CN108929311B - 2- (2,4, 5-substituted aniline) pyrimidine derivatives - Google Patents
2- (2,4, 5-substituted aniline) pyrimidine derivatives Download PDFInfo
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- CN108929311B CN108929311B CN201710361541.0A CN201710361541A CN108929311B CN 108929311 B CN108929311 B CN 108929311B CN 201710361541 A CN201710361541 A CN 201710361541A CN 108929311 B CN108929311 B CN 108929311B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Disclosed are a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a process for producing the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof, and the use of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof:
wherein R is1、R2And R3As defined herein.
Description
FIELD
The present application relates generally to the field of pharmaceutical chemistry. In particular, the present application relates to EGFR and/or EGFR mutant inhibitors.
Background
EGFR (epidermal Growth Factor receptor) is one of the members of the family of epidermal Growth Factor receptors (HER), which includes HER1(ErbB1, EGFR), HER2(ErbB2, neu), HER3(ErbB3) and HER4(ErbB4), which plays an important regulatory role in the cellular physiological processes EGFR is a receptor for Epidermal Growth Factor (EGF) cell proliferation and signaling, mutation or overexpression of which typically triggers tumors, EGFR is a glycoprotein, which belongs to the tyrosine kinase type receptor, which is cell membrane-penetrating, has a molecular weight of 170 kda.egfr is located on the cell membrane surface and is activated by binding to ligands, including EGF and TGF α (Transforming Growth Factor α), after activation, EGFR monomers are converted to dimers, although evidence also exists that dimers before activation are also likely to be activated by polymerization with other members of the ErbB receptor family, such as ErbB2/HER 2/neu.
SUMMARY
In one aspect, the present application relates to a compound represented by formula (I):
wherein the content of the first and second substances,
R1selected from O, S or-NH；
R2Selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In another aspect, the present application relates to a process for preparing a compound of formula (I):
wherein the method comprises the following steps:
reacting a compound shown in a formula (II) with acryloyl chloride to obtain a compound shown in a formula (I):
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In yet another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In a further aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her):
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer and/or a tumour:
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In other aspects, the application relates to a method of treating a tumor and/or cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
Detailed description of the invention
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated meaning, i.e. the word "comprising" and "comprises", in an open-ended, inclusive sense, i.e. to mean "including but not limited to".
Reference throughout this specification to "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
Definition of
The barrel legend preceded by certain chemical groups named herein indicates the total number of carbon atoms present at the indicated chemical group. E.g. C7-C12Alkyl describes an alkyl group having a total of 7 to 12 carbon atoms, as defined below, and C3-C10Cycloalkyl describes cycloalkanes having a total of 3 to 10 carbon atoms as defined belowAnd (4) a base. The total number of carbons in the canyon does not include carbons that may be present in the substituents of the group.
Furthermore, unless indicated to the contrary, the following terms used in the specification and appended claims have the following meanings:
"amino" means-NH2A group.
"cyano" refers to the group-CN.
"hydroxy" means an-OH group.
"nitro" means-NO2A group.
"oxo" refers to an ═ O substituent.
"mercapto" means an-SH group.
"carboxy" refers to the-COOH group.
"Sulfonyl" means R-S (═ O)2-a group.
"carbamoyl" refers to-CONH2A group.
"halogen" means fluorine, chlorine, bromine or iodine.
The term "alkyl" as used herein refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturated bonds, having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms, and which is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
The term "alkylene" as used herein refers to a straight or branched divalent hydrocarbon chain linking the remainder of the molecule to a group, consisting only of carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. The alkylene group is connected to the rest of the molecule by a single bond and to the group by a single bond. The alkylene group may be attached to the rest of the molecule and to this group via one or any two carbons in the chain.
The term "cycloalkyl" as used herein refers to a stable non-aromatic mono-or polycyclic alkyl group, consisting solely of carbon and hydrogen atoms, which may comprise a fused or bridged ring system, having 3 to 18 carbon atoms, preferably having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, preferably having 2 to 6 carbon atoms, which is saturated and connected to the rest of the molecule by a single bond. Examples of monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like.
The term "substituted cycloalkyl" as used herein refers to a cycloalkyl group having a substituent replacing one or more hydrogens on one or more (typically no more than four) carbon atoms of the cycloalkyl backbone. The substituents are independently selected from: halogen (e.g. I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (e.g. C)1-C6Alkoxy), substituted alkoxy, aryloxy (e.g., phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (e.g., trifluoromethyl), aryl, substituted aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, and-OCF3. When the specification and claims refer to a particular substituent of a cycloalkyl group, the substituent may occupy one or more substitutable positions of the cycloalkyl group. For example, a cycloalkyl group with a fluorine substituent is recited, and would include mono-, di-, and possibly higher degrees of substitution on the cycloalkyl group.
The term "alkoxy" as used herein refers to the general formula-ORaGroup, wherein RaIs an alkyl group as defined above. The alkyl portion of the alkoxy group may be substituted as defined above for "substituted cycloalkyl".
The term "cycloalkyloxy" as used herein refers to the general formula-ORbGroup, wherein RbIs cycloalkyl as defined above. The cycloalkyl moiety of cycloalkyloxy may be substituted as defined above for "substituted cycloalkyl".
The term "aryl" as used herein means consisting only of hydrogen and carbon and containingAn aromatic monocyclic or polycyclic hydrocarbon ring system of 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, wherein said ring system may be partially or fully saturated. Examples of aryl groups include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar- (ar-)" (such as "aralkyl") is meant to include aryl groups optionally substituted with one or more substituents independently selected from: halogen (e.g. I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (e.g. C)1-C6Alkoxy), substituted alkoxy, aryloxy (e.g., phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (e.g., trifluoromethyl), aryl, substituted aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, and-OCF3。
The term "heterocyclyl" as used herein refers to a stable 3 to 18 membered non-aromatic ring group consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In certain embodiments of the present application, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocyclyl group can be optionally oxidized; the nitrogen atoms may optionally be quaternized; and the heterocyclyl group may be partially saturated or fully saturated. Examples of heterocyclyl groups include, but are not limited to, dioxane, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above optionally substituted with one or more substituents independently selected from: halogen (e.g. I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (e.g. C)1-C6Alkoxy), substituted alkoxy, aryloxy (e.g., phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (e.g., trifluoromethyl), aryl, substituted aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, and-OCF3。
The term "heteroaryl" as used herein refers to a 5 to 18 membered aromatic ring group consisting of carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In certain embodiments of the present application, the heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused ring systems or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. Examples of heteroaryl groups include, but are not limited to, aza
A group selected from the group consisting of an acridinyl group, a benzimidazolyl group, a benzothiazolyl group, a benzindolyl group, a benzothiadiazolyl group, a benzonaphthofuranyl group, a benzoxazolyl group, a benzodioxolyl group, a benzoxazinyl group, a benzopyranyl group, a benzopyranonyl group, a benzofuranyl group, a benzofuranonyl group, a benzothiophenyl group (benzothiophenyl group), a benzotriazolyl group, a benzo [4,6 ] carbonyl group]Imidazo [1,2-a ]]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-aza-azanyl
Examples of the substituent include, but are not limited to, an oxazolyl group, an oxirane group, a phenazinyl group, a phenothiazinyl group, a phenoxazinyl group, a 2, 3-naphthyridinyl group, a pteridinyl group, a purinyl group, a pyrrolyl group, a pyrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a quinazolinyl group, a quinoxalinyl group, a quinolyl group, a quinuclidinyl group, an isoquinolyl group, a thiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group. Unless otherwise specifically stated in the specification, the term "heteroaryl" is intended to include any substituted or unsubstituted groupA substituted heteroaryl group as defined above, said substituents being independently selected from: halogen (e.g. I, Br, Cl, F), hydroxy, amino, cyano, alkoxy (e.g. C)1-C6Alkoxy), substituted alkoxy, aryloxy (e.g., phenoxy), nitro, mercapto, carboxyl, oxo, carbamoyl, alkyl, substituted alkyl (e.g., trifluoromethyl), aryl, substituted aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl, and-OCF3。
The term "pharmaceutically acceptable salt" as used herein includes acid addition salts and base addition salts.
The term "pharmaceutically acceptable acid addition salt" as used herein refers to salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed with inorganic or organic acids. Examples of exemplary inorganic acids that can be used in the present application include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of exemplary organic acids that can be used in the present application include, but are not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, phenylglycolic acid, glycolic acid, Methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid and the like.
The term "pharmaceutically acceptable base addition salt" as used herein refers to a salt that retains the biological effectiveness and properties of the free acid, which is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Exemplary salts derived from inorganic bases that can be used in the present application include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Exemplary salts derived from organic bases that can be used in the present application include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzethylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
The term "mammal" as used herein includes humans and domestic animals such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), as well as non-domestic animals such as wild animals and the like.
The term "pharmaceutical composition" as used herein refers to a formulation of a compound in the present application with a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human. The medium includes all pharmaceutically acceptable carriers for its use. The pharmaceutical composition facilitates administration of the compound to an organism. There are a variety of methods in the art for administering compounds including, but not limited to, oral administration, injection, aerosol administration, parenteral administration, and topical administration. Pharmaceutical compositions can also be obtained by reacting the compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
The term "carrier" as used herein is defined as a compound that facilitates the introduction of the compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.
The term "tumor (tumor)" as used herein refers to a neoplasm (neograwth) formed by local tissue cell proliferation of the body under the action of various tumorigenic factors. According to the cellular characteristics of the new organism and the degree of harm to the organism, tumors are divided into two major categories, namely benign tumors and malignant tumors.
The term "cancer" as used herein refers to a general term for malignant tumors.
The term "therapeutically effective amount" as used herein refers to an amount of a compound of the present application which, when administered to a mammal, preferably a human, is sufficient to effectively treat (as defined below) tumors and/or cancers in the mammal, preferably a human. The amount of the compound of the present application which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age of the mammal to be treated, but can be determined routinely by those skilled in the art, based on their own knowledge and this disclosure
The term "treating" or "treatment" as used herein encompasses treating a related disease or condition in a mammal, preferably a human, suffering from the related disease or condition and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when the mammal is susceptible to said disease condition but has not been diagnosed as having such a disease condition;
(ii) inhibiting a disease or disease state, i.e., preventing its occurrence; or
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.
As used herein, the terms "disease" and "disease state" may be used interchangeably, or may be different, in that a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and is therefore not recognized as a disease, but rather is considered an undesirable disease state or condition, in which a clinician has identified a more or less specific series of symptoms.
In vivo administration may be carried out as a single administration, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for treatment, the purpose of the treatment, the target cells being treated and the individual being treated. Single or multiple administrations may be carried out, the dose level and pattern being selected by the attending physician.
Detailed Description
In one aspect, the present application relates to compounds of formula (I):
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In certain embodiments, R1Selected from O or S.
In certain embodiments, R2Selected from single bonds or unsubstituted alkylene groups.
In certain embodiments, R2Selected from single bonds or unsubstituted C1-C6An alkylene group.
In certain embodiments, R2Selected from single bonds or unsubstituted C1-C4An alkylene group.
In certain embodiments, R2Is a single bond.
In some implementationsIn the scheme, R2Selected from methylene, ethylene, propylene or butylene.
In certain embodiments, R1Is selected from O or S, and R2Selected from single bonds or unsubstituted alkylene groups.
In certain embodiments, R1Is selected from O, and R2Selected from single bonds or unsubstituted alkylene groups.
In certain embodiments, R1Is selected from O or S, and R2Selected from single bonds or unsubstituted C1-C4An alkylene group.
In certain embodiments, R1Is selected from O or S, and R2Selected from methylene, ethylene, propylene or butylene.
In certain embodiments, R3Is an unsubstituted cycloalkyl group.
In certain embodiments, R3Selected from unsubstituted C3-C18A cycloalkyl group.
In certain embodiments, R3Selected from unsubstituted C3-C15A cycloalkyl group.
In certain embodiments, R3Selected from unsubstituted C3-C10A cycloalkyl group.
In certain embodiments, R3Selected from unsubstituted C3-C6A cycloalkyl group.
In certain embodiments, R3Selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In certain embodiments, R3Is selected from substituted cycloalkyl, wherein the substituents are selected from halogen, hydroxy, amino, cyano, alkoxy, substituted alkoxy, aryloxy, nitro, mercapto, carboxy, oxo, carbamoyl, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, heteroaryl, alkylsulfonyl, arylsulfonyl or-OCF3。
In certain embodiments, R1Selected from O or S, R2Selected from single bonds or unsubstituted alkylene, and R3Is selected fromA substituted cycloalkyl group.
In certain embodiments, R1Selected from O, R2Selected from single bonds or unsubstituted alkylene, and R3Selected from unsubstituted cycloalkyl groups.
In certain embodiments, R1Selected from O or S, R2Selected from single bonds or unsubstituted C1-C4Alkylene, and R3Selected from unsubstituted C3-C6A cycloalkyl group.
In certain embodiments, R1Selected from O or S, R2Selected from a single bond or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R3Selected from unsubstituted C3-C6A cycloalkyl group.
In certain embodiments, R1Selected from O or S, R2Selected from single bonds or unsubstituted C1-C4Alkylene, and R3Selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In certain embodiments, the compound of formula (I) is selected from:
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclobutyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopentyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclohexyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclobutylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopentylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclohexylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclobutylethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopentylethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclohexylethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylpropoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclobutyl-propoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopentylpropoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclohexylpropoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylbutoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclobutyl butoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide;
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopentylbutoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide; and
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclohexylbutoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide.
In certain aspects, the compounds of the present application have improved pharmacodynamic properties.
In certain aspects, the compounds of the present application have improved epidermal growth factor receptor inhibitory activity.
In certain aspects, the compounds of the present application have improved pharmacokinetic properties.
In certain aspects, the compounds of the present application have improved metabolic properties in vivo.
In certain aspects, the compounds of the present application have improved in vivo tumor suppression activity.
In certain aspects, the compounds of the present application have improved safety.
In certain aspects, the compounds of the present application have improved tolerability.
In certain embodiments, the compounds of the present application refer inter alia to the following compounds:
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide; and
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide.
In another aspect, the present application relates to a process for preparing a compound of formula (I):
wherein the method comprises the following steps:
reacting a compound shown in a formula (II) with acryloyl chloride to obtain a compound shown in a formula (I):
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In certain embodiments, the compound of formula (II) is reacted with acryloyl chloride in the presence of a strong base to provide the compound of formula (I).
Examples of exemplary strong bases that can be used in the present application include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, and sodium tert-butoxide.
In certain embodiments, the compound of formula (II) is reacted with acryloyl chloride in the presence of a polar solvent to provide the compound of formula (I).
Examples of exemplary polar solvents that can be used in the present application include, but are not limited to, water, formamide, trifluoroacetic acid, dimethyl sulfoxide (DMSO), acetonitrile, N-Dimethylformamide (DMF), hexamethylphosphoramide, methanol, ethanol, acetic acid, isopropanol, pyridine, tetramethylethylenediamine, acetone, triethylamine, N-butanol, dioxane, and Tetrahydrofuran (THF).
In yet another aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
Examples of exemplary "pharmaceutically acceptable carriers" that can be used in the present application include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is approved by the national drug administration for acceptable use in humans or livestock.
In a further aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her):
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In certain embodiments, the epidermal growth factor receptor (Her) is EGFR (Her 1).
In certain embodiments, EGFR (Her1) is wild-type.
In certain embodiments, EGFR (Her1) is a mutant.
In certain embodiments, EGFR (Her1) is a single mutant or double mutant.
In certain embodiments, the compounds of formula (I) and pharmaceutically acceptable salts thereof have inhibitory activity against L858R EGFR mutants, T790M EGFR mutants, and Exon19 deletion activation mutants.
In another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer and/or a tumour:
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
Since the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present application have inhibitory activity against L858R EGFR mutants, T790M EGFR mutants and Exon19 deletion activating mutants, they are useful in the treatment of diseases or disease states mediated by EGFR mutant activity, such as cancer.
In certain embodiments, the compounds of formula (I) and pharmaceutically acceptable salts thereof of the present application are useful in the treatment of diseases or disease states mediated by L858R EGFR mutants and/or T790M EGFR mutants and/or Exon19 deletion activation mutants, such as cancer.
In certain embodiments, the cancer is selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AM L), multiple myeloma, melanoma, and mesothelioma.
In certain embodiments, the lung cancer is selected from small cell lung cancer (SC L C) and non-small cell lung cancer (NSC L C).
In other aspects, the application relates to a method of treating a tumor and/or cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
wherein the content of the first and second substances,
R1selected from O, S or-NH;
R2selected from single bonds or substituted or unsubstituted alkylene groups; and
R3selected from substituted or unsubstituted cycloalkyl.
In certain embodiments, the subject is a mammal.
In certain embodiments, the subject is a human.
In certain embodiments, a unit dose of 0.1mg to 1000mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject in need of treatment for a tumor and/or cancer.
In certain embodiments, a unit dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 1mg to 1000mg administered to a subject in need of treatment for a tumor and/or cancer.
Examples
In addition, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and are available from common commercial sources.
Unless otherwise stated, it is to be understood that,1HNMR was measured using deuterated dimethyl sulfoxide at a frequency of 400 or 500MHz at about 20-30 ℃. Standard NMR abbreviations are used: s is singlet; d is bimodal; dd bimodal; t is a triplet; q is quartet; p is quintuple; m is multiplet; br is broadband.
Preparation examples
Intermediate 1
1 1 4N- (2-dimethylaminoethyl) -5-cyclopropylmethoxy-N-methyl-N- [4- (1-methyl-indol-3-yl)
Pyrimidin-2-yl]Benzene-1, 2, 4-triamines
Mixing N '- (2-dimethylaminoethyl) -2-cyclopropylmethoxy-N' -methyl-N- [4- (1-methyl-indol-3-yl) pyrimidin-2-yl]-5-Nitrobenzene-1, 4-diamine (intermediate 2, 30g), iron (20g) and NH4A mixture of Cl (2g) in ethanol (100m L) and water (30m L) was heated at reflux for 2 h, the crude mixture was purified by ion exchange chromatography using a SCX column, eluted from the column with methanol-ammonia and concentrated in vacuo to give the title compound (90%). m/z:486
Intermediate 2
N '- (2-dimethylaminoethyl) -2-cyclopropylmethoxy-N' -methyl-N- [4- (1-methyl-indol-3-yl)
Pyrimidin-2-yl]-5-Nitrobenzene-1, 4-diamine
Adding 230m L DMA, 32g N, N ', N' -trimethylethane and 41g DIPEA into a 1000m L three-necked bottle, stirring at room temperature for 30 minutes, adding 58g N- (4-fluoro-2-cyclopropylmethoxy-5-nitrophenyl) -4- (1-methyl-indol-3-yl) pyrimidin-2-amine (intermediate 3), heating the solid-liquid suspension to 85 ℃ for reaction for 2-3 hours, monitoring the reaction by T L C and mass spectrometry, filtering while hot, adding 300m L acetonitrile (including the acetonitrile content for washing filter cakes) into the filtrate, cooling to about 5 ℃, separating out a large amount of red products, filtering, drying at 50 ℃ under reduced pressure to obtain the title compound, wherein the yield is 87%. m/z:516
Intermediate 3
N- (4-fluoro-2-cyclopropylmethoxy) -5-nitrophenyl) -4- (1-methyl-indol-3-yl) pyrimidine-2-amines
P-toluenesulfonic acid hydrate (43.25g) was added in one portion to a mixture of 3- (2-chloropyrimidin-4-yl) -1-methyl-indole (intermediate 4, 32.17g) and 4-fluoro-2-cyclopropylmethoxy-5-nitroaniline (intermediate 5, 24.14g) in 2-pentanol (500m L.) the resulting mixture was stirred at 105 ℃ for 2.5 hours then cooled to room temperature the resulting precipitate was collected by filtration, washed with 2-pentanol (50m L), dried under vacuum to give some of the desired product as a yellow solid, the filtrate was cooled, the resulting precipitate was collected by filtration, washed with 2-pentanol (10m L.) the two batches were combined, combined with CH3CN was triturated to obtain a solid, which was collected by filtration and dried under vacuum to give the title compound in 86% yield. m/z:433
Intermediate 4
3- (2-Chloropyrimidin-4-yl) -1-methyl-indoles
At 0 ℃ in 10 minutes under N2In the atmosphere, adding CH3MgBr (3M in ether, 22.68M L, 68.03mmol) was added dropwise to a stirred solution of 1-H-indole (7.97g, 68.03mmol) in 1, 2-dichloroethane (250M L), the resulting solution was stirred for 15 minutes, then 2, 4-dichloropyrimidine (15.00g, 100.69mmol) was added all at once, the resulting solution was allowed to warm to room temperature and stirred for a further 16 hours by the addition of CH3The reaction was quenched with OH (25m L) and the mixture was concentrated in vacuo and adsorbed onto silica gel2Cl20-20% of CH in3Elution of OH gave the title compound as a yellow solid (7.17g, 46%). m/z 244
Intermediate 5
4-fluoro-2-cyclopropylmethoxy-5-nitroaniline
4-fluoro-2-cyclopropylmethoxy-aniline (5.2g) was added portionwise to concentrated H cooled in an ice/water bath2SO4(30m L) the temperature was kept below 15 ℃ during the addition the mixture was stirred until all the solid formed had dissolved3(1.357m L) to keep the temperature below 10 ℃. the mixture was stirred overnight and then poured onto ice/water4Basifying OH. The resulting solid was filtered off and then dissolved in CH2Cl2Washed with water and dried (Na)2SO4) And concentrated on silica gel. Purification by FCC with 50-0% in CH2Cl2Eluting with heptane to give the title compound in 90% yield. m/z:226
Intermediate 6
4-fluoro-2-cyclopropyloxy-5-nitroaniline
4-fluoro-2-cyclopropyloxy-aniline (3g) was added portionwise to concentrated H cooled in an ice/water bath2SO4(25m L) the temperature was kept below 15 ℃ during the addition the mixture was stirred until all the solid formed had dissolved3(1.357m L) to keep the temperature below 10 ℃. the mixture was stirred overnight and then poured onto ice/water, the mixture was basified with concentrated NH4OH, the resulting solid was filtered off and then dissolved in CH2Cl2Washed with water and dried (Na)2SO4) And concentrated on silica gel. Purification by FCC with 50-0% in CH2Cl2Heptane elution from (1) gave the title compound in 85% yield. m/z 212
Example 1
N- (2- [ 2-dimethylaminoethyl-methylamino)]-4-Cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl)
Pyrimidin-2-yl]Amino } phenyl) prop-2-enamides
Under ice-bath condition to N1- (2-dimethylaminoethyl) -5-cyclopropylmethoxy-N1-methyl-N4- [4- (1-H-indol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine (intermediate 1, 30g) 10g of sodium hydroxide was added to THF (300m L) and water (30m L). Acryloyl chloride 6g was added to the stirred solution, the mixture was stirred at room temperature for 30 minutes, and the mixture was stirred at room temperature for 1 hour.after completion of the reaction, as detected by T L C, 200m L water and 20m L aqueous ammonia were added to the reaction solution to precipitate a solid, which was then filtered, collected, washed with water, and dried at 50 ℃ for 8 hours to obtain the title compound (yield 93%).
1HNMR:0.06-0.32(4H,m),0.71(1H,d),2.72(3H,s),2.80(6H,d),3.31(4H,s),3.87(2H,s),3.94(3H,s),5.75(1H,d),6.27(1H,d),6.71(1H,dd),7.02-7.23(2H,m),7.24(1H,t),7.46(1H,d),7.56(1H,d),8.25(2H,s),8.87(1H,s),9.42(1H,s),9.54(1H,s)
m/z:ES+MH+540
N- (2- [ 2-dimethylaminoethyl-methylamino)]-4-Cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl)
Pyrimidin-2-yl]Amino } phenyl) prop-2-enamide methanesulfonate
20.5g (1.0eq) of N- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) propan-2-enamide obtained in the above step was charged into a 500m L three-necked flask, dissolved in 120m L ethanol and 80m L ethyl acetate, 4.1g of methanesulfonic acid (1.05eq) +40m L ethyl acetate was added dropwise at room temperature, after dropping, the mixture was kept at that temperature for 1.5 to 2 hours, then slowly cooled to room temperature, filtered, and the filter cake was washed 1 time with an ethyl acetate/ethanol solution (2:1, v/v), filtered and dried to obtain the title compound in 92% yield.
Example 2
N- (2- [ 2-dimethylaminoethyl-methylamino)]-4-cyclopropyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidine
Pyridin-2-yl]Amino } phenyl) Prop-2-enamides
Preparation method and N- (2- [ 2-dimethylaminoethyl-methylamino)]-4-Cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl]Amino } phenyl) prop-2-enamide same, using N1- (2-dimethylaminoethyl) -5-cyclopropyloxy-N1-methyl-N4- [4- (1-methyl-indol-3-yl) pyrimidin-2-yl]Replacement of N by benzene-1, 2, 4-triamine1- (2-dimethylaminoethyl) -5-cyclopropylmethoxy-N1-methyl-N4- [4- (1-methyl-indol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamine, yield 87%.
1HNMR:0.47-0.77(4H,m),2.42(1H,d),2.68(3H,s),2.85(6H,d),3.38(4H,s),3.94(3H,s),5.75(1H,d),6.26(1H,d),6.70(1H,dd),7.05-7.25(2H,m),7.28(1H,t),7.47(1H,d),7.60(1H,d),8.25(2H,s),8.85(1H,s),9.44(1H,s),9.55(1H,s)
m/z:ES+MH+526
N- (2- [ 2-dimethylaminoethyl-methylamino)]-4-cyclopropyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidine
Pyridin-2-yl]Amino } phenyl) prop-2-enamide methanesulfonate
The procedure was the same as for N- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide methanesulfonate to give a yellow solid in 79% yield.
Example 3
N- (2- (2-dimethylaminoethyl-methylamino) -4-methoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-
Base of]Amino } phenyl) prop-2-enamides
To a stirred solution of 3-chloro-N- (2- [ 2-dimethylaminoethyl (methyl) amino ] -4-methoxy-5- { [4- (1-methylindol-3-yl) pyrimidin-2-yl ] amino } phenyl) propanamide (31.5g, 58.76mmol) in acetonitrile (310m L) was added triethylamine (17.84g, 176.28mmol) at room temperature the resulting mixture was heated to 80 ℃ and maintained for 6 hours, then cooled to room temperature water (130m L) was added and the mixture stirred for 12 hours then the mixture was filtered, washed with a mixture of water and acetonitrile (160m L, 1:1) and dried at 50 ℃ overnight to give the title compound (19.2g, 94%).
1HNMR:2.69(3H,s),2.83(6H,d),3.35(4H,s),3.84(3H,s),3.91(3H,s),5.75(1H,d),6.28(1H,d),6.67(1H,dd),7.05-7.23(2H,m),7.29(1H,t),7.43(1H,d),7.56(1H,d),8.21(2H,s),8.81(1H,s),9.47(1H,s),9.52(1H,s)
m/z:ES+MH+500
Biological examples
Calu 3(WT), Calu6(WT), NCI-H1975 (T790M/67858R) and PC9(Ex19del) PC9VanR (Ex19 del/T790M) cell lines were seeded onto 384 well plates at 500-1000 cells per well (depending on the cell line), 70. mu. L RPMI medium containing 10% fetal bovine serum, 2mM L-glutamine and 1% penicillin/streptomycin was added per well, day 0 plates were prepared in duplicate for each cell line at 37 ℃ 5% CO 52Add titrated test compound to assay plate the next day using Echo L liquid Handler, and treated cells at 37 ℃ with 5% CO2A further 72 hours of incubation was performed, each compound was measured as an 11-point dose response with a maximum concentration of 10 μ M, 1:3 dilution, day 0 plates in parallel with the dosing assay plates were treated with Sytox Green and saponin and the number of viable cells in each well was determined after incubating the compound treated plates for 72 hours, 5 μ L2 μ M Sytox Green per well was added and the plates were incubated at room temperature for 1 hour50The value is obtained.
The results in the following table show that the compounds of examples 1 and 2 and the compound of example 3 (control group) have a proliferation inhibiting effect on cell lines expressing mutant EGFR (Ex19del, L858R and/or T790MEGFR) in vitro, but the proliferation inhibiting effect of the compounds of examples 1 and 2 on cell lines expressing wild-type EGFR is smaller than that of example 3, which suggests that examples 1 and 2 have better selectivity and are expected to reduce toxic and side effects caused by inhibition on wild-type EGFR in clinical application.
Inhibition of proliferation (IC) of a panel of NSC L C cell lines expressing mutant or wild-type EGFR by test compounds50μM)
All patents, patent application publications, patent applications, and non-patent publications cited in this specification are herein incorporated by reference in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the scope of the invention should be limited only by the attached claims.
Claims (10)
1. A compound, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropyloxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide; and
n- (2- [ 2-dimethylaminoethyl-methylamino ] -4-cyclopropylmethoxy-5- { [4- (1-methyl-indol-3-yl) pyrimidin-2-yl ] amino } phenyl) prop-2-enamide.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a mesylate salt.
3. A process for preparing a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising:
will N1- (2-dimethylaminoethyl) -5-cyclopropyloxy-N1-methyl-N4- [4- (1-methyl-indol-3-yl) pyrimidin-2-yl]Benzene-1, 2, 4-triamines or N1- (2-dimethylaminoethyl) -5-cyclopropylmethoxy-N1-methyl-N4- [4- (1-H-indol-3-yl) pyrimidin-2-yl]The benzene-1, 2, 4-triamine and acryloyl chloride react to obtain the compound.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her).
6. The use of claim 5, wherein the epidermal growth factor receptor (Her) is EGFR (Her 1).
7. The use of claim 6, wherein the EGFR (Her1) is wild type or mutant.
8. The use of claim 7, wherein the mutant is a single mutant or a double mutant.
9. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer and/or tumour.
10. The use of claim 9, wherein the cancer and/or tumor is non-small cell lung cancer.
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