WO2019010619A1

WO2019010619A1 - 2-(2,4,5-substituted aniline) pyrimidine derivative

Info

Publication number: WO2019010619A1
Application number: PCT/CN2017/092415
Authority: WO
Inventors: 焦玉奇
Original assignee: 焦玉奇
Priority date: 2017-07-10
Filing date: 2017-07-10
Publication date: 2019-01-17

Abstract

Disclosed are a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, a method for preparing the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, and a use for the compound as shown in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R6 are as defined in the present application.

Description

2-(2,4,5-substituted aniline)pyrimidine derivatives

field

This application relates generally to the field of medicinal chemistry. In particular, the present application relates to EGFR and/or EGFR mutant inhibitors.

background

EGFR (Epidermal Growth Factor Receptor) is a member of the epidermal growth factor receptor (HER) family. This family includes HER1 (ErbB1, EGFR), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4). The HER family plays an important regulatory role in the process of cell physiology. EGFR is a receptor for epidermal growth factor (EGF) cell proliferation and signaling, and its mutation or overexpression generally triggers tumors. EGFR is a glycoprotein, a tyrosine kinase receptor, with a cell membrane that penetrates and has a molecular weight of 170 kDa. EGFR is located on the surface of the cell membrane and is activated by binding to ligands, including EGF and TGFα (Transforming Growth Factorα). Upon activation, EGFR is converted from a monomer to a dimer, although there is also evidence that a dimer is present prior to activation. EGFR may also be activated by polymerization with other members of the ErbB receptor family, such as ErbB2/HER2/neu.

Overview

In one aspect, the application relates to a compound of formula (I) and pharmaceutically acceptable salts thereof:

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{3 is} selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R _{4 is} selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

The condition is that at least one deuterium atom is contained in R ₁ to R ₆ .

In another aspect, the present application relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein the method comprises:

The compound of the formula (II) is reacted with acryloyl chloride to give a compound of the formula (I):

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In a further 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:

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In still another aspect, the present application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her):

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In another aspect, the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer and/or tumor:

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In other aspects, the present application relates to a method of treating a tumor and/or cancer comprising administering to a subject in need of such a method a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount. a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

Detailed

In the following description, certain specific details are included to provide a comprehensive understanding of the various disclosed embodiments. However, one skilled in the relevant art will recognize that the embodiments may be practiced without the use of one or more of these specific details, and other methods, components, materials, and the like.

The word "comprise" and its English variants such as "comprises" and "comprising" should be interpreted as open throughout the specification and the appended claims. Inclusive, meaning "including but not limited to".

References throughout the specification to "an embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" are meant to include in at least one embodiment Relevant specific reference elements, structures or features. The appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in some embodiments" 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 will be understood that the singular articles "a", "the", "the", "the" Clearly stated. Thus, for example, a reaction including a "catalyst" includes a catalyst, or two or more catalysts. It is also to be understood that the term "or" is generally used in its meaning including "and/or" unless it is specifically defined otherwise.

definition

Unless otherwise stated to the contrary, the following terms used in the specification and the appended claims have the following meanings:

The term "isotope" as used herein refers to a different species of nuclei of the same element having the same number of protons and different numbers of neutrons.

The term "abundance" as used herein refers to the percentage of atoms of an isotope in the natural element to which it belongs.

The term "isotopic natural abundance" or "natural abundance" as used herein refers to the percentage of atoms in a natural element that are present in a natural element. For example, the natural abundance of isotopes of hydrogen: ¹ H = 99.985%, ² H = 0.015%. Natural abundance of oxygen isotope: ¹⁶ O = 99.76%, ¹⁷ O = 0.04%, ¹⁸ O = 0.20%.

The term "isotopic enrichment index" as used herein refers to the ratio of the abundance of an isotope to the natural abundance of that isotope. For example, a helium atomic index with an isotopic enrichment index of 6000 Abundance is 90% of helium atoms.

The term "hydrogen"("H") as used herein refers to hydrogen consisting of ¹ H (99.985%) and ² H (0.015%) having the natural abundance of isotopes.

The term "氘"("D" and "d") as used herein refers to an isotope of hydrogen (H) having a proton and a neutron in the nucleus of the nucleus with a natural abundance of 0.015%. "d _xy " refers to a substitution with x to y deuterium atoms. For example, methoxy-d ₃ refers to CD ₃ O-.

The term "pharmaceutically acceptable salt" as used herein includes both acid addition salts and base addition salts.

The term "pharmaceutically acceptable acid addition salt" as used herein, refers to a salt that retains the biological effectiveness and properties of the free base, which is not biologically or otherwise undesirable, and which is associated with inorganic acids. Formation of organic 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, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4 -acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecyl sulfate, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, Glutamate, 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, 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-toluene Sulfonic 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. Examples of exemplary inorganic base-derived salts that can be used in the present application include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, rhodium, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. An exemplary salt derived from an organic base that can be used in the present application Examples include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines including naturally 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, baibamin, choline, betaine, phenylethylbenzylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, Piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

The term "pharmaceutical composition" as used herein refers to a formulation of a compound of the present application and a medium generally accepted in the art for delivering a biologically active compound 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 the organism. There are a variety of methods for administering compounds in the art including, but not limited to, oral administration, injectable administration, aerosol administration, parenteral administration, and topical administration. A pharmaceutical composition can also be obtained by reacting a compound with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or the like.

The term "carrier" as used herein is defined to mean a compound that facilitates the introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it is easy to introduce certain organic compounds into cells or tissues of an organism.

The term "tumour" as used herein refers to a neogrowth formed by local tissue cell proliferation under the action of various tumorigenic factors. According to the cell characteristics of the new organism and the degree of harm to the body, the tumor is divided into two major categories: benign tumor and malignant tumor.

The term "cancer" as used herein refers to a generic term for malignant tumors.

The term "therapeutically effective amount" as used herein means that when administered to a mammal, preferably to a human, the compound of the present application is sufficient to effectively treat (as defined below) the amount of a tumor, and/or cancer of a 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 state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art can, based on their own knowledge and the present disclosure, According to Conventional determination of the amount of the compound of the present application

The term "treating" or "treating" as used herein encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:

(i) preventing a disease or disease state occurring in a mammal, especially when the mammal is susceptible to the disease state but has not been diagnosed with the disease state;

(ii) inhibiting the disease or disease state, ie preventing it from occurring; or

(iii) alleviating the disease or condition, even if the disease or condition resolves.

As used herein, the terms "disease" and "disease state" may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology). Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.

In vivo administration can be carried out in a single administration, continuous or intermittent administration (e.g., administration at appropriate intervals in divided doses) 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 the treatment, the purpose of the treatment, the target cells being treated, and the individual being treated. Single or multiple administrations can be performed, and the dosage level and mode are selected by the attending physician.

Detailed ways

In the art, because of the unpredictability of the effects of oxime modification on drug activity and on the metabolic properties of drugs, those skilled in the art will often question or even abandon the idea of 氘 modification as a viable drug design strategy.

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In certain embodiments, R _{1 is} selected from -CH ₂ D, -CHD _2, or -CD ₃ .

In certain embodiments, R _{2 is} selected from -CH ₂ D, -CHD _2, or -CD ₃ .

In certain embodiments, R _{3 is} selected from -CHD- or -CD ₂ -.

In certain embodiments, R _{4 is} selected from -CHD- or -CD ₂ -.

In certain embodiments, R _{5 is} selected from -CH ₂ D, -CHD _2, or -CD ₃ .

In certain embodiments, R _{6 is} selected from -CH ₂ D, -CHD _2, or -CD ₃ .

In certain embodiments, R ₁ is —CD ₃ .

In certain embodiments, R ₂ is —CD ₃ .

In certain embodiments, R ₃ is —CD ₂ —.

In certain embodiments, R ₄ is -CD ₂ -.

In certain embodiments, R ₅ or R ₆ is —CD ₃ .

In certain embodiments, both R ₅ and R ₆ are -CD ₃ .

In certain embodiments, R ₁ is -CD ₃ , R ₂ is -CH ₃ , R ₃ is -CH ₂ -, R ₄ is -CH ₂ -, R ₅ is -CD ₃ , and R ₆ is -CH ₃ .

In certain embodiments, R ₁ is -CD ₃ , R ₂ is -CH ₃ , R ₃ is -CH ₂ -, R ₄ is -CH ₂ -, R ₅ is -CD ₃ , and R ₆ is -CD ₃ .

In certain embodiments, R ₁ is -CD ₃ , R ₂ is -CD ₃ , R ₃ is -CD ₂ -, R ₄ is -CD ₂ -, R ₅ is -CD ₃ , and R ₆ is -CD ₃ .

In certain embodiments, R ₁ is —CH ₃ , R ₂ is —CH ₃ , R ₃ is —CH ₂ —, R ₄ is —CH ₂ —, R ₅ is —CH ₂ D, and R ₆ is — CH ₃ .

In certain embodiments, R ₁ is —CH ₃ , R ₂ is —CH ₃ , R ₃ is —CH ₂ —, R ₄ is —CH ₂ —, R ₅ is —CHD ₂ , and R ₆ is —CH. ₃ .

In certain embodiments, R ₁ is -CH _₂ D, R ₂ is -CH _{_3,} R ₃ is -CH ₂ -, R ₄ is -CH ₂ -, R ₅ is -CD _3, and R ₆ is - CH ₃ .

In certain embodiments, R ₁ is —CHD ₂ , R ₂ is —CH ₃ , R ₃ is —CH ₂ —, R ₄ is —CH ₂ —, R ₅ is —CD ₃ , and R ₆ is —CH. ₃ .

In certain embodiments, R ₁ is -CD ₃ , R ₂ is -CH ₃ , R ₃ is -CHD-, R ₄ is -CH ₂ -, R ₅ is -CD ₃ , and R ₆ is -CH ₃ .

In certain embodiments, R ₁ is -CD ₃ , R ₂ is -CH ₃ , R ₃ is -CH ₂ -, R ₄ is -CHD-, R ₅ is -CD ₃ , and R ₆ is -CH ₃ .

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 200, that is, the abundance of the ruthenium atom as a substituent is 3%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 400, that is, the abundance of the ruthenium atom as a substituent is 6%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 666.67, that is, the abundance of the ruthenium atom as a substituent is 10%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 1000, that is, the abundance of the ruthenium atom as a substituent is 15%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 2000, that is, the abundance of the ruthenium atom as a substituent is 30%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 3333.33, that is, the abundance of the ruthenium atom as a substituent is 50%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 4000, that is, the abundance of the ruthenium atom as a substituent is 60%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 5000, that is, the abundance of the ruthenium atom as a substituent is 75%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6000, that is, the abundance of the ruthenium atom as a substituent is 90%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6333.33, that is, the abundance of the ruthenium atom as a substituent is 95%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6466.67, that is, the abundance of the ruthenium atom as a substituent is 97%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6533.33, that is, the abundance of the ruthenium atom as a substituent is 98%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6566.67, that is, the abundance of the ruthenium atom as a substituent is 98.5%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6,600, that is, the abundance of the ruthenium atom as a substituent is 99%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6633.33, that is, the abundance of the ruthenium atom as a substituent is 99.5%.

In certain embodiments, the ruthenium atom as a substituent has an isotopic enrichment index of 6,660, that is, the abundance of the ruthenium atom as a substituent is 99.9%.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent is at least 60%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent has a abundance of at least 75%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent is at least 90%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the atom atom as a substituent has an abundance of at least 95%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent has a abundance of at least 97%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent is at least 98%, while other isotopes have their natural abundance.

In certain embodiments, the compound of formula (I), and pharmaceutically acceptable salts thereof, The abundance of the ruthenium atom as a substituent is at least 98.5%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent is at least 99%, while other isotopes have their natural abundance.

In certain embodiments, in the compound of formula (I) and pharmaceutically acceptable salts thereof, the aze atom of the substituent has a abundance of at least 99.5%, while other isotopes have their natural abundance.

In certain embodiments, the compound of formula (I) is selected from the group consisting of

N-(2-{2-[Methyl(methyl-d ₃ )amino]ethyl-methylamino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidine-2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-bis(methyl-d ₃ )aminoethyl-methylamino]-4-methoxy-5-{[4-(1-H-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylaminoethyl-methylamino]-4-(methoxy-d ₃ )-5-{[4-(1-H-indol-3-yl)pyrimidine-2 -amino]phenyl}prop-2-enamide;

N-(2-[2-Dimethylaminoethyl-(methyl-d ₃ )amino]-4-methoxy-5-{[4-(1-H-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylamino-1,1-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-indol-3-yl)) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylamino-2,2-didecylethyl-methylamino]-4-methoxy-5-{[4-(1-H-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 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 in vivo metabolic properties.

In certain aspects, the compounds of the present application have improved in vivo tumor suppressor activity.

In certain aspects, the compounds of the present application have improved safety.

In certain aspects, the compounds of the present application have improved tolerance.

In certain embodiments, a compound of the present application refers specifically to the following compounds:

Wherein the method comprises:

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In certain embodiments, the compound of formula (II) is reacted with acryloyl chloride in the presence of a strong base to provide a 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 t-butoxide.

In certain embodiments, the compound of formula (II) is reacted with acryloyl chloride in the presence of a polar solvent to provide a 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,N-dimethylformamide (DMF). , hexamethylphosphoramide, methanol, ethanol, acetic acid, isopropanol, pyridine, tetramethylethylenediamine, acetone, triethylamine, n-butanol, dioxane and tetrahydrofuran (THF).

In a further 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:

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

Examples of exemplary "pharmaceutically acceptable carriers" that can be used in the present application include, but are not limited to, any adjuvants, carriers, excipients, glidants approved by the National Drug Administration for acceptable use in humans or livestock. , sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In certain embodiments, the epidermal growth factor receptor (Her) is EGFR (Her1).

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 a 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 activating mutants.

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

Since the compound of the formula (I) of the present application and a pharmaceutically acceptable salt thereof have inhibitory activity against L858R EGFR mutant, T790M EGFR mutant and Exon19 deletion activating mutant, which can be used for mediated by EGFR mutant activity The treatment of a disease or disease state such as cancer.

In certain embodiments, the compounds of Formula (I) and pharmaceutically acceptable salts thereof of the present application are used to treat mediated by L858R EGFR mutants and/or T790M EGFR mutants and/or Exon19 deletion activating mutants The treatment of a disease or disease state such as cancer.

In certain embodiments, the cancer is selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodge Gold lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, renal cancer, anaplastic large cell lymphoma, acute myeloid leukemia ( AML), multiple myeloma, melanoma, and mesothelioma.

In certain embodiments, the lung cancer is selected from the group consisting of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

among them:

R _{1 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{2 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{5 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R _{6 is} selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

In certain embodiments, the individual is a mammal.

In certain embodiments, the individual is a human.

In certain embodiments, the unit dosage of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual in need of treatment for a tumor and/or cancer, from 0.1 mg to 1000 mg.

In certain embodiments, the unit dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof, administered to an individual in need of treatment for a tumor and/or cancer, is from 1 mg to 1000 mg.

Example

While any person skilled in the art will be able to prepare the compounds of the present application in light of the general techniques disclosed above, for the sake of convenience, the synthesis techniques of the compounds of the present application are provided in more detail elsewhere in this specification. Additionally, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and can be obtained from common commercial sources. For example, various reagents including deuterated reagents used in the examples are commercially available from Sigma-Aldrich Company Ltd. The various cell lines used in the examples are commercially available, for example, from the Cell Culture Bank of the Chinese Academy of Sciences' Type Culture Collection Committee.

¹ H NMR was determined using deuterated dimethyl sulfoxide at a frequency of 400 or 500 MHz at about 20-30 ° C unless otherwise stated. Standard NMR abbreviations are used: s = singlet; d = doublet; dd = doublet of doublet; t = triplet; q = quartet; p = quintuple; m = multiplet;

Preparation example

Intermediate 1

N ¹ -(2-[methyl(methyl-d ₃ )amino]ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-H-吲哚-3- Pyrimidin-2-yl]benzene-1,2,4-triamine

N'-(2-[Methyl(methyl-d ₃ )amino]ethyl)-2-methoxy-N'-methyl-N-[4-(1-H-吲哚-3- Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (intermediate 6, 44 g), iron (31 g) and NH ₄ Cl (1.9 g) in ethanol (120 mL) and water (40 mL) The mixture in the mixture was heated to reflux for 3.5 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The title compound (90%) was obtained from EtOAc. m/z: 434

Intermediate 2

N1-(2-[bis(methyl-d ₃ )amino]ethyl)-5-methoxy-N1-methyl-N4-[4-(1-H-吲哚-3- Pyrimidin-2-yl]benzene-1,2,4-triamine

N'-(2-[Di(methyl-d ₃ )amino]ethyl)-2-methoxy-N'-methyl-N-[4-(1-H-indol-3-yl) Pyrimidine-2-yl]-5-nitrobenzene-1,4-diamine (intermediate 7, 44 g), iron (31 g) and NH ₄ Cl (1.9 g) in ethanol (120 mL) and water (40 mL) The mixture was heated to reflux for 3.5 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The title compound (95%) was obtained from EtOAc. m/z: 437

Intermediate 3

N ¹ -(2-dimethylaminoethyl)-5-(methoxy-d ₃ )-N ¹ -methyl-N ⁴ -[4-(1-H-indol-3-yl) Pyrimidin-2-yl]benzene-1,2,4-triamine

N'-(2-Dimethylaminoethyl)-2-(methoxy-d ₃ )-N'-methyl-N-[4-(1-H-indol-3-yl)pyrimidine 2-yl]-5-nitrobenzene-1,4-diamine (intermediate 8, 44 g), iron (31 g) and NH ₄ Cl (1.9 g) in ethanol (120 mL) and water (40 mL) The mixture was heated to reflux for 3.5 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The title compound (86%) was obtained eluted eluted elute m/z: 434

Intermediate 4

N ¹ -(2-dimethylamino-1,1-dimercaptoethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-1-H-吲哚 -3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

N'-(2-Dimethylamino-1,1-dimercaptoethyl)-2-methoxy-N'-methyl-N-[4-(1-H-indol-3-yl) Pyrimidine-2-yl]-5-nitrobenzene-1,4-diamine (intermediate 9, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH ₄ Cl (17.32 mg, 0.32 mmol) The mixture in ethanol (12 mL) and water (4 mL) was evaporated and evaporated. The crude mixture was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column with 7M MeOH-EtOAc. It was purified using FCC used in 0-5% CH _₂ Cl ₂ in a 7N methanol - ammonia to afford the title compound as a beige foam (175mg, 85%). m/z: 433

Intermediate 5

N1-(2-Dimethylamino-2,2-dimercaptoethyl)-5-methoxy-N1-methyl-N4-[4-(1-H-吲哚 -3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine

N'-(2-Dimethylamino-2,2-decylethyl)-2-methoxy-N'-methyl-N-[4-(1-H-indol-3-yl) Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine (intermediate 10, 220 mg, 0.46 mmol), iron (155 mg, 2.78 mmol) and NH4Cl (17.32 mg, 0.32 mmol) in ethanol (12 mL) The mixture in water (4 mL) was heated to reflux for 2 hours. The crude mixture was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column with 7M MeOH-EtOAc. The title compound (175 mg, 85%) was obtained eluting eluting eluting eluting m/z: 433

Intermediate 6

N'-(2-[Methyl(methyl-d ₃ )amino]ethyl)-2-methoxy-N'-methyl-N-[4-(1-H-吲哚-3- Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

In a 500 mL three-necked flask, 190 mL of DMA, 16.9 g of N,N'-dimethyl-N'-(methyl-d ₃ )-ethane, 23.1 g of DIPEA were added, and after stirring at room temperature for 30 minutes, 47 g of N-( 4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11), then this solid-liquid suspension The temperature was raised to 85 ° C for 2-3 hours, and the reaction was monitored by TLC and mass spectrometry, and filtered while hot. 300mL of acetonitrile (including the amount of acetonitrile for washing the filter cake) was added to the filtrate, and after cooling to about 5 °C, a large amount of red product was precipitated, filtered, and dried under reduced pressure at 50 ° C to obtain 51 g of product, the yield was 90%. It is used directly in the next step without purification. m/z: 464

Intermediate 7

N'-(2-[bis(methyl-d3)amino]ethyl)-2-methoxy-N'-methyl-N-[4-(1-H-indol-3-yl) Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

In a 500 mL three-necked flask, 190 mL of DMA, 16.9 g of N-methyl-N', N'-(methyl-d ₃ )-ethane, 23.1 g of DIPEA were added, and after stirring at room temperature for 30 minutes, 47 g of N-(4) was added. -Fluoro-2-methoxy-5-nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11), then warming the solid-liquid suspension The reaction was carried out at 85 ° C for 2-3 hours, and after TLC and mass spectrometry were monitored, the reaction was filtered while hot. 300mL of acetonitrile (including the amount of acetonitrile for washing the filter cake) was added to the filtrate, and after cooling to about 5 °C, a large amount of red product was precipitated, filtered, and dried under reduced pressure at 50 ° C to obtain 51 g of product, the yield was 90%. It is used directly in the next step without purification. m/z: 467

Intermediate 8

N'-(2-Dimethylamino-ethyl)-2-(methoxy-d3)-N'-methyl-N-[4-(1-H-indol-3-yl)pyrimidine Pyridin-2-yl]-5-nitrobenzene-1,4-diamine

In a 500 mL three-necked flask, 190 mL of DMA, 16.9 g of N, N', N'-trimethylethane, 23.1 g of DIPEA were added, and after stirring at room temperature for 30 minutes, 47 g of N-(4-fluoro-2-(methoxy) was added. Base-d ₃ )-5-nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 12), then warming the solid-liquid suspension to 85 ° C After reacting for 2-3 hours, the reaction was monitored by TLC and mass spectrometry, and filtered while hot. 300mL of acetonitrile (including the amount of acetonitrile for washing the filter cake) was added to the filtrate, and after cooling to about 5 °C, a large amount of red product was precipitated, filtered, and dried under reduced pressure at 50 ° C to obtain 51 g of product, the yield was 90%. It is used directly in the next step without purification. m/z: 464

Intermediate 9

N'-(2-Dimethylamino-1,1-deuteroethyl)-2-methoxy-N'-methyl-N-[4-(1-methylindole-3- Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

Adding N ¹ ,N ¹ ,N ² -trimethyl-2,2-diindoleethane-1,2-diamine (80 mg, 0.79 mmol) to N-(4-fluoro-2-methoxyl) -5-Nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11, 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) A suspension in 2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140 ° C for 1 hour. The cooled reaction mixture was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column with 7M MeOH-EtOAc. Using the FCC, eluting with CH _₂ Cl ₂ at 0-4% 7N in methanol - ammonia to afford the title compound as an orange solid (230mg, 62%). m/z: 463

Intermediate 10

N'-(2-Dimethylamino-2,2-decylethyl)-2-methoxy-N'-methyl-N-[4-(1-methylindole-3- Pyrimidin-2-yl]-5-nitrobenzene-1,4-diamine

Adding N ¹ ,N ¹ ,N ² -trimethyl-1,1-dihaloethane-1,2-diamine (80 mg, 0.79 mmol) to N-(4-fluoro-2-methoxyl) -5-Nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine (Intermediate 11, 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) A suspension in 2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140 ° C for 1 hour. The cooled reaction mixture was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column with 7M MeOH-EtOAc. Using the FCC, eluting with CH _₂ Cl ₂ at 0-4% 7N in methanol - ammonia to afford the title compound as an orange solid (230mg, 62%). m/z: 463

Intermediate 11

N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine

p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to 3-(2-chloropyrimidin-4-yl)-1-H-indole (intermediate 13, 24.27 g, 99.58 mmol). A mixture of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 14, 18.54 g, 99.58 mmol) in 2-pentanol (500 mL). The resulting mixture was stirred at 105 ° C for 2.5 hours. It was then cooled to room temperature. The resulting precipitate was collected by EtOAc (EtOAc) elute The filtrate was cooled, and the obtained precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two batches were combined, triturated with CH ₃ CN, to obtain a solid, the solid was collected by filtration, dried under vacuum to give the title compound (37.4g, 95%) as a yellow solid. m/z: 379

Intermediate 12

N-(4-fluoro-2-(methoxy-d ₃ )-5-nitrophenyl)-4-(1-H-indol-3-yl)pyrimidin-2-amine

p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to 3-(2-chloropyrimidin-4-yl)-1-H-indole (intermediate 13, 24.27 g, 99.58 mmol). in 2-fluoro-2-pentanol (500 mL) of 5-nitroaniline (intermediate 15,18.54g, 99.58mmol) (methyloxy -d ₃₎ in. The resulting mixture was stirred at 105 ° C for 2.5 hours. It was then cooled to room temperature. The resulting precipitate was collected by suction, washed with ethyl acetate (50mL) and dried under vacuo to give the desired product as a yellow solid. The filtrate was cooled, and the obtained precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two batches were combined, triturated with CH ₃ CN, to obtain a solid, the solid was collected by filtration, dried under vacuum to give the title compound (37.4g, 95%) as a yellow solid. m/z: 382

Intermediate 13

3-(2-chloropyrimidin-4-yl)-1H-indole

In a period of 10 minutes at 0 ℃ in N ₂ atmosphere, the CH ₃ MgBr (3M, in diethyl ether, 22.68mL, 68.03mmol) was added dropwise to 1-H- indole (7.97g, 68.03mmol) In a stirred solution of 1,2-dichloroethane (250 mL). The resulting solution was stirred for 15 minutes and then 2,4-dichloropyrimidine (15.00 g, 100.69 mmol) was added in one portion. The resulting solution was allowed to warm to room temperature and stirred for additional 16 hours. ₃ OH (25mL) The reaction was quenched by addition of CH, and the mixture was then concentrated in vacuo, adsorbed onto silica gel. Using the FCC, eluting with CH _₂ Cl ₂ at 0-20% CH ₃ OH eluted the title compound was obtained (7.17g, 46%) as a yellow solid. m/z: 229

Intermediate 14

4-fluoro-2-methoxy-5-nitroaniline

4-fluoro-2-methoxy aniline (2.4g, 17.00mmol) was added portionwise to a cooled in an ice / water bath in concentrated H ₂ SO ₄ (15mL), during the addition the temperature was kept below 15 ℃ . The mixture was stirred until all solids formed had dissolved. KNO ₃ (0.815 mL, 17.00 mmol) was added in portions to maintain the temperature below 10 °C. The mixture was stirred overnight and then poured onto ice/water. The mixture was basified with concentrated NH4OH. The resulting solid was filtered off, then dissolved in CH _₂ Cl _2, washed with water, dried (Na ₂ SO _4), concentrated onto silica gel. It was purified using FCC eluting with 50-0% heptane in CH _₂ Cl ₂ to give the title compound as a yellow crystalline solid (2.450g, 77%). m/z: 186

Intermediate 15

4-fluoro-2-(methoxy-d ₃ )-5-nitroaniline

4-Fluoro-2- (methyloxy -d ₃₎ aniline (2.4g, 17.00mmol) was added portionwise to a cooled in an ice / water bath in concentrated H ₂ SO ₄ (15mL), maintaining the temperature during the addition Below 15 ° C. The mixture was stirred until all solids formed had dissolved. KNO ₃ (0.815 mL, 17.00 mmol) was added in portions to maintain the temperature below 10 °C. The mixture was stirred overnight and then poured onto ice/water. The mixture was basified with concentrated NH4OH. The resulting solid was filtered off, then dissolved in CH _₂ Cl _2, washed with water, dried (Na ₂ SO _4), concentrated onto silica gel. It was purified using FCC eluting with 50-0% heptane in CH _₂ Cl ₂ to give the title compound as a yellow crystalline solid (2.450g, 77%). m/z: 189

Example 1

N-(2-{2-[Methyl(methyl-d ₃ )amino]ethyl-methylamino}-4-methoxy-5-{[4-(1-H-吲哚) -3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

Under ice bath conditions to N ¹ -(2-[methyl(methyl-d ₃ )amino]ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-H- Indole-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 1, 20 g) 6.9 g of sodium hydroxide were added to THF (200 mL) and water (20 mL). To the stirred solution, 4.05 g of acryloyl chloride was added, and the mixture was stirred at room temperature for 30 minutes, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction was completed, 200 mL of water and 20 mL of aqueous ammonia were added to the reaction mixture, and the solid was precipitated and filtered. The obtained solid was collected, washed with water and dried at 50 <0>C for 8 hours to give the title compound (yield 86%).

¹ H NMR: 2.23 (3H, s), 2.28 (2H, t), 2.71 (3H, s), 2.89 (2H, t), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd ), 6.46 (1H, dd), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 488

N-(2-{2-[Methyl(methyl-d ₃ )amino]ethyl-methylamino}-4-methoxy-5-{[4-(1-H-吲哚) 3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate

N-(2-{2-[methyl(methyl-d ₃ )amino]ethyl-methylamino}-4-methoxy-5-{[4-(1-H-吲) obtained in the previous step 20.5 g (1.0 eq) of indole-3-ylpyrimidin-2-yl]amino}phenyl)prop-2-enamide was added to a 500 mL three-necked flask, dissolved in 120 mL of ethanol and 80 mL of ethyl acetate, and added dropwise at room temperature. 4.1 g methanesulfonic acid (1.05 eq) + 40 mL ethyl acetate, about 1 hour, after the completion of the dropwise addition, the temperature was kept at this temperature for 1.5-2 hours, then slowly cooled to room temperature, filtered, and the filter cake was treated with ethyl acetate/ethanol solution. (2:1, v/v) After washing once, it was filtered and dried to obtain 18.0 g of a product, yield 83%.

Example 2

N-(2-{2-bis(methyl-d ₃ )aminoethyl-methylamino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To N ¹ -(2-[bis(methyl-d ₃ )amino]ethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-H-吲) under ice bath Indole-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 2, 20 g) 6.9 g of sodium hydroxide were added to THF (200 mL) and water (20 mL). To the stirred solution, 4.05 g of acryloyl chloride was added, and the mixture was stirred at room temperature for 30 min, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction was completed, 200 mL of water and 20 mL of aqueous ammonia were added to the reaction mixture, and the solid was precipitated and filtered. The obtained solid was collected, washed with water and dried at 50[deg.] C. for 8 hr to give the title compound (yield 88%).

¹ H NMR: 2.28 (2H, t), 2.71 (3H, s), 2.89 (2H, t), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd), 6.46 (1H, dd ), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 491

N-(2-{2-bis(methyl-d ₃ )aminoethyl-methylamino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate

N-(2-{2-bis(methyl-d ₃ )aminoethyl-methylamino}-4-methoxy-5-{[4-(1-H-吲哚-3) obtained in the above step 2-ylpyrimidin-2-yl]amino}phenyl)prop-2-enamide 20.5 g (1.0 eq) was added to a 500 mL three-necked flask, dissolved in 120 mL of ethanol and 80 mL of ethyl acetate, and 4.1 g of A was added dropwise at room temperature. Sulfonic acid (1.05 eq) + 40 mL of ethyl acetate, after about 1 hour, after completion of the dropwise addition, the mixture was kept at this temperature for 1.5-2 hours, then slowly cooled to room temperature, filtered, and the filter cake was treated with ethyl acetate/ethanol (2: 1, v/v) After washing once, it was filtered and dried to give a yellow solid in a yield of 85%.

Example 3

N-(2-[2-Dimethylaminoethyl-methylamino]-4-(methoxy-d ₃ )-5-{[4-(1-H-indol-3-yl)pyrimidine Pyridin-2-yl]amino}phenyl)prop-2-enamide

To N ¹ -(2-dimethylaminoethyl)-5-(methoxy-d ₃ )-N ¹ -methyl-N ⁴ -[4-(1-H-吲哚) under ice bath -3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 3, 20 g) 6.9 g of sodium hydroxide were added in THF (200 mL) and water (20 mL). To the stirred solution, 4.05 g of acryloyl chloride was added, and the mixture was stirred at room temperature for 30 min, and the mixture was stirred at room temperature for 1 hour. After the TLC detection reaction was completed, 200 mL of water and 20 mL of aqueous ammonia were added to the reaction mixture, and the solid was precipitated and filtered. The obtained solid was collected, washed with water and dried at 50[deg.] C. for 8h to afford the title compound (yield 85%).

¹ H NMR: 2.23 (6H, s), 2.28 (2H, t), 2.71 (3H, s), 2.89 (2H, t), 5.75 (1H, dd), 6.25 (1H, dd), 6.46 (1H, dd ), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 488

N-(2-{2-dimethylaminoethyl-methylamino}-4-(methoxy-d ₃ )-5-{[4-(1-H-indol-3-yl)pyrimidine Pyridin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate

N-(2-{2-dimethylaminoethyl-methylamino}-4-(methoxy-d ₃ )-5-{[4-(1-H-吲哚-3-) obtained in the above step 20.5 g (1.0 eq) of pyrimido-2-yl]amino}phenyl)-2-enamide was added to a 500 mL three-necked flask, dissolved in 120 mL of ethanol and 80 mL of ethyl acetate, and 4.1 g of methanesulfonic acid was added dropwise at room temperature. (1.05 eq) + 40 mL of ethyl acetate, about 1 hour, after completion of the dropwise addition, the temperature was kept at this temperature for 1.5-2 hours, then slowly cooled to room temperature, filtered, and the filter cake was treated with ethyl acetate/ethanol (2:1, After v/v) washing, the mixture was filtered and dried to give a yellow solid.

Example 4

N-(2-{2-Dimethylaminoethyl-(methyl-d ₃ )amino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide

Preparation method and N-(2-{2-dimethylaminoethyl-methylamino}-4-(methoxy-d ₃ )-5-{[4-(1-H-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide identical, using N ¹ -(2-dimethylaminoethyl)-5-(methoxy)-N ¹ -(methyl-d ₃ )-N ⁴ -[4-(1-H-indol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine in place of N ¹ -(2-dimethylaminoethyl -5-(methoxy-d ₃ )-N ¹ -methyl-N ⁴ -[4-(1-H-indol-3-yl)pyrimidin-2-yl]benzene-1,2,4 - Triamine, yield 70%.

¹ H NMR: 2.23 (6H, s), 2.28 (2H, t), 2.89 (2H, t), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd), 6.46 (1H, dd ), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 488

N-(2-{2-Dimethylaminoethyl-(methyl-d ₃ )amino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate

Preparation method and N-(2-{2-dimethylaminoethyl-methylamino}-4-(methoxy-d ₃ )-5-{[4-(1-H-indol-3-yl) The pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate was identical, yellow solid, yield 79%.

Example 5

N-(2-[2-Dimethylamino-1,1-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-吲哚) -3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To N ¹ -(2-dimethylamino-1,1-dihydroxyethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-1-H) under ice bath Stirred solution of -indol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (intermediate 4, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) Chloropropionyl chloride (3.28 g, 25.59 mmol) was added. The mixture was stirred at room temperature for 15 minutes then NaOH (3.48 g, 85.28 mmol). The resulting mixture was heated to 65 ° C for 10 hours. The mixture was then cooled to room temperature, add CH ₃ OH (40mL) and water (70mL). The resulting mixture was stirred overnight. The obtained solid was collected by EtOAcjjjjjjjjjjj

¹ H NMR: 2.23 (6H, s), 2.28 (2H, t), 2.71 (3H, s), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd), 6.46 (1H, dd ), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 487

To N-(2-[2-dimethylamino-1,1-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-吲哚) at 50 °C Addition of acetone to acetone in a stirred solution of acetone (45.5 mL) A solution of methanesulfonic acid (0.893 g, 9.11 mmol) in (4.55 mL). The resulting mixture was stirred for 1.5 hours. The resulting solid was collected by EtOAc (EtOAc)EtOAc.

Example 6

N-(2-[2-Dimethylamino-2,2-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-吲哚) -3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

To N ¹ -(2-dimethylamino-2,2-dimercaptoethyl)-5-methoxy-N ¹ -methyl-N ⁴ -[4-(1-H-吲) under ice bath Indole-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 5, 10 g, 21.32 mmol) was added to a stirred solution of THF (95 mL) and water (9.5 mL) Chloropropionyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at room temperature for 15 minutes then NaOH (3.48 g, 85.28 mmol). The resulting mixture was heated to 65 ° C for 10 hours. The mixture was then cooled to room temperature, add CH ₃ OH (40mL) and water (70mL). The resulting mixture was stirred overnight. The obtained solid was collected by EtOAcjjjjjjjjjjj

¹ H NMR: 2.23 (6H, s), 2.71 (3H, s), 2.89 (2H, t), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd), 6.46 (1H, dd ), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 487

To N-(2-[2-dimethylamino-2,2-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-吲哚) at 50 °C -3-yl)pyrimidin-2-yl]amino}phenyl}prop-2-enamide (4.44 g, 9.11 mmol) in acetone (45.5 mL) and water (4.55 mL) A solution of methanesulfonic acid (0.893 g, 9.11 mmol) in (4.55 mL) <RTI ID=0.0></RTI> %).

Example 7

N-(2-[2-Dimethylaminoethyl-methylamino]-5-{[4-(1H-indol-3-yl)pyrimidin-2-yl]ammonia -4-]-4-methoxyphenyl)prop-2-enamide

A solution of acryloyl chloride (0.584 mL, 1 M in CH ₂ Cl ₂ , 0.58 mmol) was added dropwise to N ¹ -(2-dimethylaminoethyl)-N ⁴ -[4-(1H-indole-3) a solution of pyrimidin-2-yl]-5-methoxy-N ¹ -methylbenzene-1,2,4-triamine (252 mg, 0.58 mmol) in CH ₂ Cl ₂ (10 mL) The mixture was then stirred at -5 °C for 1 hour. The mixture was then diluted with CH _₂ Cl ₂ (100mL), the resulting solution was washed with saturated NaHCO ₃ (25mL), water (25mL), then washed with saturated brine (25mL), and then concentrated in vacuo. It was purified using FCC eluting with CH _₂ Cl ₂ in the 0-30% CH ₃ OH, to obtain the title compound as a white solid (76mg, 27%).

¹ H NMR: 2.23 (6H, s), 2.28 (2H, t), 2.71 (3H, s), 2.89 (2H, t), 3.88 (3H, s), 5.75 (1H, dd), 6.25 (1H, dd ), 6.46 (1H, dd), 7.03 (1H, s), 7.12 (1H, t), 7.21-7.28 (2H, m), 7.55 (1H, d), 7.90 (1H, s), 8.24 (1H, d), 8.35 (1H, d), 8.65 (1H, s), 9.15 (1H, s), 10.24 (1H, s)

m/z: ES ⁺ MH ⁺ 485

Biological example

Example 1

Calu 3 (WT), Calu6 (WT), NCI-H1975 (T790M/L8 58R) and PC9 (Ex19del) PC9VanR (Ex19del/T 790M) cell lines were seeded in 384-well plates at 500-1000 cells per well ( Depending on the cell line), 70 μL of RPMI medium containing 10% fetal calf serum, 2 mM L-glutamine, and 1% penicillin/streptomycin was added per well. Day 0 plates were prepared in the form of two rows per cell line. The cells were incubated overnight at 37 ° C, 5% CO ₂ . The titrated test compound was added to the assay plate the next day using the Echo Liquid Handler, and the treated cells were incubated for an additional 72 hours at 37 ° C, 5% CO ₂ . Each compound was assayed by an 11-point dose reaction with a maximum concentration of 10 μM and a 1:3 dilution. The day 0 plate parallel to the dosing assay plate was 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 μL of 2 μM of Sytox green was added to each well, and the plate was incubated at room temperature for 1 hour. The number of fluorescent cells per well was determined using Acumen. 10 μL of 0.25% saponin was added to each well, and the plate was incubated overnight at room temperature. The total number of fluorescent cells in each well was read on Acumen. The number of viable cells was calculated by subtracting the number of dead cells from the total number of cells. The data obtained for each compound was entered into a suitable software package to perform a curve fit analysis. Based on this data, the IC ₅₀ value was determined by calculating the concentration of the compound required to obtain a 50% effect.

The results in Table 1 show that the compounds of Examples 1-6 and the compound of Example 7 (control) proliferated against cell lines expressing wild type EGFR and cell lines expressing mutant EGFR (Ex19del, L858R and/or T790M EGFR). The inhibition is equivalent.

Table 1 Inhibition of proliferation of a panel of NSCLC cell lines expressing mutant or wild-type EGFR by test compounds (IC ₅₀ μM)

Example 2

Eight male healthy volunteers were recruited for a single drug pharmacokinetic comparison study. The subjects were randomly divided into 2 groups, and the compounds of Example 7 (control group) and the compound group of Examples 1-6 were respectively 4 subjects. The other example compounds were tested after re-grouping after a 7-day wash period. After the subject was fasted for 10 hours, the test substance was orally administered after the standard meal was taken the next morning. The dose was 0.4 mg/kg (this dose is about 1/50 of the acute toxicity dose of the animal, so there is no Potential side effects). During the entire study period, subjects were required to collect blood samples at the set 9 time points (before administration, 30 minutes after administration, 1, 2, 3, 6, 12, 24, 48, 72 hours after administration). Used to determine the concentration of a drug in plasma. At each sampling point, about 5 mL of venous whole blood was collected and placed in dried heparin or EDTA test tube. After standing at 4 ° C for 2 hours, the serum was separated by centrifugation (6000 rpm, 10 min) at 4 ° C, and the serum was transferred to the sample storage tube, -20 The °C refrigerator is stored until the measurement. Reversed-phase high performance liquid chromatography (HPLC) plus Turbo Ion

The tandem mass spectrometry (MS/MS) assay was used to determine the lower limit of quantitation (LLOQ) of this assay is 0.025 ng/mL, the upper limit of linear assay is 25 ng/mL, and the intra-assay precision is between 1.5% and 10.7%. Inter-assay precision is 3.0% to 6.8%, intra-assay accuracy is between 96.0% and 108.0%, and inter-assay accuracy is 97.6% to 105.0%. The plasma concentration was calculated using Watson LIMS v.7.3.0.01 (Thermo Scientific Inc.) software, and the pharmacokinetic parameters were analyzed using the non-compartmental model of WinNonLin v5.2.1 (Pharsight Inc.) software (the main pharmacokinetics in this study) The parameters are the area under the curve of the drug, AUC0-t and the elimination half-life, t1/2).

The results of the study are shown in Table 2 below. The AUC0-t of the compounds of Examples 1-6 was increased by 46-84% compared to the compound of Example 7 (control compound), and the t1/2 was increased by 54- compared with the control compound. 88%.

Table 2 Results of comparative study of single administration of healthy subjects

Example 3

Experimental methods: nude mice (Balb/c nude mice, 6-8 weeks old, 20-22 g) were subcutaneously inoculated with human cell line H1975 (L858R/T790M). After the tumors were grown to 100-300 mm ³ , the animals were randomly divided. There were 5 groups, of which 8 were in each group and 12 in the solvent group, female. There were three dose groups of Compounds 1-6, 2.5, 5, 10 mg/kg/d, a compound of Example 7 at a dose of 5 mg/kg/d, and a solvent control group. The above groups were given a total of 21 days of continuous gavage. In the experiment, the tumor volume was measured 2-3 times per week, and the tumor weight was called. Tumor volume (TV), relative tumor volume (RTV), tumor growth inhibition rate (TGI), and tumor growth rate (T/C) are as follows:

TV = 1/2 a × b2 (where a and b represent the long and short diameters of the tumor, respectively)

RTV=TVDt/TVD0

Relative tumor proliferation rate (T/C%) = RTV treatment group / RTV control group × 100%

Tumor growth inhibition rate (TGI%) = 100% × (1-(TVDt (treatment group) - TVD0 (treatment group)) / (TVDt (control group) - TVD0 (control group)))

Experimental results: The compounds of Examples 1-6 all significantly inhibited the growth of human lung cancer H1975 nude mice xenografts, resulting in tumor regression in some mice. The compound of Example 7 was also effective against H1975. At the same dose, the compounds of Examples 1-6 were significantly better than the compound of Example 7, with an increase of about 19-43%. Tumor-bearing mice are well tolerated by the above compounds.

Table 3 Effect of the compounds of Examples 1-7 on human cell line H1975 nude mice xenografts

All of the patents, patent application publications, patent applications and non-patent publications cited in the specification are hereby incorporated by reference in their entirety.

It is to be understood that the specific embodiments of the present invention are described herein, and the various embodiments of the invention may be made without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be limited only by the appended claims.

Claims

a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

among them:

R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

The condition is that at least one deuterium atom is contained in R 1 to R 6 .
The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of:

N-(2-{2-[Methyl(methyl-d 3 )amino]ethyl-methylamino}-4-methoxy-5-{[4-(1-H-indol-3-yl) Pyrimidine-2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-bis(methyl-d 3 )aminoethyl-methylamino]-4-methoxy-5-{[4-(1-H-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylaminoethyl-methylamino]-4-(methoxy-d 3 )-5-{[4-(1-H-indol-3-yl)pyrimidine-2 -amino]phenyl}prop-2-enamide;

N-(2-[2-Dimethylaminoethyl-(methyl-d 3 )amino]-4-methoxy-5-{[4-(1-H-indol-3-yl)pyrimidine- 2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylamino-1,1-dihydroxyethyl-methylamino]-4-methoxy-5-{[4-(1-H-indol-3-yl)) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide;

N-(2-[2-Dimethylamino-2,2-didecylethyl-methylamino]-4-methoxy-5-{[4-(1-H-indol-3-yl)) Pyrimidin-2-yl]amino}phenyl)prop-2-enamide.
The compound of the formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a methanesulfonate.
A method of preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof:

Wherein the method comprises:

The compound of the formula (II) is reacted with acryloyl chloride to give a compound of the formula (I):

among them:

R 1 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 2 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 3 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R 4 is selected from methylene or methylene substituted by 1 to 2 deuterium atoms;

R 5 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

R 6 is selected from methyl or methyl substituted by 1 to 3 deuterium atoms;

The condition is that at least one deuterium atom is contained in R 1 to R 6 .
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.
Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, for the manufacture of a medicament for inhibiting epidermal growth factor receptor (Her).
The use according to claim 6, wherein the epidermal growth factor receptor (Her) is EGFR (Her1).
The use according to claim 7, wherein the EGFR (Her1) is a wild type or a mutant, preferably a single mutant or a double mutant.
Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, for the manufacture of a medicament for the treatment of cancer and/or tumor.
The use according to claim 9, wherein the cancer and/or tumor is non-small cell lung cancer.