kinase Detection Buffer (Kinase Detection Buffer) was dissolved at room temperature, and the presence or absence of a precipitate was observed.
② if precipitation occurs, incubation (Kinase Detection Buffer) at 37 ℃ for 15 minutes and shaking frequently dissolves the precipitation. Alternatively, the supernatant was carefully aspirated to remove the precipitate.
Preparation of kinase assay reagent
First, the Kinase Detection Buffer (Kinase Detection Buffer) and (KinaseDetection Substrate) were equilibrated at room temperature before use.
Secondly, pouring all the Kinase Detection Buffer solution (Kinase Detection Buffer) into a brown bottle filled with a Kinase Detection Substrate (Kinase Detection Substrate) to dissolve the freeze-dried powder Substrate, thus preparing the Kinase Detection reagent.
③ lightly shaking, whirling or reversing the mixture to be mixed evenly to become a homogeneous solution, and the substrate should be dissolved within 1 minute.
And fourthly, immediately using the kinase detection reagent after the preparation, or subpackaging the reagent at-20 ℃, wherein the activity of the circulating signal is not lost after the prepared reagent is frozen and thawed for several times.
Standard Curve for conversion of ATP to ADP was generated
The Ultra PureATP and ADP provided by the kit are diluted by kinase reaction buffer solution (kinase reaction buffer) to prepare 900 mu L of 50 mu M ATP and 500 mu L of 50 mu M ADP.
② mixing the prepared 50 μ M ATP and 50 μ M ADP solution in the previous step in 384-well plate A1-A12 according to the table 1, simulating the concentration of ATP and ADP of each conversion percentage, and mixing well.
TABLE 1 preparation of 50. mu.M series of ATP + ADP standards
Number of holes A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 A12
50μM ADP(μL) 100 80 60 40 20 10 5 4 3 2 1 0
50μM ATP(μL) 0 20 40 60 80 90 95 96 97 98 99 100
③ mu.L of ADP-Glo was added per wellTMReagents to terminate the kinase reaction. Incubate at room temperature for 40 minutes.
Add 10 mul Kinase Detection Reagent (Kinase Detection Reagent) to each well to convert ADP to ATP and introduce luciferase and luciferin to detect ATP.
And fifthly, incubating for 30-60 minutes at room temperature, measuring fluorescence by using a multifunctional microplate reader and recording the fluorescence value.
Sixthly, drawing a standard curve for converting ATP into ADP.
Determination of IC of kinase inhibitors50Value of
Firstly, preparing a kinase reaction buffer (kinase reaction buffer), 50 ng/. mu.L of kinase, 0.5. mu.g/. mu.L of substrate and 125. mu.MATP according to the instructions of a promega kit.
② add 3. mu.L of kinase reaction buffer, 2. mu.L of 0.5. mu.g/. mu.L substrate and 125. mu.M ATP to the enzyme-free control well. mu.L of kinase reaction buffer (kinase reaction buffer), 2. mu.L of 50 ng/. mu.L of kinase, 2. mu.L of 0.5. mu.g/. mu.L of substrate and 125. mu.M ATP were added to the negative control wells. mu.L of the test drug, 2. mu.L of 50 ng/. mu.L of kinase, 2. mu.L of 0.5. mu.g/. mu.L of substrate and 125. mu.M ATP were added to the test wells.
③ mix the plate and incubate for 60 minutes.
④ mu.L of ADP-Glo was added per wellTMReagents to terminate the kinase reaction. Incubate at room temperature for 40 minutes.
Fifthly, adding 10 mul of Kinase Detection Reagent (Kinase Detection Reagent) into each hole to convert ADP into ATP, and introducing luciferase and luciferin to detect ATP. Incubate at room temperature for 30-60 minutes, measure fluorescence with a multifunctional microplate reader and record the fluorescence value.
Analysis of results. As shown in table 2.
2. Cell growth experiments (MTT assay)
Cell inoculation: collecting cells in logarithmic growth phase, adjusting cell suspension concentration, inoculating 7000 cells per well and 100 μ L per well volume to 96-well plate, each set of which is provided with 3 multiple wells (the marginal wells are filled with sterile PBS);
cell culture: after the cells are attached to the wall, the culture solution in a 96-well plate is poured out and spin-dried, a blank group and a control group are cultured by using a blank culture medium, an administration group is cultured by using a drug solution with the blank culture medium as a solvent, the temperature is 37 ℃, and the CO content is 5 percent2Continuously culturing in an incubator (culturing for different times according to experimental requirements);
color generation: adding 10 μ L MTT solution (5mg/mL) into three groups of cells after culturing for 72h, terminating the culture after 4h, adding 100 μ L triple solution into each well, and oscillating on a shaking table at low speed for 10min to fully dissolve crystals;
color comparison: the absorbance (OD) of each well was measured on an ELISA detector, the wavelength of 570nm was selected, and the absorbance of each well was measured by zeroing a blank well of cell-free, i.e., blank, culture medium. The experiment was repeated three times.
The results are recorded: cell growth inhibition rate = (control absorbance value-experimental absorbance value)/control absorbance value x 100%, cell proliferation rate = (experimental absorbance value/control absorbance value) × 100;
drawing a cell growth curve: the cell growth curve was plotted with time as abscissa and inhibition/proliferation rate as ordinate.
Inhibitor concentrations were plotted in GraphPad prism5.0 plotting software in GraphPad software to determine log [ inhibitor [ ]]Variable slope model estimation of IC versus response50。
The test results are shown in table 2, and the obtained compounds have activity effects in inhibiting EGFR tyrosine kinase and resisting tumor cell proliferation.
TABLE 2
H1975 (mutant lung cancer cell line, EGF)RT790M/L858R) A549 (lung cancer cell line, EGFR)WTThe mutation of/K-ras), A431 (squamous cell line of epidermal carcinoma, EGFRoverexpression) AsPC-1 (pancreatic cancer cell line, K-ras mutation).
The above biological activity results show that the molecules of the invention are against EGFR and EGFRT790MThe kinase has strong inhibiting effect, most compounds reach the activity level of nanomolar level, and more than half of the compounds have effective inhibiting concentration IC50The value is less than 15nmol, which is significantly better than Gefitinib and Erlotinib. The result of anti-cell proliferation activity reveals that most compounds have very effective inhibition effect on drug-resistant cells H1975 of lung cancer, wherein the compounds I-2, I-3 and I-10 obviously show unexpected activity superior to Gefitinib, which indicates that the molecules are further developed into the application of drugs for resisting non-small cell lung cancer; meanwhile, most compounds also show a certain inhibiting effect on pancreatic cancer cells AsPC-1, and particularly, the activities of I-2, I-9 and I-13 are obviously superior to those of Gefitinib and Erlotinib, indicating that the molecules have further application in the aspect of pancreatic cancer drugs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (9)

1. A compound of formula (i) or a pharmaceutically acceptable salt thereof, said compound of formula (i) having the structure:
wherein,
R1selected from chlorine, fluorine, trifluoromethyl or nitro;
R2selected from hydrogen, methyl, methoxy or cyano;
(R3)nin each R3Independently selected from hydrogen, methyl, methoxy, hydroxy, fluoro, chloro or bromo;
n is an integer between 1 and 4;
x is selected from NH or O.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2Selected from hydrogen.
3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the general formula (I) has a structure represented by I-1 to I-44:
4. a pharmaceutical composition comprising an effective amount of a compound of formula (i) as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound of formula (i) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 3, or a pharmaceutical composition as defined in claim 4, for the preparation of an EGFR epidermal factor receptor protein tyrosine kinase inhibitor.
6. Use of a compound of formula (i) as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 4, for the manufacture of a medicament for the treatment of a tumour.
7. Use according to claim 6, wherein the tumour is selected from one or more of squamous cell carcinoma, small cell undifferentiated carcinoma, large cell undifferentiated carcinoma and adenocarcinoma.
8. The use of claim 7, wherein the tumor is lung cancer or pancreatic cancer.
9. Use according to any one of claims 6 to 8, wherein the use is primarily by inhibiting EGFR epidermal factor receptor protein tyrosine kinase.
CN201610938467.XA 2016-10-25 2016-10-25 Diphenylethyllene pyrimidines, composition and application thereof Expired - Fee Related CN106565612B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610938467.XA CN106565612B (en) 2016-10-25 2016-10-25 Diphenylethyllene pyrimidines, composition and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610938467.XA CN106565612B (en) 2016-10-25 2016-10-25 Diphenylethyllene pyrimidines, composition and application thereof

Publications (2)

Publication Number Publication Date
CN106565612A true CN106565612A (en) 2017-04-19
CN106565612B CN106565612B (en) 2018-10-16

Family

ID=58536159

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610938467.XA Expired - Fee Related CN106565612B (en) 2016-10-25 2016-10-25 Diphenylethyllene pyrimidines, composition and application thereof

Country Status (1)

Country Link
CN (1) CN106565612B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111004215A (en) * 2019-12-22 2020-04-14 华北理工大学 2, 4-substituted pyrimidine derivatives, preparation method thereof and application thereof in preparing antitumor drugs
CN112891357A (en) * 2019-12-03 2021-06-04 大连医科大学 New use of pyrimidine heterocycles for treating fibrotic diseases
CN113816903A (en) * 2021-09-22 2021-12-21 蚌埠医学院 Tetrahydroisoquinoline stilbene compound and preparation method and application thereof
WO2024112746A1 (en) * 2022-11-22 2024-05-30 Denali Therapeutics Inc. Processes and intermediates for the preparation of a pyrimidine aminopyrazole compound

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102321031A (en) * 2011-07-15 2012-01-18 中国海洋大学 Polysubstituted 4, 6-distyryl pyrimidine compound and preparation method and application thereof
CN102947316A (en) * 2010-06-23 2013-02-27 韩美科学株式会社 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
CN103269704A (en) * 2010-11-01 2013-08-28 西建阿维拉米斯研究公司 Heterocyclic compounds and uses thereof
CN105481841A (en) * 2015-11-12 2016-04-13 上海开迈生物科技有限公司 Compounds possessing kinase inhibition activity, preparation method and uses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102947316A (en) * 2010-06-23 2013-02-27 韩美科学株式会社 Novel fused pyrimidine derivatives for inhibition of tyrosine kinase activity
CN103269704A (en) * 2010-11-01 2013-08-28 西建阿维拉米斯研究公司 Heterocyclic compounds and uses thereof
CN102321031A (en) * 2011-07-15 2012-01-18 中国海洋大学 Polysubstituted 4, 6-distyryl pyrimidine compound and preparation method and application thereof
CN105481841A (en) * 2015-11-12 2016-04-13 上海开迈生物科技有限公司 Compounds possessing kinase inhibition activity, preparation method and uses

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANNETTE O. WALTER等: "Discovery of a Mutant-Selective Covalent Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in NSCLC", 《CANCER DISCOVERY》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112891357A (en) * 2019-12-03 2021-06-04 大连医科大学 New use of pyrimidine heterocycles for treating fibrotic diseases
CN111004215A (en) * 2019-12-22 2020-04-14 华北理工大学 2, 4-substituted pyrimidine derivatives, preparation method thereof and application thereof in preparing antitumor drugs
CN111004215B (en) * 2019-12-22 2022-08-09 华北理工大学 2, 4-substituted pyrimidine derivatives, preparation method thereof and application thereof in preparing antitumor drugs
CN113816903A (en) * 2021-09-22 2021-12-21 蚌埠医学院 Tetrahydroisoquinoline stilbene compound and preparation method and application thereof
CN113816903B (en) * 2021-09-22 2023-11-14 蚌埠医学院 Tetrahydroisoquinoline stilbene compound and preparation method and application thereof
WO2024112746A1 (en) * 2022-11-22 2024-05-30 Denali Therapeutics Inc. Processes and intermediates for the preparation of a pyrimidine aminopyrazole compound

Also Published As

Publication number Publication date
CN106565612B (en) 2018-10-16

Similar Documents

Publication Publication Date Title
Liu et al. Design, synthesis and biological evaluation of novel thieno [3, 2-d] pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents
CN109983016B (en) Pyrimido [5,4-b ] indolizine or pyrimido [5,4-b ] pyridine compound, preparation method and application thereof
CN105968056A (en) Diarylpyrimidine compound, composition and application
CN112585119A (en) Substituted indoles and methods of use thereof
CN106565612B (en) Diphenylethyllene pyrimidines, composition and application thereof
CN102675286B (en) One class indazole compounds and preparation method thereof, purposes and pharmaceutical composition
KR101335746B1 (en) Disubstituted phthalazine hedgehog pathway antagonists
CN108191874A (en) A kind of C-Kit inhibitor and its application
CN113045582B (en) PARP-1/PI3K double-target inhibitor or pharmaceutically acceptable salt thereof, and preparation method and application thereof
CN106565614A (en) Diphenylaminopyrimidine compound, composition and application
CN107383004B (en) 2-amino imidazopyridine derivative and preparation and application thereof
Yu et al. Design, synthesis and antitumor activity of 4-aminoquinazoline derivatives targeting VEGFR-2 tyrosine kinase
CN115160309A (en) KRAS G12C Preparation and application of mutant protein heterocyclic inhibitor
CN103382182B (en) Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage
JP7101781B2 (en) Salt morphology as an Akt inhibitor and its crystalline morphology
CN108101926A (en) Pyrimido five-membered heterocycles containing quinolinone, preparation method and applications
US11236112B2 (en) Crystal form and salt form of TGF-βRI inhibitor and preparation method therefor
CN106243044A (en) Pyridine derivatives containing halo acrylamide side chain and preparation and application
CN115304603A (en) Preparation and application of quinazoline inhibitor
CN106749042A (en) Sulfoamido pyrimidines, composition and purposes
CN106565782B (en) Phosphoryl pyrimidines, composition and purposes
CN107235931A (en) New pyrimidine anti-tumor compounds and preparation method thereof and purposes
WO2014071824A1 (en) 4-quinazolinamine heterocyclic compound and use thereof
CN106632273A (en) Pyrimidine compound containing azole heterocycle, composition and applications of pyrimidine compound and combination
CN108047132A (en) Diphenylamines yl pyridines anti-tumor compounds and preparation method thereof and purposes

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20181016

Termination date: 20201025