CN111617083A - Application of methoxy-substituted phenylamide aminopyrimidine derivative - Google Patents

Application of methoxy-substituted phenylamide aminopyrimidine derivative Download PDF

Info

Publication number
CN111617083A
CN111617083A CN201910152392.6A CN201910152392A CN111617083A CN 111617083 A CN111617083 A CN 111617083A CN 201910152392 A CN201910152392 A CN 201910152392A CN 111617083 A CN111617083 A CN 111617083A
Authority
CN
China
Prior art keywords
formula
substituted
alkyl
compound shown
aryl
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
CN201910152392.6A
Other languages
Chinese (zh)
Other versions
CN111617083B (en
Inventor
黄军海
王彩月
谭绍英
吕志良
李明
胡锦
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.)
Shanghai Xinshengyuan Pharmaceutical Co ltd
Shanghai Institute of Pharmaceutical Industry
Original Assignee
Shanghai Xinshengyuan Pharmaceutical Co ltd
Shanghai Institute of Pharmaceutical Industry
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 Shanghai Xinshengyuan Pharmaceutical Co ltd, Shanghai Institute of Pharmaceutical Industry filed Critical Shanghai Xinshengyuan Pharmaceutical Co ltd
Priority to CN201910152392.6A priority Critical patent/CN111617083B/en
Publication of CN111617083A publication Critical patent/CN111617083A/en
Application granted granted Critical
Publication of CN111617083B publication Critical patent/CN111617083B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F17/00—Metallocenes
    • C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System

Abstract

The invention discloses an application of methoxy-substituted phenylamide aminopyrimidine derivatives. The compound shown in the formula I or the pharmaceutically acceptable salt thereof can be used for preparing an EGFR inhibitor. The compound shown as the formula I or the pharmaceutically acceptable salt thereof has an inhibitory effect on EGFR, has small toxicity on normal cells, and has high patent medicineAnd (4) foreground.

Description

Application of methoxy-substituted phenylamide aminopyrimidine derivative
Technical Field
The invention relates to application of methoxyl substituted phenylamide aminopyrimidine derivatives.
Background
Specific cysteine (Cys797) residues exist near openings of ATP binding domains of EGFR receptor family, and cysteine residues at similar positions exist only in 11 kinases such as EGFR, HER2, HER4, Jak3, Blk, Lkb1, 95Bmx, Btk, Itk, Tec and Txk. The specific cysteine residue, unlike the glutamate or serine residues of other kinases, is nucleophilic and can undergo a michael addition reaction with an electrophilic michael acceptor group. The introduction of an electrophilic michael acceptor group into the inhibitor to react with nucleophilic Cys797 through michael addition irreversibly prevents the binding of the kinase to ATP, thus realizing irreversible selective inhibition of EGFR kinase and improving the action strength of the inhibitor.
Currently, EGFR inhibitors and the mainstream drugs developed by the EGFR inhibitors are designed based on the above mechanisms, such as the second generation EGFR inhibitor afatinib, the structural formula of which is shown in the specification
Figure BDA0001981863340000011
Also for example, the third generation EGFR inhibits oxitinib, which has the structural formula
Figure BDA0001981863340000012
However, second generation EGFR inhibitors have a deficiency in that they lack selectivity for EGFR mutant T790M and wild-type EGFR kinase. On the basis, the developed third-generation EGFR inhibitor oxitinib has good selectivity on T790M mutant and wild-type EGFR kinase. Therefore, the third generation EGFR inhibitor ocitiniHas received a lot of attention after coming into the market.
However, the allyl structure of the EGFR inhibitor also has the defect of certain toxicity to wild-type EGFR kinase, and the defect of drug resistance brought by the single main bond functional group is inevitable.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects that the existing EGFR inhibitor has certain toxicity and drug resistance to wild EGFR kinase in the prior art, and provides the application of the methoxy-substituted phenylamide aminopyrimidine derivative. The inhibitor has an inhibiting effect on EGFR, has small toxicity on normal cells, and has good selectivity on EGFR mutant strains.
The invention provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof, and an application of the compound in preparation of an EGFR inhibitor:
Figure BDA0001981863340000021
wherein R is
Figure BDA0001981863340000022
R1Is C1～10Alkyl, halogen substituted C1～10Alkyl radical, C3～10Cycloalkyl radical, C6～30Aryl radical, R1-1Substituted C6～30Aryl, 3-to 30-membered heteroaryl or
Figure BDA0001981863340000023
The heteroatoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the heteroatoms is 1,2 or 3; when the number of the hetero atoms is plural, the species of the hetero atoms are the same or different;
said halogen substituted C1～10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;
each R1-1Independently of one another, halogen, C1～10Alkyl radical, C1～10Alkoxy or
Figure BDA0001981863340000024
The R is1-11,2, 3 or 4; when said R is1-1When plural, R is1-1The same or different;
the R is1-1-1aAnd R1-1-1bIndependently is C1～4An alkyl group;
R2is C6～30Aryl or R2-1Substituted C6～30An aryl group;
each R2-1Independently of one another, halogen, C1～10Alkyl or C1～10An alkoxy group; the R is2-1Is 1 or more; when said R is2-1When there are plural, R is2-1The same or different.
Wherein, the pharmaceutically acceptable salt of the compound shown in formula I can be a salt which is conventional in the field, preferably a methanesulfonate, ethanesulfonate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, preferably a methanesulfonate.
In the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10C in alkyl1～10The alkyl group may be C1～6Alkyl, preferably C1～3An alkyl group. Said C is1～3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably ethyl.
In the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10The halogen in the alkyl group may be F, Cl, Br or I, preferably Cl.
In the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10Halogen substitution in alkyl groupsThe number of (A) may be1 or more, preferably 1.
In the compound shown in the formula I, when the halogen is substituted C1～10When the alkyl group has a chiral center, the halogen is substituted C1～10The steric configuration of the alkyl group may be R-type.
In the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10Alkyl chloride substituted C1～3Alkyl, more preferably
Figure BDA0001981863340000031
Further preferred is
Figure BDA0001981863340000032
In the compound shown in the formula I, when R is1Is C3～10When a cycloalkyl group is present, C is3～10Cycloalkyl radicals may be C3～6A cycloalkyl group. Said C is3～6Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
In the compound shown in the formula I, when R is1Is R1-1Substituted C6～30When aryl is said to R1-1Substituted C6～30C in aryl6～30Aryl may be C6～20Aryl, preferably C6～14And (4) an aryl group. Said C is6～14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
In the compound shown in the formula I, when R is1Is R1-1Substituted C6～30When aryl is said to R1-1The number of (a) may be1, 2 or 3.
In the compound shown in the formula I, when R is1Is R1-1Substituted C6～30When aryl is said to R1-1Substituted C6～30Aryl may be "substituted by 1,2 or 3 times", halogen or
Figure BDA0001981863340000033
"substituted phenyl radical, further preferred
Figure BDA0001981863340000034
In the compound shown in the formula I, when R is1In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group.
In the compound shown in the formula I, when R is1In the case of a 3-to 30-membered heteroaryl group, the heteroatom in the 3-to 30-membered heteroaryl group may be N and/or O, preferably N.
In the compound shown in the formula I, when R is1In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group may be1 or 2, preferably 1.
In the compound shown in the formula I, when R is1In the case of the 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "3-to 10-membered heteroaryl group in which the number of hetero atoms is 1 or 2", preferably a "3-to 6-membered heteroaryl group in which the number of hetero atoms is 1", and more preferably a pyrrolyl group.
In the compound shown in the formula I, when R is1-1When halogen, the halogen may be F, Cl, Br or I, preferably F, Cl or Br.
In the compound shown in the formula I, when R is1-1Is C1～10At alkoxy, the C1～10Alkoxy may be C1～6Alkoxy, preferably C1～3An alkoxy group. Said C is1～3The alkoxy group may be methoxy, ethoxy, n-propoxy or isopropoxy, with methoxy being preferred.
In the compound shown in the formula I, when R is1-1-1aAnd R1-1-1bIndependently is C1～4When alkyl, said C1～4The alkyl group independently may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
In the compound shown in the formula I, when R is2Is R2-1Substituted C6～30When aryl is said to R2-1Substituted byC6～30C in aryl6～30Aryl may be C6～20Aryl, preferably C6～14And (4) an aryl group. Said C is6～14Aryl can be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
In the compound shown in the formula I, when R is2-1Is C1～10When alkyl, said C1～10The alkyl group may be C1～6Alkyl, preferably C1～3An alkyl group. Said C is1～3The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl.
In one embodiment, in the application, in the compound shown as the formula I, R is
Figure BDA0001981863340000041
In one embodiment, in the application, in the compound shown in the formula I, when R is
Figure BDA0001981863340000042
When R is in the above-mentioned range1Is halogen substituted C1～10Alkyl radical, C3～10Cycloalkyl radical, R1-1Substituted C6～30Aryl, 3-to 30-membered heteroaryl or
Figure BDA0001981863340000043
In one embodiment, in the application, in the compound shown in the formula I, when R is
Figure BDA0001981863340000044
When R is in the above-mentioned range1Is halogen substituted C1～10An alkyl group.
In a certain embodiment, in the application, in the compound shown in the formula I, when R is
Figure BDA0001981863340000051
R1Is R1-1Substituted C6～30When aryl is said each R1-1Independently of one another, halogen, C1～10Alkyl or
Figure BDA0001981863340000052
In a certain embodiment, in the application, in the compound shown in the formula I, when R is
Figure BDA0001981863340000053
When R is in the above-mentioned range2Is R2-1Substituted C6～30And (4) an aryl group.
In a certain embodiment, in the application, in the compound shown in the formula I, when R is
Figure BDA0001981863340000054
R2Is R2-1Substituted C6～30When aryl is said each R2-1Is C1～10An alkyl group.
In one embodiment, in the application, in the compound shown as the formula I, R is1Is halogen substituted C1～10Alkyl radical, C3～10Cycloalkyl radical, R1-1Substituted C6～30Aryl, 3-to 30-membered heteroaryl or
Figure BDA0001981863340000055
R2Is R2-1Substituted C6～30And (4) an aryl group.
In one embodiment, in the application, in the compound shown as the formula I, R is1Is halogen substituted C1～10An alkyl group; r2Is R2-1Substituted C6～30And (4) an aryl group.
In the application, the compound shown in the formula I or the pharmaceutically acceptable salt thereof is preferably any one of the following compounds:
Figure BDA0001981863340000056
Figure BDA0001981863340000061
the application can also further comprise a preparation method of the pharmaceutically acceptable salt of the compound shown as the formula I, which is a method 1, a method 2 or a method 3:
the method comprises the following steps: the method comprises the following steps of carrying out condensation reaction of a compound shown in a formula II and a compound shown in a formula III in an organic solvent under the action of a condensing agent and an alkaline reagent to obtain a compound shown in a formula I;
Figure BDA0001981863340000071
the method 2 comprises the following steps: the method comprises the following steps of carrying out acylation reaction on a compound shown in a formula II and a compound shown in a formula IV in an organic solvent in the presence of an acid binding agent to obtain a compound shown in a formula I;
Figure BDA0001981863340000072
the method 3 comprises the following steps: the method comprises the following steps of reacting a compound shown as a formula I with acid in a solvent to obtain a salt of the compound shown as the formula I;
wherein R in the method 1, the method 2 and the method 3 is the same as the above.
In method 1, the conditions and operation of the condensation reaction may be those conventional in the art.
In method 1, the condensing agent may be a condensing agent conventional in this reaction in the art, preferably 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), Dicyclohexylcarbodiimide (DCC) or Carbonyldiimidazole (CDI), such as HATU.
In the method 1, the molar ratio of the condensing agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 2.0, for example 1.5.
In method 1, the basic reagent may be a reagent conventional in the art, preferably Triethylamine (TEA) and/or N, N-Diethylisopropylamine (DIEA), such as TEA.
In the method 1, the molar ratio of the alkaline agent to the compound II can be a molar ratio which is conventional in the art for this reaction, and is preferably 1.0 to 5.0, for example 3.0.
In the method 1, the molar ratio of the compound III to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.
In the method 1, the organic solvent may be an organic solvent that is conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.
In the process 1, the compound III may be
Figure BDA0001981863340000081
Figure BDA0001981863340000082
In method 1, the condensation reaction may be at a temperature conventional in the art for such reactions, preferably 10-40 deg.C, for example 25 deg.C.
In method 1, the progress of the condensation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 3 to 10 hours, for example 5 hours.
In the method 1, after the condensation reaction is finished, the method may further include a post-treatment step: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.
In method 2, the conditions and operation of the acylation reaction may be those conventional in the art for such reactions.
In the method 2, the acid-binding agent can be a reagent conventional in the art, and is preferably an organic weak base. The weak organic base may be one or more of pyridine, Triethylamine (TEA) and N, N-Diethylisopropylamine (DIEA), such as TEA.
In the method 2, the molar ratio of the acid-binding agent to the compound II may be a molar ratio conventional in this reaction in the art, and is preferably 1.0-5.0, for example 2.0.
In the method 2, the molar ratio of the compound IV to the compound II can be a molar ratio which is conventional in the reaction in the field, and is preferably 1.0-2.0, such as 1.0.
In method 2, the organic solvent may be an organic solvent conventional in this reaction in the art, preferably one or more of a halogenated hydrocarbon solvent, an amide solvent and a sulfone solvent, more preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent may be one or more of dichloromethane, dichloroethane and chloroform, preferably dichloromethane.
In method 2, the compound IV can be
Figure BDA0001981863340000091
Figure BDA0001981863340000092
In method 2, the temperature of the acylation reaction may be a temperature conventional in the art for such reactions, preferably 0 to 40 ℃, e.g. 25 ℃.
In method 2, the progress of the acylation reaction can be monitored by monitoring methods conventional in the art (e.g., TLC, LCMS), and the end point of the reaction is generally the disappearance or no longer reaction of compound II. The reaction time is preferably 1 to 5 hours, for example, 1 hour.
After the condensation reaction is finished, the method can further comprise the following post-treatment steps: and (3) washing, drying, concentrating and carrying out column chromatography on the reaction solution after the reaction is finished.
In the method 3, the salt of the compound shown in the formula I can be prepared according to the conventional method and conditions of salt forming reaction in the field.
In method 3, the acid may be an organic acid or an inorganic acid capable of salt formation, which is conventional in the art. The organic acid can be one or more of methanesulfonic acid, ethanesulfonic acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid and glutamic acid, and preferably methanesulfonic acid. The inorganic acid may be one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
In the method 3, the molar ratio of the acid to the compound represented by the formula I may be1 to 3, for example, 1.
In method 3, the solvent may be a ketone solvent, such as acetone.
In the method 3, the reaction temperature may be 10 to 60 ℃, for example, 50 ℃.
The invention also provides the application of the compound shown as the formula I or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to EGFR mediation.
In the above application, preferably, the medicament is used for preventing and/or treating diseases related to EGFR mutation mediation.
Wherein the disease can be ovarian cancer, cervical cancer, colorectal cancer, breast cancer, membrane adenocarcinoma, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, Acute Myeloid Leukemia (AML), multiple myeloma, melanoma, or mesothelioma; preferably lung cancer, and more preferably non-small cell lung cancer.
The invention also provides a pharmaceutical composition, which comprises the compound shown as the formula I or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The pharmaceutical composition can also consist of the compound shown as the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In the present invention, the pharmaceutically acceptable carrier may be a carrier conventional in the art, including one or more of a lubricant, a binder, a filler and a disintegrant. The lubricant is selected from one or more of magnesium stearate, aerosil, silicon dioxide and talcum powder; the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, starch and crospovidone; the binder is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and methyl cellulose; the filler is selected from one or more of lactose, pregelatinized starch and microcrystalline cellulose.
In the present invention, the amount of the pharmaceutically acceptable carrier is not particularly limited as long as it meets the requirements of a formulation which is conventional in the art.
In the invention, the pharmaceutical composition can be prepared into various dosage forms, such as tablets, capsules, pills, powder, emulsion, granules, suppositories, injections and the like.
In the present invention, the term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to occur in a subject who may be exposed to a disease causing agent or predisposing disease prior to the onset of the disease).
In the invention: the term "R-S configuration" is the term used to designate the R-S system nomenclature in the nomenclature of chiral C. The specific nomenclature of the R-S system is as follows: when a, b, c, d attached to the central carbon atom are different groups, the molecule is chiral. Assuming that the four substituents in the molecule are arranged in the CIP order rule in the order a > b > c > d, if the smallest d group is placed at the position furthest from the viewer, the other three groups are viewed in a-b-c precedence order, with a → b → c being observed in a clockwise direction, the configuration of this carbon center is defined as R (latin recatus); otherwise, S (Latin Sinister) is identified.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and raw materials used in the invention are commercially available, wherein S-2-chloropropionic acid is purchased from Annaiji (batch number: BE170142), the purity is 98%, and the specific rotation degree is-13.5 degrees; r-2-chloropropionic acid was purchased from Annaiji (batch No.: EE040098) and had a purity of 98% and a specific rotation of +13.4 °.
The positive progress effects of the invention are as follows: the methoxy-substituted phenylamide aminopyrimidine derivative has low toxicity to normal cells and good selectivity and activity to EGFR mutant strains.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-N, N-dimethylamino) benzamide
Figure BDA0001981863340000111
The compound N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (1.0g,2.24mmol,1eq), 3- (N, N-dimethylamino) benzoic acid (445mg, 2.69mmol, 1.2eq) and HATU (1.28g, 3.37mmol,1.5eq) were dissolved in dichloromethane (20ml), DIPEA (1.11ml,6.73mmol,3.0eq) was added, after stirring at room temperature for 4 hours, the reaction solution was washed with water three times, dried and concentrated, and the crude product was column chromatographed (dichloromethane/methanol) to give a product (1.33 g).
1H NMR(400MHz,DMSO-d6) 10.37(s,1H),9.30(s,1H),8.79(s,1H),8.36(d, J, 5.2Hz,1H),8.25(d, J, 8.0Hz,1H),7.91(s,1H),7.53(d, J, 8.0Hz,1H),7.36(t, J, 8.0Hz,1H),7.29-7.19(m,4H),7.19-7.12(m,1H),7.11(s,1H),6.95(dd, J, 8.0,2.4Hz,1H),3.94(s,3H),3.89(s,3H),3.00(m,2H),2.98(s,6H),2.73(s,3H),2.25(s,2H),2.02 (s, 6H); ES-API (m/z) calculated value C34H40N8O2[M+H]+, 593.3; theoretical value, 593.3.
Example 2 preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-chloro) benzamide
Figure BDA0001981863340000121
Preparation of N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-chloro) benzamide (1.31g) prepared in reference example 1
1H NMR(400MHz,DMSO-d6) 10.91(s,1H),9.22(s,1H),8.70(s,1H),8.35(d, J) 5.2Hz,1H),8.25(d, J) 8.0Hz,1H),7.96(s,1H),7.63(dd, J) 7.2,2.4Hz,1H),7.59(dd, J) 7.6,1.6Hz,1H),7.55-7.45(m,3H),7.28-7.21(m,2H),7.19-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.86(s,3H),2.89(s,2H),2.74(s,3H),2.16(s,2H),1.76 (s, 6H); ES-API (m/z) calculated value C32H34ClN7O2[M+H]+, 584.2; theoretical value, 584.2.
Example 3N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 6-difluoro) benzamide
Figure BDA0001981863340000122
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 6-difluoro) benzamide (1.29g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 11.12(s,1H),9.17(s,1H),8.64(1H),8.35(d, J) 5.2Hz,1H),8.24(d, J) 8.0Hz,1H),7.97(s,1H),7.65-7.55(m,1H),7.52(d, J) 8.0Hz,1H),7.33-7.21(m,4H),7.20-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.85(s,3H),2.89(t, J) 5.6Hz,2H),2.74, (s,3H),2.19(t, J) 5.6Hz,2H),1.81ppm (s, 6H); ES-API (m/z) calculated value C32H33F2N7O2[M+H]+, 586.3; theoretical value, 586.3.
Example 4N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (4-methoxy) benzamide
Figure BDA0001981863340000131
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (4-methoxy) benzamide (1.30g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.38(s,1H),9.25(s,1H),8.72(s,1H),8.35(d, J, 5.2Hz,1H),8.26(d, J, 8.0Hz,1H),8.00-7.90(m,3H),7.52(d, J, 8.0Hz,1H),7.25(d, J, 5.2Hz,1H),7.24-7.18(m,1H),7.16-7.07(m,4H),3.91(s,3H),3.88(s,3H),3.86(s,3H),3.99(t, J, 5.6Hz,2H),2.73(s,3H),2.22(t, J, 5.6Hz,2H),2.04 (s,6 ppm); ES-API (m/z) calculated value C33H37N7O3[M+H]+, 580.3; theoretical value, 580.3.
Example 5N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-bromo-3, 5-dimethoxy) benzamide
Figure BDA0001981863340000132
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-bromo-3, 5-dimethoxy) benzamide (1.55g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.79(s,1H),9.19(s,1H),8.72(s,1H),8.34(d, J, 5.2Hz,1H),8.24(d, J, 8.0Hz,1H),7.95(s,1H),7.52(d, J, 8.0Hz,1H),7.30-7.22(m,2H),7.20-7.12(m,1H),7.13-7.05(m,1H),6.78(d, J, 2.8Hz,1H),6.73(d, J, 2.8Hz,1H),3.89(s,3H),3.87(s,3H),3.86(s,3H),3.82(s,3H),2.90(t, J, 6.5, 2H), 2.84 (s,3H), 6.84 ppm); ES-API (m/z) calculated value C34H38BrN7O4[M+H]+,688.2,690.2; theoretical value, 688.2,690.2.
Example 6N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-ferrocenecarboxamide
Figure BDA0001981863340000141
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-ferrocenecarboxamide (1.48g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 9.63(s,1H),9.18(s,1H),8.80(s,1H),8.37(s,1H),8.23(d, J ═ 8.0Hz,1H),7.89(s,1H),7.53(d, J ═ 8.0Hz,1H),7.31-7.21(m,2H),7.17(t, J ═ 7.6Hz,1H),7.11(s,1H),4.88(t, J ═ 2.0, 2H),4.49(t, J ═ 2.0Hz,2H),4.25(s,5H),3.97(s,3H),3.88(s,3H),3.06(t, J ═ 5.6Hz,2H),2.75(s,3H),2.27(t, J ═ 2H), 6.6 (s,2H), 18.6 (s, 6H); ES-API (m/z) calculated value C36H39FeN7O2[M+H]+, 657.2; theoretical value, 657.2.
Example 7N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 4-dichloro) benzamide
Figure BDA0001981863340000142
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2, 4-dichloro) benzamide (1.39g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.94(s,1H),9.20(s,1H),8.68(s,1H),8.34(d, J, 5.2Hz,1H),8.25(d, J, 8.0Hz,1H),7.96(s,1H),7.78(d, J, 2.0Hz,1H),7.66(d, J, 8.0Hz,1H),7.59(dd, J, 8.0,2.0Hz,1H),7.51(d, J, 8.0Hz,1H),7.30-7.20(m,2H),7.19-7.12(m,1H),7.10(s,1H),3.87(s,3H),3.86(s,3H),2.89(t, 6.4, 2H), 3.17 (t, 6.17H), 4.17H, 4(s, 6H), 4.17H); ES-API (m/z) calculated value C32H33Cl2N7O2[M+H]+, 618.2; theoretical value, 618.2.
Example 8N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-pyrrolyl) carboxamide
Figure BDA0001981863340000151
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-pyrrolyl) carboxamide (1.18g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 11.34(s,1H),9.62(s,1H),9.16(s,1H),8.77(s,1H),8.34(d, J ═ 5.2Hz,1H),8.25(d, J ═ 8.0Hz,1H),7.88(s,1H),7.52(d, J ═ 8.0Hz,1H),7.48-7.32(m,1H),7.29-7.20(m,2H),7.20-7.12(m,1H),7.05(s,1H),6.87(dd, J ═ 2.4Hz,1H),6.58(dd, J ═ 2.4Hz,1H),3.94(s,3H),3.88(s,3H),3.05(m,2H),2.69(s, 2H), 3.40 (s,2H), 2.21H), 2(s, 2H); ES-API (m/z) calculated value C30H34N8O2[M+H]+, 539.3; theoretical value, 539.3.
Example 9N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3, 4-dimethoxy) benzamide
Figure BDA0001981863340000152
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3, 4-dimethoxy) benzamide (1.37g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.31(s,1H),9.23(s,1H),8.75(s,1H),8.35(d, J, 5.2Hz,1H),8.26(d, J, 8.0Hz,1H),7.91(s,3H),7.60(dd, J, 8.0Hz,1H), 7.57-7.49(m,2H),7.26(d, J, 5.2Hz,1H),7.24-7.19(m,1H),7.18-7.11(m,2H),7.10(s,1H),3.93(s,3H),3.89(s,3H),3.86(s,3H),3.85(s,3H),3.02(t, J, 6.0, 2H), 3.73 (s,2H), 6.73 (s,2H), 6.09 (s,2H), 2H, 6.09 (m, 2H); ES-API (m/z) calculated value C34H39N7O4[M+H]+, 610.3; theoretical value, 610.3.
Example 10N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-pyrrolyl) carboxamide
Figure BDA0001981863340000161
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-pyrrolyl) carboxamide (1.15g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 11.62(s,1H),9.76(s,1H),9.00(s,1H),8.50(s,1H),8.36-8.25(m,2H),7.94(s,1H),7.51(d, J ═ 8.0Hz,1H),7.24-7.15(m,2H),7.16-7.09(m,1H),7.06(s,1H),7.00-6.94(m,1H),6.88-6.79(m,1H),6.24-6.17(m,1H),3.87(s,3H),3.86(s,3H),3.01(t, J ═ 6.0Hz,2H),2.71(s,3H),2.33(t, J ═ 6.0, 2H),2.16 (s, 16 ppm); ES-API (m/z) calculated value C30H34N8O2[M+H]+, 539.3; theoretical value, 539.3.
Example 11N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropylcarboxamide
Figure BDA0001981863340000162
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropanecarboxamide (1.15g) was prepared according to example 1.
1H NMR(400MHz,DMSO-d6) 10.21(s,1H),9.05(s,1H),8.66(s,1H),8.32(d, J, 5.2Hz,1H),8.23(d, J, 8.0Hz,1H),7.85(s,1H),7.53(d, J, 8.0Hz,1H),7.29-7.23(m,1H),7.22(d, J, 5.2Hz,1H),7.20-7.13(m,1H),7.02(s,1H),3.90(s,3H),3.85(s,3H),2.92(t, J, 6.0Hz,2H),2.72(s,3H),2.37(t, J, 6.0, 2H),2.28(s,6H), 1.83-1H), 1.70(m, 0 ppm), 4.75-m, 1H); ES-API (m/z) calculated value C29H35N7O2[M+H]+, 514.3; theoretical value, 514.3.
Example 12N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-p-toluenesulphonic acid amine
Figure BDA0001981863340000171
The compound N1- (2- (dimethylamino) ethyl) -5-methoxy-N1-methyl-N4- (4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl) benzene-1, 2, 4-triamine (1.0g,2.24mmol,1eq), DIPEA (0.74ml,4.49mmol,2.0eq) were dissolved in dichloromethane, the corresponding p-toluenesulfonyl chloride (428mg,2.24mmol,1.0eq) was added dropwise, after stirring at room temperature for 1 hour, the reaction was washed twice with water, dried and concentrated, and the crude product was subjected to column chromatography (dichloromethane/methanol) to give a product (1.27 g).
1H NMR(400MHz,DMSO-d6) 12.03(s,1H),8.49(s,1H),8.37(s,1H),8.36-8.29(m,2H),7.89(s,1H),7.61-7.49(m,3H),7.30-7.21(m,4H),7.20-7.13(m,1H),6.87(s,1H),3.89(s,3H),3.78(s,3H),2.74(t, J ═ 5.2Hz,2H),2.33(s,6H),2.28(s,3H),2.24(t, J ═ 5.2Hz,2H),2.20ppm (s, 3H); ES-API (m/z) calculated value C32H37N7O3S[M+H]+, 600.3; theoretical value, 600.3.
Example 13N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((S) -2-chloro) propanamide
Figure BDA0001981863340000172
S-2-chloropropionic acid (365mg, 3.37mmol,1.5eq) was dissolved in 50mL DCM, starting material (1g, 2.24mol,1eq) was added, the mixture was stirred for 10min under ice-bath, EDCI (1.5g, 4.49mmol,2eq) and DMAP (110mg,0.90mmol,0.4eq) were added, and the mixture was stirred to room temperature under ice-bath and reacted overnight. After the reaction was complete, extraction was performed with water and DCM, and the organic phase was taken, spin dried and purified by silica gel chromatography to give the product (700 mg). .
1H NMR(400MHz,DMSO-d6)10.10(s,1H),8.95(s,1H),8.62(s,1H),8.33(d, J ═ 4.4Hz,1H),8.25(d, J ═ 6.4Hz,1H),7.91(s,1H),7.53(d, J ═ 6.8Hz,1H),7.27-7.23(m,2H),7.18(t, J ═ 6.4Hz,1H),7.02(s,1H),5.08(br,1H),3.93(s,3H),3.88(s,3H),3.10(brs,2H),2.67(s,3H),2.42(br,8H),1.64(d, J ═ 5.2Hz, 3H); ES-API (m/z) calculated value C28H34ClN7O2[M+H]+, 536.1; theoretical value, 536.1.
Example 14N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propanamide
Figure BDA0001981863340000181
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propionamide (665mg) was prepared according to example 13.
1H NMR(400MHz,DMSO-d6)10.16(s,1H),9.01(s,1H),8.64(s,1H),8.33(d, J ═ 5.2Hz,1H),8.23(d, J ═ 8.0Hz,1H),7.90(s,1H),7.53(d, J ═ 8.4Hz,1H),7.27-7.23(m,2H),7.17(t, J ═ 7.6Hz,1H),7.05(s,1H),4.85(br,1H),3.93(s,3H),3.87(s,3H),2.99(br, 2H),2.69(s,3H),2.35(br,2H),2.25(br,6H),1.66(d, J ═ 6.8, 3H); ES-API (m/z) calculated value C28H34ClN7O2[M+H]+, 536.1; theoretical value, 536.1.
Example 15N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((S) -2-chloro) propanamide methanesulfonate
Figure BDA0001981863340000182
The product from example 13 (535mg, 1.0mmol, 1eq) was dissolved in 5ml of acetone and gradually stirred to 50 ℃ and the prepared methanesulfonic acid solution (96mg, 1.0mol, 1eq, methanesulfonic acid in 96mg, 0.5ml of acetone) was added and reacted for about 3 h. After the reaction was completed, suction filtration and drying were carried out to obtain a product (86 mg).
1H NMR(400MHz,DMSO-d6) 9.98(s,1H),9.92(s,1H),8.75(s,1H),8.40(s,2H),8.24(s,2H),7.59(d, J ═ 8.2Hz,1H),7.38(d, J ═ 6.3Hz,1H),7.31(t, J ═ 7.5Hz,1H),7.23(t, J ═ 7.2Hz,1H),7.05(s,1H),5.32(t, J ═ 4.7Hz,1H),3.94(s,3H),3.87(s,3H), 3.33-3.30 (m,4H),2.79(s,6H),2.67(s,3H),2.32(s,3H),1.58(d, J ═ 6, 3 Hz); ES-API (m/z): calculated value, C29H38ClN7O5S[M-CH3SO3]+, 536.1; theoretical value, 536.1.
Example 16N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propanamide methanesulfonate
Figure BDA0001981863340000191
The product obtained in example 14 was prepared according to the preparation method of example 15 to give N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propionamide methanesulfonate (79 mg).
1H NMR(400MHz,DMSO-d6)10.17(s,1H),9.97(s,1H),8.75(s,1H),8.46(s,1H),8.4-8.1(br,3H),7.59(d, J ═ 8.1Hz,1H),7.38(d, J ═ 6.3Hz,1H),7.31(t, J ═ 7.5Hz,1H),7.24(t, J ═ 7.4Hz,1H),7.04(s,1H),5.41(q, J ═ 6.6Hz,1H),3.95(s,3H),3.88(s,3H),3.39-3.35(m,2H),3.35-3.31(m,2H),2.79(s,6H),2.68(s,3H),2.34(s,3H),1.59 (s,6H), 6.59 (d, 6H); ES-API (m/z): calculated value, C29H38ClN7O5S[M-CH3SO3]+, 536.1; theoretical value, 536.1.
Effects of the embodiment
1. Test method
Cells in logarithmic growth phase were seeded at 3-6 ten thousand per mL per well in 96-well culture plates in a volume of 100. mu.L per well, and the plates were then transferred to CO2In an incubator at 37 deg.C and 5% CO2And culturing for 24h under saturated humidity condition. Gradient dilutionAdding a test compound into a hole corresponding to a 96-well plate, incubating with cells, culturing and incubating for 72h in a cell culture box, adding 10 mu L of CCK8 reagent into each hole after the incubation is finished, then placing the cells in the culture box for incubation for 2-4 h, measuring an OD value at 450nm, calculating the survival rate of the drug on the cell growth according to the following formula, wherein the survival rate (%) is (OD dosing-OD blank)/(OD control-OD blank) × 100%, fitting to obtain an inhibition curve, and calculating the corresponding IC50See table 1 for details.
2. Primary reagent
CCK8 kit (Biyuntian), reference compound (AZD9291)
Figure BDA0001981863340000201
TABLE 1 test Compounds IC50Test results
Figure BDA0001981863340000202
Figure BDA0001981863340000211
TABLE 2 selectivity of test compounds HWB 14-17 for different cell lines
Figure BDA0001981863340000212
Remarking: h1975 in tables 1 and 2 is EGFR mutant non-small cell lung cancer cell; HCC827 is EGFR mutant non-small cell lung cancer cell; a431 is a tumor cell with high expression of normal EGFR; wi38 was normal cells.
As can be seen from Table 1, the compounds of the present application have inhibitory effects on EGFR-mutated H1975 and HCC827, and normal EGFR-overexpressed A431, and IC thereof50The values are all below 1000nM, and the toxicity to normal cell Wi38 is extremely low, and the IC is50The value can reach more than 10000nM, has better patent medicine prospect, especially represents the compound HWB17, the inhibiting activity to EGFR mutation H1975 and HCC827 is in the same order of magnitude as that of the marketed medicine AZD9291It is more selective for a431 of non-mutated EGFR.
As can be seen from table 2, the compounds of the present application have higher selectivity for EGFR mutant cancer cells than EGFR highly expressed cancer cells. In particular, compound HWB17 (example 16) was 107-fold selective for a431/H1975 and a431/HCC827 was 1337-fold more selective than AZD9291 (control, ocitinib) by 1-fold; HWB16 also showed comparable selectivity to AZD9291 (control drug, ocitinib) for EGFR-highly expressed and mutant cancer cells.

Claims (10)

1. The application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing an EGFR inhibitor is as follows:
Figure FDA0001981863330000011
wherein R is
Figure FDA0001981863330000012
R1Is C1～10Alkyl, halogen substituted C1～10Alkyl radical, C3～10Cycloalkyl radical, C6～30Aryl radical, R1-1Substituted C6～30Aryl, 3-to 30-membered heteroaryl or
Figure FDA0001981863330000013
The heteroatoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the heteroatoms is 1,2 or 3; when the number of the hetero atoms is plural, the species of the hetero atoms are the same or different;
said halogen substituted C1～10The number of halogen substitution in the alkyl group is 1 or more; when the number of the halogen substitution is plural, the halogens are independently the same or different;
each R1-1Independently of one another, halogen, C1～10Alkyl radical, C1～10Alkoxy or
Figure FDA0001981863330000014
The R is1-11,2, 3 or 4; when said R is1-1When plural, R is1-1The same or different;
the R is1-1-1aAnd R1-1-1bIndependently is C1～4An alkyl group;
R2is C6～30Aryl or R2-1Substituted C6～30An aryl group;
each R2-1Independently of one another, halogen, C1～10Alkyl or C1～10An alkoxy group; the R is2-1Is 1 or more; when said R is2-1When there are plural, R is2-1The same or different.
2. Use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a mesylate, esylate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate or phosphate salt, preferably a mesylate salt;
in the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10C in alkyl1～10Alkyl is C1～6Alkyl, preferably C1～3An alkyl group; more preferably methyl, ethyl, n-propyl or isopropyl, and still more preferably ethyl;
in the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10Halogen in the alkyl is F, Cl, Br or I, preferably Cl;
in the compound shown in the formula I, when R is1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10The number of halogen substitution in the alkyl group is 1 or more, preferably 1;
in the compound shown in the formula I, when the halogen is substituted C1～10When the alkyl group has a chiral center, the halogen is substituted C1～10The spatial configuration of the alkyl is R type;
in the compound shown in the formula I, when R is1Is C3～10When a cycloalkyl group is present, C is3～10Cycloalkyl being C3～6Cycloalkyl, further preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, further preferably cyclopropyl;
in the compound shown in the formula I, when R is1Is R1-1Substituted C6～30When aryl is said to R1-1Substituted C6～30C in aryl6～30Aryl is C6～20Aryl, preferably C6～14Aryl, more preferably phenyl, naphthyl, phenanthryl or anthryl, and still more preferably phenyl;
in the compound shown in the formula I, when R is1Is R1-1Substituted C6～30When aryl is said to R1-1The number of (a) is 1,2 or 3;
in the compound shown in the formula I, when R is1In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group is a 3-to 10-membered heteroaryl group, preferably a 3-to 6-membered heteroaryl group, and more preferably a 5-membered heteroaryl group;
in the compound shown in the formula I, when R is1In the case of 3-30-membered heteroaryl, the heteroatom in the 3-30-membered heteroaryl is N and/or O, preferably N;
in the compound shown in the formula I, when R is1In the case of a 3-to 30-membered heteroaryl group, the number of heteroatoms in the 3-to 30-membered heteroaryl group is 1 or 2, preferably 1;
in the compound shown in the formula I, when R is1-1When halogen, the halogen may be F, Cl, Br or I, preferably F, Cl or Br;
in the compound shown in the formula I, when R is1-1Is C1～10At alkoxy, the C1～10Alkoxy is C1～6Alkoxy, preferably C1～3Alkoxy, more preferably methoxy or ethoxyN-propoxy or isopropoxy, more preferably methoxy;
in the compound shown in the formula I, when R is1-1-1aAnd R1-1-1bIndependently is C1～4When alkyl, said C1～4Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl;
in the compound shown in the formula I, when R is2Is R2-1Substituted C6～30When aryl is said to R2-1Substituted C6～30C in aryl6～30Aryl is C6～20Aryl, preferably C6～14Aryl, more preferably phenyl, naphthyl, phenanthryl or anthryl, and still more preferably phenyl;
in the compound shown in the formula I, when R is2-1Is C1～10When alkyl, said C1～10Alkyl is C1～6Alkyl, preferably C1～3An alkyl group.
3. The use of claim 1, wherein in the compound of formula I, when R is
Figure FDA0001981863330000031
When R is in the above-mentioned range1Is halogen substituted C1～10Alkyl radical, C3～10Cycloalkyl radical, R1-1Substituted C6～30Aryl, 3-to 30-membered heteroaryl or
Figure FDA0001981863330000032
Preferably halogen-substituted C1～10An alkyl group;
in the compound shown in the formula I, when R is
Figure FDA0001981863330000033
When R is2Is R2-1Substituted C6～30And (4) an aryl group.
4. The method of claim 3Characterized in that in the compound shown in the formula I, when R is
Figure FDA0001981863330000034
R1Is R1-1Substituted C6～30When aryl is said each R1-1Independently of one another, halogen, C1～10Alkyl or
Figure FDA0001981863330000035
In the compound shown in the formula I, when R is
Figure FDA0001981863330000036
R2Is R2-1Substituted C6～30When aryl is said each R2-1Independently is C1～10An alkyl group.
5. The use of claim 1, wherein in the compound of formula I, when R is
Figure FDA0001981863330000037
R1Is halogen substituted C1～10When alkyl, said halogen being substituted by C1～10Alkyl chloride substituted C1～3Alkyl, more preferably
Figure FDA0001981863330000038
Further preferred is
Figure FDA0001981863330000039
In the compound shown in the formula I, when R is
Figure FDA00019818633300000310
R1Is R1-1Substituted C6～30When aryl is said to R1-1Substituted C6～30Aryl is "substituted by 1,2 or 3Halogen or
Figure FDA00019818633300000311
Substituted phenyl, further preferred
Figure FDA00019818633300000312
In the compound shown in the formula I, when R is
Figure FDA00019818633300000313
R1In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "3-to 10-membered heteroaryl group in which the number of heteroatoms is 1 or 2" and the number of heteroatoms is 1 "and 3-to 6-membered heteroaryl group, and a pyrrolyl group is more preferable;
in the compound shown in the formula I, when R is
Figure FDA0001981863330000041
R2Is R2-1Substituted C6～30When aryl is said to R2-1Is C1～10An alkyl group.
6. The use according to claim 1, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is any one of the following compounds:
Figure FDA0001981863330000042
Figure FDA0001981863330000051
7. the application of a compound shown as a formula I or a pharmaceutically acceptable salt thereof in preparing a medicament; the medicament is used for preventing and/or treating diseases related to EGFR mediation; the compound shown in the formula I or the pharmaceutically acceptable salt thereof is as described in any one of claims 1-6.
8. The use according to claim 7, wherein the medicament is for the prevention and/or treatment of diseases associated with EGFR mutation-mediated diseases.
9. The use of claim 8, wherein the disease is ovarian cancer, cervical cancer, colorectal cancer, breast cancer, membranous adenocarcinoma, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, or mesothelioma; preferably lung cancer, and more preferably non-small cell lung cancer.
10. A pharmaceutical composition, which comprises a compound shown as a formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the compound shown as the formula I or the pharmaceutically acceptable salt thereof is as claimed in any one of claims 1 to 6.
CN201910152392.6A 2019-02-28 2019-02-28 Application of methoxy substituted phenylamide aminopyrimidine derivative Active CN111617083B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910152392.6A CN111617083B (en) 2019-02-28 2019-02-28 Application of methoxy substituted phenylamide aminopyrimidine derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910152392.6A CN111617083B (en) 2019-02-28 2019-02-28 Application of methoxy substituted phenylamide aminopyrimidine derivative

Publications (2)

Publication Number Publication Date
CN111617083A true CN111617083A (en) 2020-09-04
CN111617083B CN111617083B (en) 2023-10-27

Family

ID=72254788

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910152392.6A Active CN111617083B (en) 2019-02-28 2019-02-28 Application of methoxy substituted phenylamide aminopyrimidine derivative

Country Status (1)

Country Link
CN (1) CN111617083B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112292378A (en) * 2019-05-22 2021-01-29 上海翰森生物医药科技有限公司 Indole derivative-containing inhibitor, preparation method and application thereof
CN113387935A (en) * 2021-07-23 2021-09-14 苏州雅深智慧科技有限公司 Compound for inhibiting triple-mutation epidermal growth factor receptor tyrosine kinase and application thereof
CN114805304A (en) * 2022-04-19 2022-07-29 辽宁大学 4-methoxyphenyl-1, 3-diamine derivatives containing 1-methyl-1H-indole structure and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106699736A (en) * 2015-11-17 2017-05-24 惠州信立泰药业有限公司 Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same
CN107793413A (en) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 Pyrimidine heterocyclic compound and its preparation method and application
CN108017620A (en) * 2016-10-31 2018-05-11 北京睿创康泰医药研究院有限公司 The methanesulfonic acid uncommon preparation method for Buddhist nun's process contaminants difficult to understand
US20190015413A1 (en) * 2015-12-31 2019-01-17 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Acrylanilide derivative, preparation method, and applications thereof in pharmacy

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106699736A (en) * 2015-11-17 2017-05-24 惠州信立泰药业有限公司 Crystal form gamma of compound A mesylate and pharmaceutical composition containing the same
US20190015413A1 (en) * 2015-12-31 2019-01-17 Ancureall Pharmaceutical (Shanghai) Co., Ltd. Acrylanilide derivative, preparation method, and applications thereof in pharmacy
CN107793413A (en) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 Pyrimidine heterocyclic compound and its preparation method and application
CN108017620A (en) * 2016-10-31 2018-05-11 北京睿创康泰医药研究院有限公司 The methanesulfonic acid uncommon preparation method for Buddhist nun's process contaminants difficult to understand

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112292378A (en) * 2019-05-22 2021-01-29 上海翰森生物医药科技有限公司 Indole derivative-containing inhibitor, preparation method and application thereof
CN112292378B (en) * 2019-05-22 2024-02-06 上海翰森生物医药科技有限公司 Indole derivative-containing inhibitor, preparation method and application thereof
CN113387935A (en) * 2021-07-23 2021-09-14 苏州雅深智慧科技有限公司 Compound for inhibiting triple-mutation epidermal growth factor receptor tyrosine kinase and application thereof
CN113387935B (en) * 2021-07-23 2022-06-10 苏州雅深智慧科技有限公司 Compound for inhibiting triple-mutation epidermal growth factor receptor tyrosine kinase and application thereof
CN114805304A (en) * 2022-04-19 2022-07-29 辽宁大学 4-methoxyphenyl-1, 3-diamine derivatives containing 1-methyl-1H-indole structure and application thereof

Also Published As

Publication number Publication date
CN111617083B (en) 2023-10-27

Similar Documents

Publication Publication Date Title
JP6889494B2 (en) Pharmaceutical salts, physical forms, and compositions of pyrrolopyrimidine kinase inhibitors, and methods of making them.
US11498922B2 (en) Pharmaceutical composition comprising N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenylacrylamide
JP7383652B2 (en) B-RAF Kinase Maleate Salt, Crystal Form, Preparation Method, and Use thereof
JP2023506308A (en) Heterocyclic compound and method for producing and using same
CN111617083B (en) Application of methoxy substituted phenylamide aminopyrimidine derivative
CN111620854A (en) 4-aminopyrimidine substituted phenylamide compound and preparation method thereof
JP2009514988A (en) Imatinib base and imatinib mesylate and methods for their preparation
JP2008519049A (en) Combination medicine of SRC kinase inhibitor and BCR-ABL inhibitor for the treatment of proliferative disease
EP3327014A1 (en) Egfr inhibitor and pharmaceutically acceptable salt and polymorph thereof, and use thereof
AU2004212067A1 (en) [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph
WO2019154252A1 (en) Substituted nicotinamide compound and pharmaceutical composition and use thereof
WO2021121146A1 (en) Crystal form a of aminopyrimidine mesylate compound, preparation method therefor, and application thereof
CN111848634B (en) Pyrimido [5,4-b ] pyridine compounds, optical isomers, preparation method and application thereof
ES2881960T3 (en) Protein kinase inhibitors
KR20220023982A (en) Novel tricyclic 5-HT2 antagonists
AU2018278284A1 (en) Carboxylic acid derivatives of pyridoquinazolines useful as protein kinase inhibitors
CN104788435A (en) I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase
CN115160298B (en) Tacrine-sulfonamide derivative and preparation method and application thereof
KR20170023003A (en) 5--n-5s-2--3-[4-56--4h-[124]-1-]-13--5--2- novel crystalline form of 5-chloro-n-5s-2-oxo-3-[4-56-dihydro-4h-[124]triazin-1-ylphenyl]-13-oxazolidin-5-ylmethylthiophene-2-carboxamide methanesulfonate and pharmaceutical composition containing same
CA3217088A1 (en) Crystalline forms of (s, e)-4-(dimethylamino)-n-(3-(4-(2-hydroxy-1-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin-5-yl)phenyl)but-2-enamide free base
CN114014804A (en) Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form thereof

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