CN106749193B - Indazole-substituted epidermal growth factor receptor inhibitors and uses thereof - Google Patents
Indazole-substituted epidermal growth factor receptor inhibitors and uses thereof Download PDFInfo
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- CN106749193B CN106749193B CN201510819539.4A CN201510819539A CN106749193B CN 106749193 B CN106749193 B CN 106749193B CN 201510819539 A CN201510819539 A CN 201510819539A CN 106749193 B CN106749193 B CN 106749193B
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Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to an epidermal growth factor receptor inhibitor with an indazole substituted structure, a pharmaceutical composition containing the inhibitor, and application of the inhibitor or the pharmaceutical composition as a cancer prevention and/or treatment drug. The compounds show good EGFR inhibitory activity, and are expected to become drugs with specific curative effect and small side effect on drug-resistant tumors caused by EGFR mutation especially against mutated EGFR.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an epidermal growth factor receptor inhibitor with an indazole substituted structure, a pharmaceutical composition containing the inhibitor, and application of the inhibitor or the pharmaceutical composition as a cancer treatment drug.
Background
Epidermal Growth Factor Receptor (EGFR) is an expression product of proto-oncogene C-erbB-1, and is one of EGFR family members. The EGFR family includes four members of EGFR (HER-1), ERBB2(HER-2), ERBB3(HER-3), and ERBB4 (HER-4). EGFR overexpression or mutation has been shown to generally trigger tumors. EGFR mutation causes the continuous activation of EGFR, the function of an autocrine loop is enhanced, a receptor down-regulation mechanism is damaged, and an abnormal signal conduction pathway is activated, thereby playing an important role in the evolution of tumors.
Treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) against EGFR has become the gold standard in the field of non-small cell lung cancer treatment. However, clinical application shows that most patients have different drug resistance phenomena 6-12 months after the EGFR-TKI inhibitors such as gefitinib and erlotinib are treated, and further the curative effect of the drug is obviously reduced, and tumors progress. Research shows that the generation of EGFR-TKI resistance is related to secondary mutation of EGFR gene, wherein the most common mutation is mutation of No. 790 exon of EGFR gene, namely T790M gene mutation. Because methionine occupies a larger space than threonine, steric hindrance is formed, the affinity of ATP in an EGFR kinase region is changed, and an EGFR-TKI small molecular drug cannot effectively block an EGFR activation signal, so that drug resistance is generated. Meanwhile, the first-generation EGFR inhibitor lacks selectivity of wild EGFR and mutant EGFR, and side effects such as rash, diarrhea and the like are commonly existed, so that the compliance of patients is influenced.
Therefore, the development of effective drugs for tumor patients with drug resistance caused by EGFR secondary mutation, particularly the development of drugs capable of further improving the selectivity of wild EGFR and mutant EGFR, enhancing the curative effect and reducing the side effect, has good application prospect.
Disclosure of Invention
The invention aims to provide a compound with an indazole substitution structure shown in a general formula I or pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein the compound shows good EGFR inhibitory activity, especially to mutant EGFR,
the invention also aims to provide the compound of the general formula II or the pharmaceutically acceptable salt thereof, the compound of the general formula I is prepared by taking the compound of the general formula II as a key intermediate, the reaction condition is mild, the yield and the purity are high,
a third object of the present invention is to provide a process for preparing the compounds of general formulae I and II of the present invention or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof.
A fourth object of the present invention is to provide a pharmaceutical composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another tumor suppressor.
The fifth purpose of the present invention is to provide a method for treating and/or preventing cancer by the compound of the general formula I or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of the present invention, and a method for treating and/or preventing cancer by the compound of the general formula I or its pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of the present invention and its use in preparing a medicament for treating and/or preventing cancer.
Aiming at the above purpose, the invention provides the following technical scheme:
in a first aspect, the present invention provides a compound represented by the general formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
wherein
Pyrimidine ring
And indazole rings
Upper N is connected to form
R1、R1a、R2And R3Each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl, aminoacyl, monoalkylaminoacyl and dialkylaminoacyl;
R4、R5and R6Each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy, and cycloalkyl, said alkyl, alkoxy, and cycloalkyl being optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl;
Raselected from the group consisting of hydrogen, alkyl, cycloalkyl, and haloalkyl; and
Rbselected from hydrogen, alkanesAlkyl and cycloalkyl optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino or hydroxy; or
Ra、RbAnd the N to which they are attached, form a nitrogen-containing heterocycloalkyl group that is optionally substituted with one or more halogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, or hydroxyalkyl groups.
In a second aspect, the invention provides a compound of general formula II or a pharmaceutically acceptable salt thereof, the compound of general formula I is prepared by taking the compound of general formula II as a key intermediate, the reaction conditions are mild, the yield and the purity are high,
wherein R is1、R1a、R2、R3、RaAnd RbHave the definition in the general formula I.
In some preferred embodiments, the present invention provides compounds of formulae I and II, wherein the pyrimidine ring
And indazole rings
Is connected with N to form
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein the pyrimidine ring
And indazole rings
Is connected with N to form
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, nitro, cyano, hydroxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino radical, amino radical C1-6Alkyl, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino radical C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl acyl, amino acyl, mono C1-6Alkylaminoacyl and di-C1-6An alkylaminoacyl group.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, nitro, cyano, hydroxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino radical, amino radical C1-3Alkyl, mono C1-3Alkylamino radical C1-6Alkyl, di-C1-3Alkylamino radical C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkyl acyl, amino acyl, mono C1-3Alkylaminoacyl and di-C1-3An alkylaminoacyl group.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein R1、R1a、R2And R3Each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, and bisFluoromethyl group, difluoroethyl group, methoxy group, ethoxy group, propoxy group, trifluoromethyloxy group, nitro group, cyano group, hydroxy group, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, N-methyl-N-ethylamino group, N-methyl-N-propylamino group, N-methyl-N-isopropylamino group, N-ethyl-N-propylamino group, N-ethyl-N-isopropylamino group, N-propyl-N-isopropylamino group, aminomethyl group, aminoethyl group, aminopropyl group, methylaminomethyl group, methylaminoethyl group, ethylaminomethyl group, ethylaminoethyl group, dimethylaminomethyl group, dimethylaminoethyl group, diethylaminomethyl group, diethylaminoethyl group, amino group, N-methyl-N-propylamino group, N, Hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl and ethoxyethyl.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein R1、R1a、R2And R3Each independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, and hydroxyethyl.
In some preferred embodiments, the present invention provides compounds of formula I and II, wherein RaSelected from hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl and halo C1-6An alkyl group.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RaSelected from hydrogen, C1-3Alkyl radical, C3-6Cycloalkyl and halo C1-3An alkyl group.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RaSelected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RaIs methyl.
In some preferred embodiments, the present invention provides compounds of formula I and II, wherein RbSelected from hydrogen, C1-6Alkyl and C3-6Cycloalkyl radical, said C1-6Alkyl and C3-6Cycloalkyl optionally substituted by one or more halogens, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino or hydroxy.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RbSelected from hydrogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Cycloalkyl optionally substituted by one or more halogens, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino or hydroxy.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RbSelected from hydrogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6The cycloalkyl group is optionally substituted with one or more halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, or hydroxy.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RbSelected from methyl, ethyl and propyl, said methyl, ethyl and propyl being optionally substituted with one or more amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino or ethylpropylamino groups.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein RbIs ethyl substituted by dimethylamino.
In some preferred embodiments, the present invention provides compounds of formula I and II, wherein Ra、RbAnd the N to which they are attached together form a four to eight membered azacycloalkyl group optionally substituted with one or more halogen, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino, hydroxy, amino C1-6Alkyl, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino radical C1-6Alkyl or hydroxyalkyl.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein Ra、RbAnd the N to which they are attached together form a four to eight membered azacycloalkyl group optionally substituted with one or more halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino, hydroxy, amino C1-3Alkyl, mono C1-3Alkylamino radical C1-3Alkyl, di-C1-3Alkylamino radical C1-3Alkyl or hydroxyalkyl.
In other preferred embodiments, the present invention provides compounds of formulae I and II, wherein Ra、RbAnd the N to which they are attached, together form a five or six membered azacycloalkyl group, optionally substituted by one or more halogens, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino, hydroxy, amino C1-3Alkyl, mono C1-3Alkylamino radical C1-3Alkyl, di-C1-3Alkylamino radical C1-3Alkyl or hydroxyalkyl.
In some preferred embodiments, the present invention provides compounds of formula I,wherein R is4、R5And R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl radical, said C1-6Alkyl radical, C1-6Alkoxy and cycloalkyl optionally substituted by one or more halogens, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino, hydroxy, amino C1-6Alkyl, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino radical C1-6Alkyl and hydroxy C1-6Alkyl substitution.
In other preferred embodiments, the present invention provides compounds of formula I, wherein R is4、R5And R6Each independently selected from hydrogen, halogen, cyano, C1-3Alkyl radical, C1-3Alkoxy radical, C3-6Cycloalkyl radical, said C1-3Alkyl radical, C1-3Alkoxy and C3-6Cycloalkyl optionally substituted by one or more halogens, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino, hydroxy, amino C1-3Alkyl, mono C1-3Alkylamino radical C1-3Alkyl, di-C1-3Alkylamino radical C1-3Alkyl or hydroxy C1-3Alkyl substitution.
In other preferred embodiments, the present invention provides compounds of formula I, wherein R is4、R5And R6Are all hydrogen.
In some preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, nitro, cyano, hydroxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino radical, amino radical C1-3Alkyl, mono C1-3Alkylamino radical C1-6Alkyl, di-C1-3Alkylamino radical C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkyl acyl, amino acyl, mono C1-3Alkylaminoacyl and di-C1-3An alkylaminoacyl group;
R4、R5and R6Are all hydrogen;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, methyl, isopropyl, trifluoromethyl, methoxy, methyl, isopropyl,Ethoxy, hydroxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, and hydroxyethyl;
R4、R5and R6Are all hydrogen;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, nitro, cyano, hydroxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino radical, amino radical C1-3Alkyl, mono C1-3Alkylamino radical C1-6Alkyl, di-C1-3Alkylamino radical C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkyl acyl, amino acyl, mono C1-3Alkylaminoacyl and di-C1-3An alkylaminoacyl group;
R4、R5and R6Are all hydrogen;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, and hydroxyethyl;
R4、R5and R6Are all hydrogen;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In some preferred embodiments, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, nitro, cyano, hydroxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino radical, amino radical C1-3Alkyl, mono C1-3Alkylamino radical C1-6Alkyl, di-C1-3Alkylamino radical C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkyl acyl, amino acyl, mono C1-3Alkylaminoacyl and di-C1-3An alkylaminoacyl group;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, and hydroxyethyl;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-3Alkyl, halo C1-3Alkyl radical, C1-3Alkoxy, halo C1-3Alkoxy, nitro, cyano, hydroxy, amino, mono C1-3Alkylamino, di-C1-3Alkylamino radical, amino radical C1-3Alkyl, mono C1-3Alkylamino radical C1-6Alkyl, di-C1-3Alkylamino radical C1-3Alkyl, hydroxy C1-3Alkyl radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkyl acyl, amino acyl, mono C1-3Alkylaminoacyl and di-C1-3An alkylaminoacyl group;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In other preferred embodiments, the present invention provides a compound of formula II, or a pharmaceutically acceptable salt thereof, wherein,
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, and hydroxyethyl;
Rais methyl;
Rbis ethyl substituted by dimethylamino.
In some specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
in other specific embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts thereof:
in a third aspect, the present invention provides a process for the preparation of the compounds of the general formulae I and II according to the invention. Wherein the pyrimidine ring
And indazole rings
Is connected with N to form
The process for the preparation of the compounds of the general formulae I and II of (1) comprises the following steps:
A) carrying out nucleophilic reaction on the raw material of the formula 1 and the raw material of the formula 2 to obtain an intermediate of the formula 3;
B) reacting the intermediate of formula 3 with the starting material of formula 4 to produce an intermediate of formula 5;
C) carrying out nucleophilic reaction on the intermediate of the formula 5 to prepare an intermediate of a formula 6;
D) the intermediate of the formula 6 is subjected to reduction reaction to prepare an intermediate of a formula II;
E) the intermediate of formula II is reacted with the starting material of formula 7 to produce the compound of formula I.
R is as defined above1、R1a、R2、R3、R4、R5、R6、Ra、RbHaving the definitions in the general formulae I and II, M represents halogen.
Pyrimidine ring
And indazole rings
Is connected with N to form
The process for the preparation of the compounds of the general formulae I and II of (1) comprises the following steps:
A) carrying out nucleophilic reaction on the raw material of the formula 1 and the raw material of the formula 2 to obtain an intermediate of a formula 3';
B) reacting the intermediate of formula 3 'with the starting material of formula 4 to produce an intermediate of formula 5';
C) carrying out nucleophilic reaction on the intermediate of the formula 5 'to prepare an intermediate of a formula 6';
D) the intermediate of the formula 6' is subjected to reduction reaction to prepare an intermediate of a formula II;
E) the intermediate of formula II is reacted with the starting material of formula 7 to produce the compound of formula I.
R is as defined above1、R1a、R2、R3、R4、R5、R6、Ra、RbHaving the definitions in the general formulae I and II, M represents halogen.
In some embodiments, the present invention provides a method of making a compound of formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, comprising using a compound of formula II of the present invention.
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and a pharmaceutically acceptable carrier.
In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula I, isomer, solvate, crystal or prodrug of the present invention, further comprising one or more compounds selected from the group consisting of: gefitinib, erlotinib, lapatinib, afatinib, vandetanib, canertinib, apatinib, dacatinib (dacomitinib), pelitinib (pelitinib), WZ4002, AG-490, AZD8931, AZD9291, and the like.
The compounds of formula I, isomers, solvates, crystals or prodrugs of the invention may be combined with pharmaceutically acceptable carriers to prepare pharmaceutical formulations suitable for oral or parenteral administration. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes. The formulations may be administered by any route, for example by infusion or bolus injection, by a route of absorption through epithelial or cutaneous mucosa (e.g. oral mucosa or rectum, etc.). Administration may be systemic or local. Examples of the formulation for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like. The formulations may be prepared by methods known in the art and include carriers conventionally used in the art of pharmaceutical formulation.
In a fourth aspect, the present invention provides a method for treating and/or preventing tumors by using the compound of the general formula I, isomer, solvate, crystal or prodrug of the present invention or the pharmaceutical composition of the present invention, and an application in preparing a medicament for treating and/or preventing tumors, comprising administering the compound of the general formula I, isomer, solvate, crystal or prodrug of the present invention or the pharmaceutical composition comprising the compound of the general formula I, isomer, solvate, crystal or prodrug of the present invention to a population prone to tumor or a tumor patient, so as to effectively reduce the incidence of tumors and prolong the life of the tumor patient.
In some embodiments, the present invention provides a method of treating a drug resistant tumor by administering to a patient having a drug resistant tumor a therapeutically effective amount of a compound of formula I, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition comprising a compound of formula I, isomer, solvate, crystal or prodrug of the present invention.
In other embodiments, the present invention provides the use of a compound of formula I, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of a drug-resistant tumor. The drug resistant tumor may be a tumor that is resistant to multiple drugs, preferably to EGFR inhibitors, such as first, second, and third generation EGFR inhibitors, such as gefitinib, erlotinib, and lapatinib. The tumor includes but is not limited to solid tumor, preferably lung cancer, head and neck tumor, colorectal cancer, bladder cancer, pancreatic cancer, breast cancer, prostate cancer, stomach cancer, oral cancer, liver cancer, ovarian cancer. More preferably, the tumor is non-small cell lung cancer. In some embodiments, the present invention provides methods of treating drug resistant tumors with a compound of formula I, isomer, solvate, crystal or prodrug of the present invention, wherein said tumor carries an EGFR mutant gene. In one embodiment, the EGFR mutant gene carried by the tumor is the T790M mutation in exon 20. In another embodiment, the EGFR mutant gene carried by the tumor is a L858R mutation and/or a deletion/insertion mutation in exon 21. In another embodiment, the EGFR mutant gene carried by the tumor is a T790M and L858R double mutation. In other embodiments, the present invention provides a compound of formula I, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention for use in the treatment of tumors, wherein the tumor treatment effect is manifested by a superior therapeutic effect, a high degree of selectivity and/or fewer side effects. In still other embodiments, the present invention provides a method of treating tumors by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, resulting in a tumor treatment effect manifested by a superior therapeutic effect, a high degree of selectivity and/or fewer side effects.
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
"isomers" in the present invention refer to cis-trans isomers in either the cis or trans configuration.
The "pharmaceutically acceptable salt" of the present invention refers to a pharmaceutically acceptable salt of the compound of the present invention with an acid, which may be selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, and the like.
"solvate" of the present invention refers to a form of the compound of the present invention which forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" as used herein refers to the various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
The "prodrug" of the present invention refers to a compound which is converted into the compound of the present invention by reaction with an enzyme, gastric acid or the like under physiological conditions of an organism, that is, a compound which is converted into the compound of the present invention by oxidation, reduction, hydrolysis or the like by an enzyme and/or a compound which is converted into the compound of the present invention by hydrolysis reaction of gastric acid or the like.
The "pharmaceutical composition" of the present invention is intended to include a mixture of any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts, or chemically protected forms thereof, and one or more pharmaceutically acceptable carriers.
The term "use in the preparation of a medicament for the treatment and/or prevention of a tumor" as used herein means to inhibit or prevent the growth, development and/or metastasis of a tumor by administering to a human or animal in need thereof a therapeutically or prophylactically effective amount of a compound of the present invention to inhibit, slow, reverse or prevent the growth, development or spread of a tumor in the subject.
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group, preferably a hydrocarbon group of 6 carbon atoms or less. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-methylbutyl and 2, 3-dimethylbutyl. The term "C1-6Alkyl "refers to a straight or branched chain saturated hydrocarbon group containing 1 to 6 carbon atoms. The term "C1-3Alkyl is meant to containA straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms.
The "cycloalkyl group" in the present invention means a cyclic saturated hydrocarbon group, preferably a cycloalkyl group having 12 or less carbon atoms, more preferably a cycloalkyl group having 8 or less carbon atoms, and still more preferably a cycloalkyl group having 6 or less carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. "C" of the invention3-6Alkyl "refers to a cyclic saturated hydrocarbon group containing 3 to 6 carbon atoms. "alkyl" and "cycloalkyl" in the context of the present invention include substituted or unsubstituted alkyl and cycloalkyl groups, which may be optionally substituted with one or more groups selected from: alkyl, alkoxy, aryloxy, alkylamino, arylamino, halogen, hydroxy, amino, nitro, cyano, alkanoyl, aminoacyl, alkylaminoacyl, sulfonyl, sulfinyl, mercapto, aryl or heteroaryl.
"alkoxy" in the context of the present invention means-O-alkyl.
The "halogen" in the present invention means fluorine, chlorine, bromine and iodine.
"haloalkyl" in the context of the present invention means an alkyl group substituted with at least one halogen atom.
"haloalkoxy" in the context of the present invention means an alkoxy group substituted by at least one halogen, preferably C substituted by at least one halogen1-6Alkoxy, more preferably C substituted by at least one halogen1-3Alkoxy, suitably halo C1-3Alkoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy or trifluoromethoxy; dichloroethoxy, difluoroethoxy, trichloroethoxy, trifluoroethoxy.
"Monoalkylamino" according to the invention means-NH-alkyl, preferably-NH-C1-6Alkyl, more preferably-NH-C1-3An alkyl group.
"dialkylamino" in the context of the present invention means-N- (alkyl), preferably-N- (C)1-6Alkyl) (C1-6Alkyl group), more preferably-N- (C)1-3Alkyl) (C1-3Alkyl groups).
"Monoalkylaminoalkyl" according to the present invention refers to-alkyl-NH-alkyl.
"Dialkylaminoalkyl" in the context of the present invention refers to-alkyl-N- (alkyl).
"Alkylacyl" as used herein refers to-C (O) -alkyl.
"aminoacyl" according to the invention is-C (O) -NH2。
"Monoalkylaminoacyl" according to the present invention refers to-C (O) -NH-alkyl.
"Dialkylaminoacyl" according to the invention is intended to mean-C (O) -N- (alkyl).
The "nitrogen-containing heterocycloalkyl group" in the present invention means a cyclic saturated alkyl group containing at least one nitrogen atom, the "four-to eight-membered azacycloalkyl group" in the present invention means a saturated four-membered, five-membered, six-membered, seven-membered or eight-membered ring containing at least one nitrogen atom, and the "five-or six-membered azacycloalkyl group" in the present invention means a saturated five-membered or six-membered ring containing at least one nitrogen atom. Suitable examples include, but are not limited to, aziridine, azetidine, tetrahydropyrrolidine, piperidine, piperazine, morpholine rings.
Detailed Description
The following representative examples are intended to better illustrate the present invention and are not intended to limit the scope of the present invention.
Example 1 Synthesis of 1A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
Step a 2-chloro-4- (1H-indazol-1-yl) pyrimidine
After 2, 4-dichloropyrimidine (14.9g, 100mmol) and 50mL of DMF were added to a 250mL reaction flask and dissolved, cesium carbonate (50g, 152mmol) was added, 30mL of DMF solution containing indazole (11.8g, 100mmol) was added dropwise at 0-4 ℃, reaction was carried out at room temperature for 1h after completion of dropwise addition, and after completion of reaction, the mixture was poured into ice water, suction-filtered, the cake was washed with 50mL of water, dried, and purified by column chromatography to obtain the title compound.
ESI-Ms m/z:231.1[M+H]。
Step b N Synthesis of- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine
In a 250mL reaction flask, 2-chloro-4- (1H-indazol-1-yl) pyrimidine (16.3g, 70mmol) obtained in step a, 4-fluoro-2-methoxy-5-nitroaniline (13.0g, 70mmol), p-toluenesulfonic acid (12.0g, 70mmol) and 50mL sec-butyl alcohol are added, dissolved, reacted at 110 ℃ for 2H, after the reaction is finished, cooled to room temperature, filtered, the filter cake is washed with 30mL sec-butyl alcohol, and dried to obtain the title compound.
ESI-Ms m/z:381.2[M+H]。
Step c N Synthesis of- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine
And (3) sequentially adding the N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine (16.8g, 44mmol) obtained in the step b, N, N, N' -trimethylethylenediamine (4.5g, 44mmol), diisopropylethylamine (17.1g, 133mmol) and 50mL dioxane into a 50mL single-neck flask, dissolving, carrying out reflux reaction at 110 ℃ for 3 hours, concentrating after the reaction is finished, and carrying out column chromatography purification to obtain the title compound.
ESI-Ms m/z:463.4[M+H]。
Step d N Synthesis of- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-aminophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine
The product of step C, N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine (18.9g, 41mmol), 10% Pd-C (60mg), and 60mL methanol were added sequentially in a 50mL single-neck flask, and after completion of the reaction, hydrogen was reduced for 1H at room temperature under 1 standard atmosphere, filtered, and concentrated to give the title product, which was used directly in the next step.
ESI-Ms m/z:433.3[M+H]。
Step e N Synthesis of- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
After dissolving the N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-aminophenyl) -4- (1H-indazol-1-yl) pyrimidin-2-amine (9.3g, 22mmol), diisopropylethylamine (2.8g, 22mmol) and 50mL of dichloromethane obtained in step d in a 150mL single-neck flask, 10mL of a dichloromethane solution in which allyl chloride (1.95g, 22mmol) is dissolved is added dropwise at 0 to 5 ℃ and reacted for 10min, and after completion of the reaction, the mixture is concentrated and purified by column chromatography to obtain the title compound.
1H-NMR(300MHz,DMSO-d6):9.59(s,1H),8.89(s,1H),8.56-8.55(d,1H),8.51(s,1H),8.44-8.43(d,1H),8.20(s,1H),7.89-7.87(d,1H),7.46-7.41(m,1H),7.32-7.29(m,2H),7.04(s,1H),6.74-6.65(m,1H),6.29-6.23(d,1H),5.77-5.74(d,1H),3.83(s,3H),3.34-3.31(s,4H),2.83-2.82(m,6H),2.50(s,3H)。
ESI-Ms m/z:486.9[M+H]。
Example 1 Synthesis of 1B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
Step a Synthesis of 2-chloro-4- (1H-indazol-2-yl) pyrimidine
After 2, 4-dichloropyrimidine (14.9g, 100mmol) and 50mL of DMF were added to a 250mL reaction flask and dissolved, cesium carbonate (50g, 152mmol) was added, 30mL of DMF solution containing indazole (11.8g, 100mmol) was added dropwise at 0-4 ℃, reaction was carried out at room temperature for 1h after completion of dropwise addition, and after completion of reaction, the mixture was poured into ice water, suction filtration was carried out, the cake was washed with 50mL of water, and the resulting mixture was dried and purified by column chromatography to obtain the titled compound.
ESI-Ms m/z:231.1[M+H]。
Step b N Synthesis of- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine
In a 250mL reaction flask, 2-chloro-4- (1H-indazol-2-yl) pyrimidine (16.3g, 70mmol) obtained in step a, 4-fluoro-2-methoxy-5-nitroaniline (13.0g, 70mmol), p-toluenesulfonic acid (12.0g, 70mmol) and 50mL sec-butyl alcohol are added, dissolved, reacted at 110 ℃ for 2H, after the reaction is finished, cooled to room temperature, filtered, the filter cake is washed with 30mL sec-butyl alcohol, and dried to obtain the title compound.
ESI-Ms m/z:381.2[M+H]。
Step c N Synthesis of- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine
And (3) sequentially adding the N- (4-fluoro-2-methoxy-5-nitrophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine (16.8g, 44mmol), N, N, N' -trimethylethylenediamine (4.5g, 44mmol), diisopropylethylamine (17.1g, 133mmol) and 50mL dioxane obtained in the step b into a 50mL single-neck flask, dissolving, carrying out reflux reaction at 110 ℃ for 3 hours, concentrating after the reaction is finished, and carrying out column chromatography purification to obtain the title compound.
ESI-Ms m/z:463.4[M+H]。
Step d N Synthesis of- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-aminophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine
The product of step C, N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine (18.9g, 41mmol), 10% Pd-C (60mg), and 60mL methanol were added sequentially in a 50mL single-neck flask, and after completion of the reaction, hydrogen was reduced for 1H at room temperature under 1 standard atmosphere, filtered, and concentrated to give the title product, which was used directly in the next step.
ESI-Ms m/z:433.3[M+H]。
Step e N Synthesis of- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
After dissolving the N- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-aminophenyl) -4- (1H-indazol-2-yl) pyrimidin-2-amine (9.3g, 22mmol), diisopropylethylamine (2.8g, 22mmol) and 50mL of dichloromethane obtained in step d in a 150mL single-neck flask, 10mL of a dichloromethane solution in which allyl chloride (1.95g, 22mmol) is dissolved is added dropwise at 0 to 5 ℃ and reacted for 10min, and after completion of the reaction, the mixture is concentrated and purified by column chromatography to obtain the title compound.
1H-NMR(300MHz,DMSO-d6):10.08(s,1H),9.44(s,1H),8.77-8.80(d,1H),8.49-8.51(d,1H),8.19(s,1H),7.71-7.74(d,1H),7.40-7.45(m,2H),7.23-7.28(m,2H),6.83(s,1H),6.31-6.40(m,2H),5.64-5.68(m,1H),3.90(s,3H),2.89-2.93(t,2H),2.74(s,3H),2.31-2.35(t,2H),2.29(s,6H)。
ESI-Ms m/z:486.9[M+H]。
Example 2 Synthesis of 2A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (5-chloro-4- (1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared in the same manner as in example 1A starting from 4-fluoro-2-methoxy-5-nitroaniline, 2,4, 5-trichloropyrimidine, indazole, N' -trimethylethylenediamine and allyl chloride.
1H NMR(300MHz,DMSO-d6)10.01(s,1H),9.06(s,1H),8.60(s,1H),8.45(s,1H),8.32(s,1H),8.00(d,1H),7.89(d,1H),7.44-7.26(m,2H),7.00(s,1H),6.53(d,1H),6.24(d,1H),5.79(d,1H),3.80(s,3H),3.04-2.91(m,2H),2.65(s,3H),2.49-2.37(m,2H),2.20(s,6H)。
ESI-Ms m/z:521.2[M+H]。
Example 2 Synthesis of 2B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (5-chloro-4- (1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared in accordance with example 1B starting from 4-fluoro-2-methoxy-5-nitroaniline, 2,4, 5-trichloropyrimidine, indazole, N' -trimethylethylenediamine and allylchloride.
Example 3 Synthesis of 3A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (5-methoxy-1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 5-methoxy-1H-indazole, N' -trimethylethylenediamine and allyl chloride by the method of example 1, compound 1A.
1H-NMR(300MHz,DMSO-d6):10.07(s,1H),8.75(s,1H),8.48-8.36(m,4H),7.29(s,1H),7.23-7.21(d,1H),7.06(s,1H),6.97-6.94(d,1H),6.49-6.40(m,1H),6.20-6.14(d,1H),5.73-5.70(d,1H),3.81(s,3H),3.77(s,3H),2.95(s,2H),2.76(s,3H),2.40(s,2H),2.24(s,6H)。
ESI-Ms m/z:517.3[M+H]。
Example 3 Synthesis of 3B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (5-methoxy-1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared as in example 1B starting from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 5-methoxy-1H-indazole, N' -trimethylethylenediamine and allyl chloride.
1H-NMR(300MHz,DMSO-d6):10.00(s,1H),9.24(s,1H),8.23-8.34(m,4H),7.25-7.26(s,1H),7.06(s,1H),6.94-6.97(d,1H),6.52-6.54(d,2H),6.16-6.21(d,1H),5.70-5.74(d,1H),3.80(s,6H),3.01(s,2H),2.71(s,3H),2.46(s,2H),2.23(s,6H)。ESI-Ms m/z:517.3[M+H]。
Example 4 Synthesis of 4A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (5-methyl-4- (1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared from 4-fluoro-2-methoxy-5-nitroaniline, 5-methyl-2, 4-dichloropyrimidine, indazole, N' -trimethylethylenediamine and allyl chloride by the method of example 1, compound 1A.
1H NMR(300MHz,DMSO-d6)10.02(s,1H),8.55-8.35(m,4H),8.27(d,1H),7.83(d,1H),7.38-7.20(m,2H),7.02(s,1H),6.47-6.31(m,1H),6.18(d,1H),5.72(d,1H),3.77(s,3H),2.89(t,2H),2.72(s,3H),2.43(s,3H),2.32(t,2H),2.19(s,6H)。
ESI-Ms m/z:501.2[M+H]。
Example 4 Synthesis of 4B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (5-methyl-4- (1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared in accordance with example 1B starting from 4-fluoro-2-methoxy-5-nitroaniline, 5-methyl-2, 4-dichloropyrimidine, indazole, N' -trimethylethylenediamine and allyl chloride.
1H NMR(300MHz,DMSO-d6)10.21(s,1H),9.69(s,1H),9.21(s,1H),8.57(s,1H),8.19(s,1H),7.70-7.77(m,2H),7.32-7.37(t,1H),7.12-7.16(t,1H),7.04(s,1H),6.37-6.51(m,2H),5.82-5.85(t,1H),3.88(s,3H),2.87(t,2H),2.71(s,3H),2.60(s,3H),2.28(t,2H),2.20(s,6H)。
ESI-Ms m/z:501.2[M+H]。
Example 5 Synthesis of 5A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (5-fluoro-1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared according to the procedure for example 1A starting from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 5-fluoro-1H-indazole, N' -trimethylethylenediamine, and allyl chloride.
1H-NMR(300MHz,CDCl3):10.06(s,1H),9.38(s,1H),8.77(dd,1H),8.49(d,1H),8.15(s,1H),7.44(s,1H),7.39(d,1H),7.34(dd,1H),7.16(td,1H),6.82(s,1H),6.33(s,2H),5.69-5.65(m,1H),3.89(s,3H),2.95-2.90(m,2H),2.74(s,3H),2.48-2.34(m,8H)。
ESI-Ms m/z:505.3[M+H]。
Example 5 Synthesis of 5B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (5-fluoro-1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared as in example 1B starting from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 5-fluoro-1H-indazole, N' -trimethylethylenediamine, and allyl chloride.
1H-NMR(300MHz,CDCl3):10.12(s,1H),9.85(s,1H),8.54-8.56(d,1H),7.95(s,1H),7.66-7.71(m,1H),7.60-7.62(d,1H),7.33-7.36(dd,1H),7.26(s,1H),7.10-7.17(td,1H),6.82(s,1H),6.56-6.61(s,1H),6.44(s,1H),5.77-5.81(d,1H),3.91(s,3H),2.92(t,2H),2.74(s,3H),2.31(s,8H)。
ESI-Ms m/z:505.3[M+H]。
Example 6 Synthesis of 6A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (3-methyl-1H-indazol-1-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared according to the procedure for example 1A starting from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 3-methyl-1H-indazole, N' -trimethylethylenediamine, and allyl chloride.
1H-NMR(300MHz,DMSO-d6):10.07(s,1H),8.71(s,1H),8.47(s,1H),8.46-8.43(m,1H),8.38-8.36(d,1H),7.81-7.79(d,1H),7.37-7.26(m,2H),7.20-7.18(d,1H),7.06(s,1H),6.45-6.36(m,1H),6.19-6.14(d,1H),5.73-5.70(d,1H),3.75(s,3H),2.93(s,2H),2.77(s,3H),2.57(s,3H),2.37(s,2H),2.22(s,6H)。
ESI-Ms m/z:501.3[M+H]。
Example 6 Synthesis of 6B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- (4- (3-methyl-1H-indazol-2-yl) pyrimidin-2-amino) phenyl) allylamide
The title compound was prepared as in example 1B starting from 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloropyrimidine, 3-methyl-1H-indazole, N' -trimethylethylenediamine, and allyl chloride.
Example 7 Synthesis of 7A N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((5-methyl-4- (3-methyl-1H-indazol-1-yl) pyrimidin-2-yl) amino) phenyl) allylamide
The title compound was obtained in the same manner as in example 1A using 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloro-5-methylpyrimidine, 3-methyl-1H-indazole, N' -trimethylethylenediamine, and allyl chloride as starting materials.
1H-NMR(300MHz,DMSO-d6):10.07(s,1H),8.71(s,1H),8.47(s,1H),8.46-8.43(m,1H),8.38-8.36(d,1H),7.81-7.79(d,1H),7.37-7.26(m,2H),7.20-7.18(d,1H),6.45-6.36(m,1H),6.19-6.14(d,1H),5.73-5.70(d,1H),3.75(s,3H),2.93(s,2H),2.77(s,3H),2.57(s,3H),2.37(s,2H),2.34(s,3H),2.22(s,6H)。
ESI-Ms m/z:515.3[M+H]。
Example 7 Synthesis of 7B N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((5-methyl-4- (3-methyl-1H-indazol-2-yl) pyrimidin-2-yl) amino) phenyl) allylamide
The title compound was obtained in the same manner as in example 1B using 4-fluoro-2-methoxy-5-nitroaniline, 2, 4-dichloro-5-methylpyrimidine, 3-methyl-1H-indazole, N' -trimethylethylenediamine, and allyl chloride as starting materials.
Experimental example 1 in vitro kinase Activity evaluation
1 materials of the experiment
1.1 enzymes
EGFRWTKinases available from Carna corporation;
EGFRT790M/L858Rkinase, available from Invitrogen.
1.2 reagents
Adenosine Triphosphate (ATP), purchased from Sigma;
peptide (Peptide FAM-P22) available from GL Biochem;
ethylenediaminetetraacetic acid (EDTA), available from Sigma.
1.3 instruments
Caliper EZ reader microfluidic chip instrument, available from Caliper Life Sciences, Inc.
2 method of experiment
2.1 preparation of 1 Xkinase base buffer and stop buffer
1 × kinase base buffer (for EGFR)WT)：50mM HEPES，pH7.5，0.0015％Brij-35，10mM MgCl2，10mM MnCl2，2mM DTT；
1 × kinase base buffer (for EGFR)T790M/L858R)：50mM HEPES，pH7.5，0.0015％Brij-35，10mM MgCl2，2mM DTT；
Stop buffer: 100mM HEPES, pH7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3, 50mM EDTA.
2.2 preparation of Compounds
The compounds of the invention were dissolved in 100% DMSO to 10mM each, diluted to 50. mu.M in complete medium, then diluted to 5. mu.M in complete medium containing 0.1% DMSO, and then sequentially diluted 3-fold for 10 concentrations (for EGFR)WT)；
The compounds of the present invention were dissolved in 100% DMSO to 10mM each, diluted to 50. mu.M in complete medium, diluted to 1. mu.M in complete medium containing 0.1% DMSO, and then sequentially diluted 3-fold for 10 concentrations(for EGFR)T790M /L858R)；
Add 100. mu.l 100% DMSO to empty wells for preparing kinase no compound control and kinase no compound control;
the 96-well plate used above was labeled as the source plate.
2.3 preparation of the intermediate plate
Transfer 10. mu.l of the solution from the source plate to a new 96-well plate as an intermediate plate, add 90. mu.l of 1 Xkinase buffer to each well of the intermediate plate, and mix by shaking for 10 min.
2.4 preparation of the test plate
From a 96-well intermediate plate, 5. mu.l of the solution was transferred per well to a 384-well plate.
2.5 kinase reaction
2.5.1. Preparation of 2.5 × kinase solution: EGFR (epidermal growth factor receptor)WTKinase and EGFRT790M/L858RAdding the kinase stock solution into 1 × basic buffer solution respectively to prepare 2.5 × kinase solution;
2.5.2. preparation of a 2.5 Xpeptide solution: adding FAM labeled peptide and ATP into 1 × basic buffer solution to prepare 2.5 × peptide solution;
2.5.3. transfer 10. mu.l of 2.5 Xkinase solution to 384 well assay plates and incubate for 10min at room temperature;
2.5.4. transfer 10. mu.l of 2.5 Xpeptide solution to 384 well plates, incubate at 28 ℃ for a period of time, and stop the reaction by adding 25. mu.l of stop buffer.
A kinase-free no compound control group (containing DMSO, 1 Xbase buffer and 2.5 Xpeptide solution) and a kinase-free no compound control group (containing DMSO, 2.5 Xkinase solution and 2.5 Xpeptide solution) were set at the same time.
Reading and fitting a curve of the Caliper instrument, and calculating the inhibition rate
Reading data on a Caliper instrument, obtaining conversion data from a Caliper program, and calculating the inhibition rate according to the following formula:
inhibition rate [% ], [% ] represents [% ], [% ] represents "[% ], [% ] represents" [% ].
2.5.6. Computing IC Using Graphpad 5.0 data processing software50The value is obtained. The results are shown in Table 1.
TABLE 1
As can be seen from the above results, the compounds of the present invention are directed against mutant EGFR kinases, such as EGFRL858R/T790MHas good inhibitory activity, IC50Values were less than 1 nM. Therefore, the compound of the invention has good inhibition effect on mutant EGFR kinase, has better selectivity on mutant cells compared with EGFR wild type cells, and is expected to be a medicament with specific curative effect for treating drug-resistant tumors, particularly drug-resistant tumors caused by EGFR mutation.
Experimental example 2 evaluation of in vitro cell Activity
1 materials of the experiment
1.1 cells
Experimental cell lines NCI-H1975(EGFR double mutant cells with L858R and T790M mutations) and A431(EGFR wild-type cells) were purchased from ATCC.
1.2 reagents
Cell Titer-Glo luminescence Cell viability assay, available from Promega corporation;
RPMI1640medium, available from Invitrogen;
DMEM medium, available from Invitrogen corporation;
fetal bovine serum, purchased from Invitrogen;
DMSO, available from Sigma company;
NCI-H1975 cells were cultured in RPMI1640medium containing 10% inactivated fetal bovine serum (GIBCO) containing 100IU/mL of penicillin and 100. mu.g/mL of streptomycin;
a431 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum (GIBCO) containing 100IU/mL of penicillin and 100. mu.g/mL of streptomycin.
2 method of experiment
2.1 Experimental Process (CTG assay)
NCI-H1975 cells and A431 cells in logarithmic growth phase were digested, blown into single cell suspension, inoculated into 96-well culture plates with 100. mu.L of culture medium per well, and plated in 3-well plates for each cell line, wherein NCI-H1975 cells were plated in 3X 10-well plates per well3Individual cells, a431 cells were seeded at 4X 10 per well3And (4) cells. Inoculating NCI-H1975 cells and A431 cells in 5% CO2After the cells are attached to the surface, the test compound (the highest test concentration of the compound on NCI-H1975 cells is 4 mu M, 3 times of dilution, and 9 concentrations in total; the highest test concentration on A431 cells is 10 mu M, 3 times of dilution, and 9 concentrations in total) is added, and the cells are cultured in the incubator for another 72 hours. Both a blank control (medium only, no cells and DMSO solution) and a DMSO control (medium with cells and 0.5% DMSO solution) were set. Add 100. mu.L of CTG solution, shake for 2min in the dark, incubate for 10 min.
2.2 reading, calculating IC50Value of
Placing the culture plate in
Reading the plate by a multi-mode microplate detector, recording the luminescence reading result, and calculating the inhibition rate according to the following formula:
inhibitor (%) - (1- (RLU)com-RLUblank)/(RLUDMSO–RLUblank))×100％，
Wherein RLUcomDenotes the absorbance, RLU, of the test Compound groupblankAbsorbance values, RLU, of blank control groupDMSOThe absorbance of the DMSO control was expressed,
the drug effect inhibition rate curve is drawn by using XLFit curve fitting software and the IC is calculated50The values and results are shown in Table 2.
TABLE 2
It has been shown that one of the major side effects of EGFR inhibitors on the market is skin rash, diarrhea, etc., which are associated with the inhibition of wild-type EGFR. The results of the above experiments show that the compound of the present invention has a good inhibitory effect on double mutant cells (NCI-H1975), and has little inhibition and good selectivity on EGFR wild-type cells (A431). Is expected to become a drug with specific curative effect and less side effect for resisting the drug-resistant tumor caused by EGFR mutation.
Experimental example 3 blood sugar Effect test
1 materials of the experiment
1.1 Compounds
Dissolving the compound with 25mM citric acid-sodium citrate buffer solution (pH4.5), preparing into 1.25mg/mL clear solution, and setting as test compound group; using 25mM citric acid-sodium citrate buffer solution (pH4.5) as solvent control group;
1.2 animals
Female BALB/C mice, each 5 in each group, weighing 18-22g, were provided by Shanghai Sphere-BiKai laboratory animals Co. The test mice are given an environmental adaptation period of 2-4 days before the experiment, and are fasted for 8-12h before the administration.
2 method of experiment
2.1 mice fasted but had free access to water for 12 hours;
2.2 taking 5 mice from step 2.1, intragastric administration (I.G.) 25mg/kg of the compound of the present invention;
2.3 blood is collected at eye orbit 0min, 15min, 30min, 1h and 2h after gastric lavage, the blood sugar value A of the animal is detected by using a Roche excellence type glucometer, and the AUC is [ (A) according to the formula15min+A0)×7.5]+[(A30min+A15min)×7.5]+[(A60min+A30min)×15]+[(A120min+A60min)×30]Calculating AUC value, and increasing AUC%Compound (I)－AUCSolvent)/AUCSolvent]X 100% AUC growth rate, where "A0"represents the blood sugar level 0min after intragastric administration," A15min"represents the blood sugar value after intragastric administration for 15min," A30min"represents the blood sugar value after 30min of intragastric administration," A60min"means after 60min of gavageBlood sugar level of "A120min"represents blood sugar value 120min after intragastric administration," AUCCompound (I)"AUC value representing test Compound," AUCSolvent"represents the AUC value of the vehicle control group, and the results are shown in Table 3.
TABLE 3
CO-1686 has been shown to induce hyperglycemia (22%) clinically. The experimental results show that the compound has small influence on blood sugar, is expected to reduce the hyperglycemia side effect of the compound and improve the patient compliance.
Experimental example 4 drug metabolism experiment
1 materials of the experiment
1.1 Compounds
The compounds of the present invention are formulated for both oral and parenteral administration. Wherein, the oral medicine is dissolved in 25mM citric acid-sodium citrate buffer solution (pH4.5) to prepare 1.25mg/mL clear solution; the tail vein injection drug formula is characterized in that the volume ratio of citric acid-sodium citrate buffer solution (pH4.5) to normal saline is 1: 1 to prepare a 0.2mg/mL solution.
1.2 animals
Female BALB/C mice, each 5 in each group, weighing 18-22g, were provided by Shanghai Sphere-BiKai laboratory animals Co. The test mice are given an environmental adaptation period of 2-4 days before the experiment, are fasted for 8-12h before the administration, are fed with water after the administration for 2h, and are fed with food after 4 h.
1.3 reagents
Methanol (chromatographically pure): manufactured by Spectrum corporation;
acetonitrile (chromatographically pure): manufactured by Spectrum corporation;
the other reagents were all commercially available analytical grade.
1.4 instruments
API 4500 model triple quadrupole LC MS, available from AB corporation, USA, equipped with electrospray ionization source (ESI), LC-30AD dual pump; SIL-30AC autosampler; a CTO-30AC column incubator; DGU-20A3R deaerator; an Analyst QS a01.01 chromatography workstation; Milli-Q ultra pure water devices (Millipore Inc); a Qilinbeier Vortex-5 oscillator; HITACHI CF16R XII desk high speed refrigerated centrifuge.
2 method of experiment
2.1 after the mice are fasted but can drink water freely for 12 hours, blank plasma at 0 moment is adopted;
2.2 taking 5 mice from step 2.1, intragastric administration (I.G.) to administer 25mg/kg of the compound of the present invention;
5 mice in step 2.1 were taken and 2mg/kg of compound of the present invention was administered to the tail vein (i.v.);
2.3 after the gavage, 5min, 15min, 30min, 1h, 2h, 4h, 10h and 24h, continuously taking blood from the fundus venous plexus, placing the blood in an EP tube distributed with heparin, centrifuging at 8000rpm/min for 5min, taking upper layer plasma, freezing and storing at-20 ℃, and waiting for LC-MS/MS analysis;
continuously taking blood from the fundus venous plexus 5min, 15min, 30min, 1h, 2h, 4h, 10h and 24h after tail vein injection administration, placing the blood in an EP tube distributed with heparin, centrifuging at 8000rpm/min for 5min, taking upper layer plasma, freezing and storing at-20 ℃, and waiting for LC-MS/MS analysis;
2.4 according to the blood concentration-time data obtained in the step 2.3, adopting WinNonlin software to calculate pharmacokinetic parameters, and showing in a table 4;
TABLE 4
As can be seen from the above table 4, the compound of the present invention has good pharmacokinetic data and good clinical application prospects.
Although the present invention has been described in detail above, those skilled in the art will appreciate that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of the invention is not to be limited by the above detailed description but is only limited by the claims.
Claims (12)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein:
pyrimidine ring
And indazole rings
Is connected with N to form
R1、R1a、R2And R3Each independently selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, nitro, cyano, hydroxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino radical, amino radical C1-6Alkyl, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino radical C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl acyl, amino acyl, mono C1-6Alkylaminoacyl and di-C1-6An alkylaminoacyl group;
R4、R5and R6Each independently selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl radical, said C1-6Alkyl radical, C1-6Alkoxy and C3-8Cycloalkyl optionally substituted by one or more halogens, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino, hydroxy, amino C1-6Alkyl, mono C1-6Alkylamino radical C1-6Alkyl, di-C1-6Alkylamino radical C1-6Alkyl and hydroxy C1-6Alkyl substitution;
Raselected from hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl and halo C1-6An alkyl group; and
Rbselected from hydrogen, C1-6Alkyl and C3-6Cycloalkyl radical, said C1-6Alkyl and C3-6Cycloalkyl optionally substituted by one or more halogens, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, amino, mono C1-6Alkylamino, di-C1-6Alkylamino or hydroxy, wherein the compound is not a compound of:
2. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
R1、R1a、R2and R3Each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, ethoxy, propoxy, trifluoromethyloxy, nitro, cyano, hydroxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-methyl-N-isopropylamino, N-ethyl-N-propylamino, N-ethyl-N-isopropylamino, N-propylamino-N-isopropylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl and ethoxyethyl.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
Raselected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.
4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
Rbselected from hydrogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6The cycloalkyl group is optionally substituted with one or more halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, or hydroxy.
5. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein:
Rbselected from hydrogen, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6The cycloalkyl group is optionally substituted with one or more halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, or hydroxy.
6. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein RbSelected from methyl, ethyl and propyl, said methyl, ethyl and propyl being optionally substituted with one or more amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino or ethylpropylamino groups.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is the following:
8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof or a composition according to claim 8 in the manufacture of a medicament for the treatment and/or prophylaxis of tumours.
10. Use according to claim 9, wherein the tumour is a drug resistant tumour.
11. Use according to claim 10, wherein the tumour is a tumour resistant to EGFR inhibitors.
12. A compound of formula II or a pharmaceutically acceptable salt thereof,
wherein R is1、R1a、R2、R3、RaAnd RbHaving the definitions as defined in any one of claims 1 to 6;
wherein the compound is not:
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| CN106661000B (en) * | 2014-10-11 | 2019-04-09 | 上海翰森生物医药科技有限公司 | EGFR inhibitor and its preparation and application |
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