CN111617083B - Application of methoxy substituted phenylamide aminopyrimidine derivative - Google Patents
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Abstract
The application discloses an application of methoxy substituted phenylamide aminopyrimidine derivatives. The compound shown in the formula I or pharmaceutically acceptable salt thereof can be used for preparing EGFR inhibitors. The compound shown in the formula I or the pharmaceutically acceptable salt thereof has an inhibiting effect on EGFR, has smaller toxicity on normal cells and has higher patent medicine prospect.
Description
Technical Field
The application relates to an application of methoxy substituted phenylamide aminopyrimidine derivatives.
Background
Specific cysteine (Cys 797) residues exist near the opening of the ATP binding domain of the EGFR receptor body family, with similarly located cysteine residues only present in 11 kinases such as EGFR, HER2, HER4, jak3, blk, lkb1, 95Bmx, btk, itk, tec and Txk. The specific cysteine residue, unlike glutamic acid or serine residues of other kinases, is nucleophilic and can undergo michael addition reaction with electrophilic michael acceptor groups. An electrophilic Michael acceptor group is introduced into the inhibitor so as to generate Michael addition reaction with nucleophilic Cys797, and irreversibly prevent the combination of kinase and ATP, thereby realizing irreversible selective inhibition of EGFR kinase and improving the action intensity of the inhibitor.
Currently EGFR inhibitors and the development of mainstream drugs are designed based on the above mechanism, for example, the second generation EGFR inhibitor afatinib, which has the structural formulaAlso for example, the third generation EGFR inhibits Ornitinib having the formula +.>However, second generation EGFR inhibitors are deficient in that they lack selectivity for EGFR mutant T790M and wild-type EGFR kinase. On the basis, the developed third-generation EGFR inhibitor, namely the Orditinib, has good selectivity on T790M mutant and wild EGFR kinase. Thus, the third generation EGFR inhibitor, octreotide, has received extensive attention after market.
However, the allyl structure in such EGFR inhibitors also potentially has some toxicity drawbacks for wild-type EGFR kinase, and the single main bond functional group that they function in inevitably leads to drug resistance drawbacks.
Disclosure of Invention
The application aims to solve the technical problems that the prior EGFR inhibitor has certain toxicity and drug resistance to wild EGFR kinase, and provides application of a methoxy substituted phenylamide aminopyrimidine derivative. The inhibitor has inhibiting effect on EGFR, has less toxicity on normal cells, and has better selectivity on EGFR mutant strains.
The application provides an application of a compound shown in a formula I or pharmaceutically acceptable salt thereof in preparation of an EGFR inhibitor, wherein the compound is shown in the formula I:
wherein R is
R 1 Is C 1～10 Alkyl, halogen substituted C 1～10 Alkyl, C 3～10 Cycloalkyl, C 6～30 Aryl, R 1-1 Substituted C 6～30 Aryl, 3-to 30-membered heteroaryl orThe hetero atoms in the 3-30 membered heteroaryl are N, O or S independently, and the number of the hetero atoms is 1,2 or 3; when the number of the hetero atoms is plural, the kinds of the hetero atoms are the same or different;
the halogen substituted C 1～10 The number of halogen substitutions in the alkyl group is 1 or more; when the number of halogen substitutions is a plurality of, the halogen is independently the same or different;
each R 1-1 Independently is halogen, C 1～10 Alkyl, C 1～10 Alkoxy orThe R is 1-1 1,2, 3 or 4; when said R is 1-1 In a plurality of cases, the R 1-1 The same or different;
the R is 1-1-1a And R is 1-1-1b Independently C 1～4 An alkyl group;
R 2 is C 6～30 Aryl or R 2-1 Substituted C 6～30 An aryl group;
each R 2-1 Independently is halogen, C 1～10 Alkyl or C 1～10 An alkoxy group; the R is 2-1 1 or more; when said R is 2-1 When there are a plurality of R 2-1 The same or different.
Wherein the pharmaceutically acceptable salt of the compound of formula I may be a salt conventional in the art, preferably mesylate, ethanesulfonate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate or phosphate, preferably mesylate.
In the compound shown in the formula I, when R 1 C substituted by halogen 1～10 In the case of alkyl, said halogen substituted C 1～10 C in alkyl 1～10 Alkyl can be C 1～6 Alkyl, preferably C 1～3 An alkyl group. The C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably ethyl.
In the compound shown in the formula I, when R 1 C substituted by halogen 1～10 In the case of alkyl, said halogen substituted C 1～10 Halogen in the alkyl group may be F, cl, br or I, with Cl being preferred.
In the compound shown in the formula I, when R 1 C substituted by halogen 1～10 In the case of alkyl, said halogen substituted C 1～10 The number of halogen substitutions in the alkyl group may be1 or more, preferably 1.
In the compound shown as the formula I, when the halogen is substituted C 1～10 When the alkyl group has a chiral center, the halogen substituted C 1～10 The steric configuration of the alkyl group may be R-type.
In the compound shown in the formula I, when R 1 C substituted by halogen 1～10 In the case of alkyl, said halogen substituted C 1～10 Alkyl chloride substituted C 1～3 Alkyl groups, more preferablyStill more preferably->
The saidIn the compound shown in the formula I, when R 1 Is C 3～10 In the case of cycloalkyl, the C 3～10 Cycloalkyl can be C 3～6 Cycloalkyl groups. The C is 3～6 Cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.
In the compound shown in the formula I, when R 1 Is R 1-1 Substituted C 6～30 In the case of aryl, said R 1-1 Substituted C 6～30 C in aryl group 6～30 Aryl may be C 6～20 Aryl, preferably C 6～14 Aryl groups. The C is 6～14 Aryl may be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
In the compound shown in the formula I, when R 1 Is R 1-1 Substituted C 6～30 In the case of aryl, said R 1-1 May be1, 2 or 3 in number.
In the compound shown in the formula I, when R 1 Is R 1-1 Substituted C 6～30 In the case of aryl, said R 1-1 Substituted C 6～30 Aryl groups may be "substituted with 1,2 or 3, halogen or"substituted phenyl group, further preferred
In the compound shown in the formula I, when R 1 In 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 1 In the case of a 3-to 30-membered heteroaryl, the heteroatom in the 3-to 30-membered heteroaryl may be N and/or O, preferably N.
In the compound shown in the formula I, when R 1 In 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.
The formula I is as shown inIn the compounds shown, when R 1 In the case of a 3-to 30-membered heteroaryl group, the 3-to 30-membered heteroaryl group may be a "heteroatom is N and/or O, the number is 1 or 2" 3-to 10-membered heteroaryl groups, preferably "heteroatom is N, the number is 1" 3-to 6-membered heteroaryl groups, and more preferably a pyrrolyl group.
In the compound shown in the formula I, when R 1-1 When 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 1-1 Is C 1～10 Alkoxy, the C 1～10 Alkoxy can be C 1～6 Alkoxy, preferably C 1～3 An alkoxy group. The C is 1～3 Alkoxy can be methoxy, ethoxy, n-propoxy or isopropoxy, preferably methoxy.
In the compound shown in the formula I, when R is 1-1-1a And R is 1-1-1b Independently C 1～4 When alkyl, the C 1～4 The alkyl groups 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 2 Is R 2-1 Substituted C 6～30 In the case of aryl, said R 2-1 Substituted C 6～30 C in aryl group 6～30 Aryl may be C 6～20 Aryl, preferably C 6～14 Aryl groups. The C is 6～14 Aryl may be phenyl, naphthyl, phenanthryl or anthracyl, preferably phenyl.
In the compound shown in the formula I, when R 2-1 Is C 1～10 When alkyl, the C 1～10 Alkyl can be C 1～6 Alkyl, preferably C 1～3 An alkyl group. The C is 1～3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.
In one embodiment, in the use, R is
In a certain implementationIn the application, in the compound shown as the formula I, when R isWhen the R is 1 C substituted by halogen 1～10 Alkyl, C 3～10 Cycloalkyl, R 1-1 Substituted C 6～30 Aryl, 3-to 30-membered heteroaryl or +.>
In one embodiment, in the use, when R isWhen the R is 1 C substituted by halogen 1～10 An alkyl group.
In one embodiment, in the application, when R isR 1 Is R 1-1 Substituted C 6～30 In the case of aryl, each R 1-1 Independently is halogen, C 1～10 Alkyl or->
In one embodiment, in the application, when R isWhen the R is 2 Is R 2-1 Substituted C 6～30 Aryl groups.
In one embodiment, in the application, when R isR 2 Is R 2-1 Substituted C 6～30 In the case of aryl, each R 2-1 Is C 1～10 An alkyl group.
In one embodiment, R in the compound of formula I 1 C substituted by halogen 1～10 Alkyl, C 3～10 Cycloalkyl, R 1-1 Substituted C 6～30 Aryl, 3-to 30-membered heteroaryl orR 2 Is R 2-1 Substituted C 6～30 Aryl groups.
In one embodiment, R in the compound of formula I 1 C substituted by halogen 1～10 An alkyl group; r is R 2 Is R 2-1 Substituted C 6～30 Aryl groups.
In the application, the compound shown as the formula I or pharmaceutically acceptable salt thereof is preferably any one of the following compounds:
the application can 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:
method 1: the method comprises the following steps of carrying out condensation reaction of a compound of the formula II and a compound of the formula III in an organic solvent under the action of a condensing agent and an alkaline reagent to obtain a compound of the formula I;
method 2: the method comprises the following steps of carrying out acylation reaction of 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;
method 3: the method comprises the following steps of reacting a compound shown in a formula I with acid in a solvent to obtain a salt of the compound shown in the formula I;
wherein R in method 1, method 2 and method 3 are as described above.
In method 1, the conditions and operation of the condensation reaction may be conventional in the art.
In method 1, the condensing agent may be one conventional in the art for this reaction, preferably 2- (7-oxybenzotriazol) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), or Carbonyldiimidazole (CDI), such as HATU.
In process 1, the molar ratio of the condensing agent to the compound II may be a molar ratio conventional in this reaction in the art, preferably from 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-Diethyl Isopropylamine (DIEA), such as TEA.
In process 1, the molar ratio of the basic reagent to the compound II may be a molar ratio conventional in this reaction in the art, preferably from 1.0 to 5.0, for example 3.0.
In process 1, the molar ratio of said compound III to said compound II may be a molar ratio conventional in this reaction in the art, preferably from 1.0 to 2.0, for example 1.0.
In the method 1, the organic solvent may be an organic solvent conventional in the art for such a reaction, 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 1, whatThe compound III may be
In process 1, the temperature of the condensation reaction may be a temperature conventional in such reactions in the art, preferably from 10 to 40 ℃, for example 25 ℃.
In method 1, the progress of the condensation reaction can be monitored using monitoring methods conventional in the art (e.g., TLC, LCMS), typically with the disappearance of compound II or no longer reacting as an endpoint of the reaction. 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: washing the reaction solution after the reaction, drying, concentrating and performing column chromatography.
In method 2, the conditions and operation of the acylation reaction may be conventional in the art for such reactions.
In method 2, the acid-binding agent may be a reagent conventional in the art, preferably an organic weak base. The weak organic base may be one or more of pyridine, triethylamine (TEA) and N, N-Diethyl Isopropylamine (DIEA), such as TEA.
In process 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, preferably from 1.0 to 5.0, for example 2.0.
In process 2, the molar ratio of said compound IV to said compound II may be a molar ratio conventional in this reaction in the art, preferably from 1.0 to 2.0, for example 1.0.
In the method 2, the organic solvent may be an organic solvent conventional in the art for such a reaction, 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 may be
In process 2, the temperature of the acylation reaction may be a temperature conventional in such reactions in the art, preferably 0 to 40 ℃, e.g. 25 ℃.
In method 2, the progress of the acylation reaction can be monitored using monitoring methods conventional in the art (e.g., TLC, LCMS), typically with the disappearance of compound II or no longer reacting as an endpoint of the reaction. 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 treatment steps: washing the reaction solution after the reaction, drying, concentrating and performing column chromatography.
In method 3, the salt of the compound of formula I may be prepared according to methods and conditions conventional in the art for salt-forming reactions.
In method 3, the acid may be a salt-forming organic acid or an inorganic acid as 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, 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 process 3, the molar ratio of the acid to the compound of formula I may be from 1 to 3, for example 1.
In method 3, the solvent may be a ketone solvent, such as acetone.
In process 3, the temperature of the reaction may be from 10 to 60 ℃, for example 50 ℃.
The application also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof in preparing medicines for preventing and/or treating EGFR-mediated related diseases.
In the above applications, it is preferable that the medicament is used for preventing and/or treating diseases related to EGFR mutation.
Wherein the disease may be 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 tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute Myelogenous Leukemia (AML), multiple myeloma, melanoma, or mesothelioma; lung cancer is preferred, and non-small cell lung cancer is further preferred.
The application also provides a pharmaceutical composition, which comprises the compound shown in the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The pharmaceutical composition can also consist of the compound shown in the formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In the present application, 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 one or more selected from magnesium stearate, micro silica gel, silicon dioxide and talcum powder; the disintegrating agent is one or more selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, starch and crospovidone; the adhesive is selected from one or more of hydroxypropyl cellulose, polyvinylpyrrolidone and methylcellulose; the filler is selected from one or more of lactose, pregelatinized starch and microcrystalline cellulose.
In the present application, the amount of the pharmaceutically acceptable carrier is not particularly limited as long as it can meet the requirements of the conventional formulation in the art.
In the application, the pharmaceutical composition can be prepared into various dosage forms, such as tablets, capsules, pills, powder, emulsion, granules, suppositories, injection and the like.
In the present application, the term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder (i.e., resulting in at least one of the clinical symptoms of a disease not occurring in a subject that may be exposed to a disease causing agent or a disease susceptible prior to the onset of the disease).
In the application, the following components are added: the term "R-S configuration" is a term used for the nomenclature of the R-S system in the naming of the chiral C. The specific nomenclature of the R-S system is as follows: when a, b, c, d attached to the central carbon atom is a different group, the molecule is chiral. Assuming that four substituents in the molecule are arranged in the order of a > b > c > d according to CIP sequence rules, if the smallest d group is placed furthest from the observer, the other three groups are observed in the order of a-b-c, and a- > b- > c is observed to be clockwise, the configuration of this carbon center is defined as R (Latin structures); otherwise, S (Latin sinister) is identified.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present application can be obtained.
The reagents and starting materials used in the present application are commercially available, wherein S-2-chloropropionic acid is purchased from An Naiji (lot number: BE 170142), purity 98%, specific rotation is-13.5 °; r-2-chloropropionic acid was purchased from An Naiji (lot number: EE 040098), 98% pure and a specific rotation of +13.4°.
The application has the positive progress effects that: the methoxy substituted phenylamide aminopyrimidine derivative has low toxicity to normal cells and good selectivity and activity to EGFR mutant strains.
Detailed Description
The application is further illustrated by means of the following examples, which are not intended to limit the scope of the application. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
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
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 (1.0 g,2.24mmol,1 eq), 3- (N, N-dimethylamino) benzoic acid (445 mg,2.69mmol,1.2 eq) and HATU (1.28 g,3.37mmol,1.5 eq) were dissolved in dichloromethane (20 ml), DIPEA (1.11 ml,6.73mmol,3.0 eq) was added, after stirring at room temperature for 4 hours, the reaction was washed three times, dried and concentrated, crude column chromatography (dichloromethane/methanol) gave the product (1.33 g).
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.37 (s, 1H), 9.30 (s, 1H), 8.79 (s, 1H), 8.36 (d, j=5.2 hz, 1H), 8.25 (d, j=8.0 hz, 1H), 7.91 (s, 1H), 7.53 (d, j=8.0 hz, 1H), 7.36 (t, j=8.0 hz, 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), 2.02ppm (s, 6H); ES-API (m/z): calculated value C 34 H 40 N 8 O 2 [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
Reference 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- (2-chloro) benzamide (1.31 g)
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.91 (s, 1H), 9.22 (s, 1H), 8.70 (s, 1H), 8.35 (d, j=5.2 hz, 1H), 8.25 (d, j=8.0 hz, 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), 1.76ppm (s, 6H); ES-API (m/z): calculated value C 32 H 34 ClN 7 O 2 [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
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 (1.29 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=11.12 (s, 1H), 9.17 (s, 1H), 8.64 (1H), 8.35 (d, j=5.2 hz, 1H), 8.24 (d, j=8.0 hz, 1H), 7.97 (s, 1H), 7.65-7.55 (m, 1H), 7.52 (d, j=8.0 hz, 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=5.6 hz, 2H), 2.74 (s, 3H), 2.19 (t, j=5.6 hz, 2H), 1.81ppm (s, 6H); ES-API (m/z): calculated value C 32 H 33 F 2 N 7 O 2 [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
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (4-methoxy) benzamide (1.30 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ):δ＝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=5.6 Hz, 2H), 2.04ppm (s, 6H); ES-API (m/z): calculated value C 33 H 37 N 7 O 3 [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
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 (1.55 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.79 (s, 1H), 9.19 (s, 1H), 8.72 (s, 1H), 8.34 (d, j=5.2 hz, 1H), 8.24 (d, j=8.0 hz, 1H), 7.95 (s, 1H), 7.52 (d, j=8.0 hz, 1H), 7.30-7.22 (m, 2H), 7.20-7.12 (m, 1H), 7.13-7.05 (m, 1H), 6.78 (d, j=2.8 hz, 1H), 6.73 (d, j=2.8 hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 2.90 (t, j=5.6 hz, 2H), 2.73 (s, 3H), 2.21 (t, j=5.6 hz, 1H), 6.84 ppm (s, 1H). ES-API (m/z): calculated value C 34 H 38 BrN 7 O 4 [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
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-ferrocenecarboxamide (1.48 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ):δ＝9.63(s,1H),9.18(s,1H),8.80(s,1H),8.37(s,1H),8.23 (d, j=8.0 hz, 1H), 7.89 (s, 1H), 7.53 (d, j=8.0 hz, 1H), 7.31-7.21 (m, 2H), 7.17 (t, j=7.6 hz, 1H), 7.11 (s, 1H), 4.88 (t, j=2.0 hz, 2H), 4.49 (t, j=2.0 hz, 2H), 4.25 (s, 5H), 3.97 (s, 3H), 3.88 (s, 3H), 3.06 (t, j=5.6 hz, 2H), 2.75 (s, 3H), 2.27 (t, j=5.6 hz, 2H), 2.18ppm (s, 6H); ES-API (m/z): calculated value C 36 H 39 FeN 7 O 2 [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
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 (1.39 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.94 (s, 1H), 9.20 (s, 1H), 8.68 (s, 1H), 8.34 (d, j=5.2 hz, 1H), 8.25 (d, j=8.0 hz, 1H), 7.96 (s, 1H), 7.78 (d, j=2.0 hz, 1H), 7.66 (d, j=8.0 hz, 1H), 7.59 (dd, j=8.0, 2.0hz, 1H), 7.51 (d, j=8.0 hz, 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, j=6.4 hz, 2.74 (s, 3H), 2.17 (t, j=6.0 hz, 1H), 7.30-7.20 (m, 2H), 7.19-7.12 (m, 1H). ES-API (m/z): calculated value C 32 H 33 Cl 2 N 7 O 2 [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
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (3-pyrrolyl) carboxamide (1.18 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=11.34 (s, 1H), 9.62 (s, 1H), 9.16 (s, 1H), 8.77 (s, 1H), 8.34 (d, j=5.2 hz, 1H), 8.25 (d, j=8.0 hz, 1H), 7.88 (s, 1H), 7.52 (d, j=8.0 hz, 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=2.4 hz, 1H), 6.58 (dd, j=2.4 hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 2.05 (m, 2H), 2.69 (s, 3H), 2.40 (s, 2H), 2.21ppm (s, 6H); ES-API (m/z): calculated value C 30 H 34 N 8 O 2 [M+H]++, 539.3; theoretical 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
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 (1.37 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.31 (s, 1H), 9.23 (s, 1H), 8.75 (s, 1H), 8.35 (d, j=5.2 hz, 1H), 8.26 (d, j=8.0 hz, 1H), 7.91 (s, 3H), 7.60 (dd, j=8.0, 2.0hz, 1H), 7.57-7.49 (m, 2H), 7.26 (d, j=5.2 hz, 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 hz, 2H), 2.73 (s, 3H), 2.30 (t, j=6.0 hz, 2H), 6ppm (s, 6H). ES-API (m/z): calculated value C 34 H 39 N 7 O 4 [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
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- (2-pyrrolyl) carboxamide (1.15 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=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=8.0 hz, 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=6.0 hz, 2H), 2.71 (s, 3H), 2.33 (t, j=6.0 hz, 2H), 2.16ppm (s, 6H); ES-API (m/z): calculated value C 30 H 34 N 8 O 2 [M+H]++, 539.3; theoretical 539.3.
Example 11N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropanecarboxamide
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2-cyclopropanecarboxamide (1.15 g) was prepared according to example 1.
1 H NMR(400MHz,DMSO-d 6 ) Delta=10.21 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.32 (d, j=5.2 hz, 1H), 8.23 (d, j=8.0 hz, 1H), 7.85 (s, 1H), 7.53 (d, j=8.0 hz, 1H), 7.29-7.23 (m, 1H), 7.22 (d, j=5.2 hz, 1H), 7.20-7.13 (m, 1H), 7.02 (s, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.92 (t, j=6.0 hz, 2H), 2.72 (s, 3H), 2.37 (t, j=6.0 hz, 2H), 2.28 (s, 6H), 1.83-1.70 (m, 1H), 0.90-0.75ppm (m, 4H); ES-API (m/z): calculated value C 29 H 35 N 7 O 2 [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-toluenesulfonamide
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 (1.0 g,2.24mmol,1 eq), DIPEA (0.74 ml,4.49mmol,2.0 eq) was dissolved in dichloromethane, and the corresponding tosyl chloride (428 mg,2.24mmol,1.0 eq) was added dropwise after stirring at room temperature for 1 hour, the reaction solution was washed twice with water, dried and concentrated, and crude product column chromatography (dichloromethane/methanol) afforded the product (1.27 g).
1 H NMR(400MHz,DMSO-d 6 ) Delta = 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 C 32 H 37 N 7 O 3 S[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
After S-2-chloropropionic acid (365 mg,3.37mmol,1.5 eq) was dissolved in 50mL DCM, the starting material (1 g,2.24mol,1 eq) was added and stirred under ice for 10min, EDCI (1.5 g,4.49mmol,2 eq) and DMAP (110 mg,0.90mmol,0.4 eq) were added and the ice bath was continued to stir to room temperature overnight. After the reaction was completed, the mixture was extracted with water and DCM, and the organic phase was collected, dried by spin-drying, and purified by silica gel chromatography to give the product (700 mg). .
1 H NMR(400MHz,DMSO-d 6 ) δ10.10 (s, 1H), 8.95 (s, 1H), 8.62 (s, 1H), 8.33 (d, j=4.4 hz, 1H), 8.25 (d, j=6.4 hz, 1H), 7.91 (s, 1H), 7.53 (d, j=6.8 hz, 1H), 7.27-7.23 (m, 2H), 7.18 (t, j=6.4 hz, 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=5.2 hz, 3H). ES-API (m/z): calculated valuesC 28 H 34 ClN 7 O 2 [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
N- [2- [ [2- (dimethylamino) ethyl ] methylamino ] -4-methoxy-5- [ [4- (1-methyl-1H-indol-3-yl) -2-pyrimidinyl ] amino ] phenyl ] -2- ((R) -2-chloro) propanamide (665 mg) was prepared according to example 13.
1 H NMR(400MHz,DMSO-d 6 ) δ10.16 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.33 (d, j=5.2 hz, 1H), 8.23 (d, j=8.0 hz, 1H), 7.90 (s, 1H), 7.53 (d, j=8.4 hz, 1H), 7.27-7.23 (m, 2H), 7.17 (t, j=7.6 hz, 1H), 7.05 (s, 1H), 4.85 (br, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.99 (brs, 2H), 2.69 (s, 3H), 2.35 (br, 2H), 2.25 (br, 6H), 1.66 (d, j=6.8 hz, 3H). ES-API (m/z): calculated value C 28 H 34 ClN 7 O 2 [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
The product obtained in example 13 (535 mg,1.0mmol,1 eq) was dissolved in 5ml of acetone, gradually stirred to 50℃and the prepared methanesulfonic acid solution (96 mg,1.0mol,1eq, methanesulfonic acid in 96mg,0.5ml of acetone) was added and reacted for about 3 hours. After the completion of the reaction, the product (86 mg) was obtained by suction filtration and drying.
1 H NMR(400MHz,DMSO-d 6 ):δ9.98(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(tJ=7.2 hz, 1H), 7.05 (s, 1H), 5.32 (t, j=4.7 hz, 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=6.6 hz, 3H); ES-API (m/z): calculated value, C 29 H 38 ClN 7 O 5 S[M-CH 3 SO 3 ]++, 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
/>
The product obtained in example 14 was prepared following 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) propanamide methanesulfonate (79 mg).
1 H NMR(400MHz,DMSO-d 6 ) δ10.17 (s, 1H), 9.97 (s, 1H), 8.75 (s, 1H), 8.46 (s, 1H), 8.4-8.1 (br, 3H), 7.59 (d, j=8.1 hz, 1H), 7.38 (d, j=6.3 hz, 1H), 7.31 (t, j=7.5 hz, 1H), 7.24 (t, j=7.4 hz, 1H), 7.04 (s, 1H), 5.41 (q, j=6.6 hz, 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 (d, j=6.6 hz, 3H). ES-API (m/z): calculated value, C 29 H 38 ClN 7 O 5 S[M-CH 3 SO 3 ]++, 536.1; theoretical value, 536.1.
Effect examples
1. Test method
Cells in logarithmic growth phase were inoculated into 96-well plates at 3-6 ten thousand/mL per well, 100. Mu.L per well volume, and the plates were then transferred to CO 2 In an incubator at 37℃and 5% CO 2 Culturing for 24h under saturated humidity condition. Test compounds were diluted in gradient and added to corresponding wells of 96-well plates, incubated with cells, and incubated in a cell incubator for 72h. After the incubation is finished, 10 mu L of CCK8 reagent is added into each hole, and the mixture is put into an incubator for incubation for 2 to 4 hoursOD was measured at 450 nm. The survival rate of the drug to cell growth was calculated according to the following formula: survival (%) = (OD dosing-OD blank)/(OD control-OD blank) ×100%, fitting to obtain inhibition curve, and calculating corresponding IC 50 See table 1 for details.
2. Main reagent
CCK8 kit (Biyundian), reference compound (AZD 9291)
TABLE 1 test compound IC 50 Test results
TABLE 2 Selectivity of test Compounds HWB 14-17 for different cell lines
Remarks: h1975 in tables 1 and 2 is an EGFR mutant non-small cell lung cancer cell; HCC827 is an EGFR mutant non-small cell lung cancer cell; a431 is tumor cells with normal EGFR high expression; wi38 is a normal cell.
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 overexpressing A431, IC thereof 50 The values are all below 1000nM, and the toxicity to normal cell Wi38 is extremely low, and the IC thereof 50 The value can reach more than 10000nM, has better patent medicine prospect, in particular to the representative compound HWB17, the inhibition activity of the compound HWB17 on EGFR mutant H1975 and HCC827 is in the same order of magnitude as that of the marketed medicine AZD9291, and the A431 selectivity of the compound HWB17 on non-mutant EGFR is better.
As can be seen from table 2, the compounds of the present application have higher selectivity for EGFR mutant cancer cells than for EGFR highly expressed cancer cells. In particular, the selectivity of the compound HWB17 (example 16) to A431/H1975 is up to 107 times, the selectivity of A431/HCC827 is up to 1337 times, and the selectivity is improved by 1 time compared with that of AZD9291 (control drug, octenib); HWB16 also showed comparable selectivity to AZD9291 (control, octenib) against EGFR-highly expressed cancer cells and mutant cancer cells.
Claims (7)
1. An application of a compound shown as a formula I or pharmaceutically acceptable salt thereof in preparing an EGFR inhibitor,wherein R is->；
Said R is 1 Is thatOr->。
2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula I is a mesylate salt.
3. 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:、、/>or (b)。
4. Use of a compound of formula I as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of diseases which are associated with EGFR mutation mediated.
5. The use according to claim 4, wherein the disease is lung cancer.
6. The use of claim 5, wherein the disease is non-small cell lung cancer.
7. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, and a pharmaceutically acceptable carrier.
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