RU2786524C2 - Inhibitors of epidermal growth factor receptor - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present group of inventions relates to new compounds of the formula I

,

their pharmaceutically acceptable salts, as well as to a pharmaceutical composition, a method for inhibition of biological activity of an epidermal growth factor receptor (hereinafter – EGFR), a method for the treatment of diseases or disorders mediated by EGFR activity, and the use of the claimed compounds or the specified composition for the treatment of a disease or a disorder mediated with EGFR activity.

EFFECT: obtaining an inhibitor for an epidermal growth factor receptor.

16 cl, 14 ex, 16 tbl

Description

Technical field

The present invention relates to new inhibitors of the epidermal growth factor receptor (EGFR), as well as their pharmaceutically acceptable salts, solvates or stereoisomers, pharmaceutical compositions containing these compounds, methods of treatment and the use of these compounds as pharmaceuticals for the treatment of diseases or disorders.

State of the art

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein tyrosine kinase that is a member of the erbB receptor family. EGFR consists of a glycosylated outer ligand-binding domain (621 residues) and a cytoplasmic domain (542 residues) linked by a short transmembrane linker of 23 amino acids. The extracellular portion of EGFR contains 25 disulfide bridges, 12 N-linked glycosylation sites, and is generally considered to be composed of four subdomains. X-ray crystal structures of EGFR suggest that the receptor can adopt both an autoinhibited bound conformation that is unable to bind epidermal growth factor (EGF) (Ferguson et al., Mol Cell, 2003, vol 11:507-517) and an active conformation that can mediate EGF ligand binding and receptor dimerization (Garrett et al., Cell 2002, vol 110:763-773; Ogiso et al., Cell, 2002, vol 110: 775-787). Upon binding a growth factor ligand such as EGF, the receptor may homodimerize with another EGFR molecule or heterodimerize with another family member such as erbB2 (HER2), erbB3 (HER3) or erbB4 (HER4). Homo- and/or hetero-dimerization of erbB receptors leads to phosphorylation of key tyrosine residues in the intracellular domain and leads to stimulation of a wide variety of intracellular signal transduction pathways involved in cell proliferation and survival. A detailed description of erbB receptor signaling and its involvement in tumorigenesis is presented in Ciardiello F.N. Engl J Med 2008; 358:1160-1174 and Robert Roskoski Jr. Biochemical and Biophysical Research Communications 319 (2004) 1-11.

The association of EGFR with cancer was first recognized when the transforming avian erythroblatosis virus v-ErbB oncogene was recognized as a mutant homologue of human EGFR (Downward J. Nature. 1984; 307:521-527). The v-ErbB oncogene has been found to contain recombinations of the transmembrane and cytoplasmic EGFR domains (Olofsson B. Eur. J. Biochem. 1986; 160:261-266) leading to oncogenic EGFR aberrations. In addition to mutations, increased expression of EGFR has been found to promote the progression of a number of malignant tumors (Gusterson B. Cell Biol. Int. Rep. 1984; 8:649-658), including sarcomas (Gusterson B. Int. J. Cancer. 1985 ; 36:689-693), non-small cell lung cancer (NSCLC) (Veale D. Br. J. Cancer. 1987; 55:513-516) and malignant gliomas (Wong A.J. Proc. Natl. Acad. Sci. USA. 1987; 84:6899-6903).

EGFR is now known to regulate numerous cellular processes through tyrosine kinase-mediated signal transduction pathways, including but not limited to the control of cell proliferation, differentiation, survival, apoptosis, tumor angiogenesis, mitogenesis, and metastasis (Atalay et al., Ann. Oncology 14: 1346-1363 [2003]; Herbst R. S. Cancer 2002; 94: 1593-1611; Modjtahedi et al., Br. J. Cancer 1996; 73: 228-235). EGFR overexpression has been documented in numerous human cancers, including bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney cancers (Atalay et al., Ann. Oncology 14: 1346 -1363 (2003); Herbst R. S. Cancer 2002; 94: 1593-1611; Modjtahedi et al., Br. J. Cancer 1996; 73: 228-235). EGFR is also expressed in cells of normal tissues, especially epithelial tissues of the skin, liver and gastrointestinal tract, although usually at lower levels than in malignant cells (Herbst R.S. Cancer. 2002; 94: 1593-1611).

Small molecular weight EGFR tyrosine kinase inhibitors are known to be used in the treatment of oncological diseases, for example, in the treatment of non-small cell lung cancer, pancreatic cancer, anti-EGFR antibodies are used in the treatment of colorectal cancer and head and neck cancer (Ping Wee. Cancers (Basel). 2017 May; 9(5): 52).

In many oncological diseases, frequent mutations and overexpression of EGFR are observed, so the development of new effective and safe drugs aimed at inhibiting EGFR activity remains relevant.

Description of the invention

The following are definitions of terms that are used in the description of this invention.

Optionally substituted at one, two, three, or more positions means that the described group may be substituted at one, two, three, or one to six positions with any one or any combination of radicals.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain, more preferably with 1-6 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. The alkyl may have substituents which may be the same or different.

"Cycloalkyl" means a fully saturated carbocyclic ring containing 3-10 carbon atoms per ring. Examples of cycloalkyl groups include, but are not limited to, monocyclic groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, bicyclic groups such as bicycloheptyl or bicyclooctyl. Cycloalkyl may have substituents which may be the same or different.

"Alkenyl" means a hydrocarbon straight or branched group with 2-12 carbon atoms in the chain, more preferably with 2-6 carbon atoms in the chain, which contains one or more carbon-carbon double bonds. Alkenyl may have substituents which may be the same or different.

"Alkynyl" means a hydrocarbon straight or branched group with 2-12 carbon atoms in the chain, more preferably with 2-6 carbon atoms in the chain, which contains one or more carbon-carbon triple bonds. The alkynyl may have substituents which may be the same or different.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, phenylene, benzenetriyl, indanyl, naphthyl, naphthylene, naphthalenetriyl, and anthrylene. Aryl may have ring system substituents which may be the same or different. Aryl can be annelated with a non-aromatic ring system or a heterocycle.

"Alkyloxy", "Alkoxy", or "alkyloxy" means an alkyl-O-group in which alkyl is defined in this section. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy.

"Aryloxy" or "aryloxy group" means an aryl-O- group in which aryl is defined in this section. An example of an aryloxy group is, but is not limited to, a phenoxy group.

"Cycloalkyloxy" or "cycloalkyloxy group" means a cycloalkyl-O- group in which cycloalkyl is defined in this section. Examples of cycloalkyloxy groups include, but are not limited to, cyclohexyloxy, cyclopentyloxy, cyclobutyloxy or cyclopropyloxy.

"Amino group" means an R'R''N- group.

"Aminocarbonyl" means a -C(=O)NR'R'' group.

Examples of R' and R'' include, but are not limited to, substituents selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or R' and R'' together with a nitrogen atom, to to which they are attached can form a 4-7 membered heterocyclyl or heteroaryl.

"Lower alkyl" means linear or branched alkyl with 1-4 carbon atoms.

"Halo" or "Halogen" (Hal) means fluorine, chlorine, bromine or iodine.

"Heterocycle", "heterocyclyl", "heterocyclic ring" means a monocyclic or polycyclic system containing from 3 to 11 carbon atoms in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur. The heterocycle may be fused to aryl or heteroaryl. The heterocycle may have one or more substituents, which may be the same or different. Nitrogen and sulfur atoms located in the heterocycle can be oxidized to N-oxide, S-oxide or S-dioxide. The heterocycle may be saturated, partially unsaturated or unsaturated. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8-diazaspiro[4.5]decane, piperazine, morpholine, and others.

"Heteroaryl" means an aromatic monocyclic or polycyclic system containing from 5 to 11 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by a heteroatom, such as nitrogen, sulfur or oxygen. The nitrogen atom found in heteroaryl can be oxidized to an N-oxide. The heteroaryl may have one or more substituents, which may be the same or different. Representative heteroaryls are pyrrolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isooxazolyl, isothiazolyl, tetrazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, triazolyl, 1,2,4-thiadiazolyl, quinoxalinyl, phthalazinyl, imidazo[1,2 -a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiazenyl, quinolinyl, imidazolyl, pyrazolyl, thienopyridyl, quinazolinyl, naphthyridinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridyl, isoquinolinyl, benzoazaindole, 1,2 ,4-triazinyl, thienopyrrolyl, furopyrrolyl, etc.

"Partially unsaturated" means a ring system that includes at least one double or triple bond. The term "partially unsaturated" refers to rings having multiple sites for saturation, but does not include aryl and heteroaryl systems as defined above.

The term "oxo" as used herein refers to the radical =O.

"Deputy" means a chemical radical that attaches to the molecular backbone (scaffold, fragment).

"Solvate" means a molecular complex of a compound of the present invention, including its pharmaceutically acceptable salts, with one or more solvent molecules. Such solvent molecules are molecules commonly used in pharmaceuticals that are known to be harmless to the recipient, such as water, ethanol, ethylene glycol and the like. Other solvents can be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butanediol, and the like.

The term "hydrate" refers to a complex in which the solvent molecule is water.

The solvates and/or hydrates preferably exist in crystalline form.

The term "bond", "chemical bond" or "single bond" refers to a chemical bond between two atoms or two groups (groups, fragments), if the two atoms connected by the bond are considered as part of a larger substructure.

The term "stereoisomers" refers to compounds that have identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, diastereomers.

The term "protecting group" refers to groups that are used to block the reactivity of functional groups such as an amino group, a carboxyl group, or a hydroxy group. Non-limiting examples of protecting groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), trialkylsilyl, alkyl(diaryl)silyl, or alkyl.

The term "excipient" is used herein to describe any ingredient other than the compound(s) of this invention.

"Pharmaceutical composition" means a composition comprising a compound of the invention and at least one excipient. The excipient may be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and receptive agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners , sweeteners, flavors, flavors, antibacterial agents, fungicides, lubricants, delayed delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be provided with agents that slow down the absorption of the active principle, for example, aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and spreaders are starch, alginic acid and its salts, silicates and the like. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in standard form of administration as a mixture with conventional pharmaceutical carriers.

Suitable unit administration forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

"Pharmaceutical salt" means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or prepared specially. In particular, base salts can be prepared specifically from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, maleates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (For a detailed description of the properties of such salts, see Berge S.M., et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specifically prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are the sodium and potassium salts. Suitable inorganic bases from which metal salts can be derived are sodium hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the declared acids can be obtained, amines and amino acids are selected that have sufficient basicity to form a stable salt and are suitable for medical use (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane, and the like. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation. As amino acids, the basic amino acids lysine, ornithine and arginine can be used.

"Drug (drug)" - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, granules, capsules, injections, ointments and other finished forms, intended to restore, correct or change physiological functions in humans and animals, and also for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.

"Treat", "treatment", and "therapy" refer to a method of alleviating or eliminating a biological disorder and/or at least one of its accompanying symptoms. The term "alleviate" a disease, disease, or condition means to reduce the severity and/or frequency of occurrence of symptoms of the disease, disorder, or condition. In addition, references herein to "treatment" include references to curative, palliative therapy.

"Prevention", "prophylactic therapy" refers to a set of measures aimed at preventing the occurrence, eliminating risk factors or early detection of a disease or disorder, their exacerbation, relapse, complications or other consequences.

In one aspect, the patient or subject of treatment or prophylaxis is a mammal, preferably a human subject.

The above subject may be male or female of any age.

The term "disorder" means any condition that can be improved as a result of the treatment of the present invention. The definition of this term includes chronic and acute diseases or pathological conditions that predispose a mammal to the occurrence of these diseases. Non-limiting examples of diseases to be treated include benign and malignant neoplasms or neoplasms of an unspecified nature, including tumors derived from blood cells and lymphoid cells. Examples include: bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma , lung cancer, hepatocellular cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

A "therapeutically effective amount" is the amount of a therapeutic agent administered during treatment that will relieve to some extent one or more of the symptoms of the disease being treated.

In the present description and in the following claims, unless the context otherwise requires, the words "have", "include" and "comprise" or variations thereof, such as "has", "having", "includes", "including", " contains" or "comprising" should be understood to mean the inclusion of the specified integer or group of integers, but not the exclusion of any other integer or group of integers.

Detailed description of the invention

In one embodiment, the present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,

where L represents -C(O)- or -CHOH-;

X ₁ represents CH or N;

A represents

X ₂ , X ₃ , X ₄ , X ₅ , X ₆ are each independently C, CH or N;

R ₁ is each independently hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from Hal, NR ₂ R ₃ , hydroxy, C ₁ -C ₆ alkyloxy, aryl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy , NR ₂ R ₃ ; aryloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyl, hydroxy, NR ₂ R ₃ ; C ₃ -C ₆ cycloalkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; NR ₂ R ₃ ; aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkyloxy, NR _{2R3 ;} 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy , NR ₂ R ₃ ; R ₂ or R ₃ each independently represents hydrogen; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3;

Hal represents a fluorine, bromine, chlorine or iodine atom.

In yet another embodiment, the present invention relates to a compound of formula I, where the fragment

selected from the group consisting of:

where R ₁ each independently represents hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, -NR ₂ R ₃ , hydroxy, C ₁ -C ₆ alkyloxy, aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy groups, -NR ₂ R ₃ ; aryloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyl, hydroxy, -NR ₂ R ₃ ; C ₃ -C ₆ cycloalkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; -NR ₂ R ₃ ; aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkyloxy, - NR ₂ R ₃ ; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy , -NR ₂ R ₃ ;

R ₂ or R ₃ is each independently hydrogen, C ₁ -C ₆ alkyl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3;

Hal represents a fluorine, bromine, chlorine or iodine atom.

In yet another embodiment, the present invention relates to a compound of formula I, where the fragment

selected from the group consisting of:

where R ₁ each independently represents hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from Hal, -NR ₂ R ₃ , hydroxy, C ₁ -C ₆ alkyloxy, aryl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy groups, -NR ₂ R ₃ ; aryloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyl, hydroxy, -NR ₂ R ₃ ; C ₃ -C ₆ cycloalkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; -NR ₂ R ₃ ; aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkyloxy, - NR ₂ R ₃ ; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy , -NR ₂ R ₃ ;

R ₂ or R ₃ is each independently hydrogen, C ₁ -C ₆ alkyl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3;

Hal represents a fluorine, bromine, chlorine or iodine atom.

In yet another embodiment, the present invention relates to a compound of formula I, where the fragment

selected from the group consisting of:

where R ₁ each independently represents hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, -NR ₂ R ₃ , hydroxy, C ₁ -C ₆ alkyloxy, aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy groups, -NR ₂ R ₃ ; aryloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyl, hydroxy, -NR ₂ R ₃ ; C ₃ -C ₆ cycloalkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; -NR ₂ R ₃ ; aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkyloxy, - NR ₂ R ₃ ; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy , -NR ₂ R ₃ ;

R ₂ or R ₃ is each independently hydrogen, C ₁ -C ₆ alkyl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, C ₁ -C ₆ alkyloxy;

k is 0, 1, 2 or 3;

Hal represents a fluorine, bromine or chlorine atom.

In yet another embodiment, the present invention relates to a compound of formula I, where the fragment

selected from the group consisting of:

where R ₁ each independently represents hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, -NR ₂ R ₃ , hydroxy, C ₁ -C ₆ alkyloxy, aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy groups, -NR ₂ R ₃ ; aryloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyl, hydroxy, -NR ₂ R ₃ ; C ₃ -C ₆ cycloalkyloxy, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl; -NR ₂ R ₃ ; aryl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, C ₁ -C ₆ alkyl, hydroxy, C ₁ -C ₆ alkyloxy, - NR ₂ R ₃ ; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from Hal, cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy , -NR ₂ R ₃ ;

R ₂ or R ₃ is each independently hydrogen, C ₁ -C ₆ alkyl unsubstituted or substituted with one or more radicals selected from Hal, hydroxy, C ₁ -C ₆ alkyloxy;

Hal represents a fluorine, bromine or chlorine atom.

The compounds described in the present invention can be obtained in the form and/or they can be used in the form of pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed by reacting a compound in free base form with a pharmaceutically acceptable inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric acids, and the like; or with an organic acid such as acetic, propionic, caproic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, trifluoroacetic, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, cinnamon, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-en-1-carboxylic, glucoheptonic, 4,4'- methylene-bis-3-hydroxy-2-ene-1-carboxylic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, laurylsulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, muconic acids, and the like.

Appropriate counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods, including but not limited to: ion exchange chromatography, ion chromatography, capillary electrophoresis, inductive plasma binding, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered using at least one of the following techniques: filtration, precipitation with a precipitant followed by filtration, solvent evaporation or, in the case of aqueous solutions, lyophilization. It is to be understood that reference to a pharmaceutically acceptable salt includes solvent addition salt forms or crystalline forms thereof, in particular solvates or polymorphs. Solvates contain a stoichiometric or non-stoichiometric amount of solvent and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described in this patent can be easily obtained or formed in the methods described in the present invention. In addition, the compounds provided by the present invention may exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms when describing the compounds and methods of the present invention.

The compounds described in the present invention can be presented in various forms, including listed, but not limited to: structureless forms, ground forms and nanoparticles. In addition, the compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include crystals with different structures of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, different infrared spectra, melting points, different densities, hardnesses, crystal shapes, optical and electrical properties, stability and solubility. Various factors such as recrystallization solvent, degree of crystallization, and storage temperature can cause one crystal form to dominate.

Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be performed by a number of methods, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal methods of analysis are directed to the study of thermochemical degradation or thermophysical processes, including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationship between polymorphs, determine the loss in mass, to find the glass transition temperature, or study compatibility with the filler. Such methods include, without limitation, differential scanning calorimetry (DSC), modulating differential scanning calorimetry (MDSC), thermogravimetric analysis (TGA), thermogravimetric and infrared analysis (TG/IR). Crystallographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic methods used include, but are not limited to, Raman spectrum (Raman), FTIR, UVIS, and NMR (liquid and solid states). Various microscopy techniques include, but are not limited to: polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), scanning electron microscopy in natural mode with EDX (in a gas or water vapor atmosphere), IR microscopy and Raman microscopy.

In yet another embodiment, the present invention relates to compounds selected from the group consisting of:

The present invention also provides a method for inhibiting EGFR biological activity in a subject, comprising contacting the EGFR with a compound described herein.

Compounds that inhibit EGFR can be used to manufacture medicaments for the treatment of any of the pathological conditions described herein, for example, compounds of formula I, pharmaceutically acceptable salts, solvates or stereoisomers will be useful in the treatment of diseases or medical conditions mediated solely or in part by EGFR activity such as cancer. Examples of cancers that can be treated using the above compounds include bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer. , leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer , liver cancer, but not limited to anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematologic malignancies.

In one embodiment, the present invention provides a pharmaceutical composition comprising, in a therapeutically effective amount, at least one of the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In yet another embodiment of the present invention, a pharmaceutical composition containing the compounds of this invention is for the prevention or treatment of a disease or disorder mediated by EGFR activity.

In yet another embodiment of the present invention, a pharmaceutical composition containing the compounds of the present invention is for the prevention or treatment of a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.

In yet another embodiment of the present invention, a pharmaceutical composition containing the compounds of the present invention is for the prevention or treatment of oncological diseases, including bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer. , glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer , bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignancies.

In yet another embodiment of the present invention, a pharmaceutical composition containing the compounds of the present invention is for the prevention or treatment of an oncological disease, which is a non-small cell lung cancer.

The pharmaceutical composition of the present invention contains, for example, from about 5% to about 100% wt. active ingredients, preferably from about 10% wt. up to about 60% wt. active ingredients. It is understood that the content of the active ingredient or ingredients in an individual dose of each dosage form does not necessarily constitute an effective amount, since the required effective amount can be achieved with the introduction of several unit dosage forms.

A typical composition is prepared by mixing a compound of the present invention and a carrier, diluent, or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The specific carrier, diluent or excipient used will depend on the means and purpose for which the compound of the present invention is being used. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (eg PEG400, PEG300), etc. and their mixtures. The compositions may also include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, matting agents, lubricants, processing aids, colors, sweeteners, flavoring agents, flavoring agents, and others. known additives to obtain a good appearance of the drug (ie, the compound of the present invention or its pharmaceutical composition) or to assist in the manufacture of a pharmaceutical product (ie, drug). The production of pharmaceutical compositions should preferably comply with GMP (Good Manufacturing Practice) requirements.

Pharmaceutical compositions also include solvates and hydrates of the compounds of the present invention, or a stabilized form of the compound (eg complexed with a cyclodextrin derivative or other known complexing agent).

The pharmaceutical compositions of the present invention are generally suitable for oral administration. Oral administration may include swallowing such that the compound enters the gastrointestinal tract and/or buccally, lingually or sublingually enters the bloodstream directly from the oral cavity.

Dosage forms suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nanoparticles, liquids or powders; granules; lozenges (including those filled with liquid); chewable forms; gels; fast-dissolving dosage forms; films; suppositories; sprays; and buccal/mucoadhesive patches. More preferred oral dosage forms are tablets, granules and capsules.

Liquid dosage forms include suspensions, solutions, syrups and elixirs. Such dosage forms may be used as fillers in soft or hard capsules (e.g. gelatin or hydroxypropyl methylcellulose) and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil and one or more emulsifying and/or suspending agents. . Liquid dosage forms can also be prepared by solid reconstitution, for example from sachets.

The compounds of the present invention may also be administered parenterally. As used herein, the term "parenteral administration" of a pharmaceutical composition includes any route of administration that physically disrupts the tissue of a subject and introduces the pharmaceutical composition through the tissue disruption, typically resulting in direct entry into the bloodstream, muscle, or internal organ. Thus, parenteral administration includes, but is not limited to, administering the pharmaceutical composition by injecting the composition, by administering the composition through a surgical incision, by applying the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is intended to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intraarticular injection or infusion; and renal dialysis infusion techniques. Intratumoral delivery, such as intratumoral injection, may also be useful. Regional perfusion is also provided.

Dosage forms of pharmaceutical compositions suitable for parenteral administration generally contain the active ingredient in association with a pharmaceutically acceptable carrier, eg sterile water or sterile isotonic saline. Such dosage forms may be formulated, packaged or sold in a form suitable for bolus administration or for continuous administration. Injectable dosage forms may be prepared, packaged or sold in unit dosage form, for example in ampoules, or in multi-dose containers containing a preservative. Dosage forms for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous bases, pastes, and the like.

The compounds of the present invention may also be administered intranasally or by inhalation, usually in the form of a dry powder (alone, as a mixture, or as particles with mixed components, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, such as an aerosol container under pressure, pump, spray, nebulizer (preferably a nebulizer that uses the principle of electrohydrodynamics to produce a fine mist) or nebulizer with or without a suitable propellant, or as nasal drops.

The pressurized container, pump, spray, nebulizer or nebulizer will typically contain a solution or suspension of a compound of this invention including, for example, a suitable agent for dispersing, dissolving or prolonging the release of the active agent, a propellant as solvent.

Prior to use as a dry powder or suspension, the drug is usually micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supercritical fluid purification to form nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters, and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of this invention, a suitable powder base, and an activity modifier.

A suitable solution formulation for use in a nebulizer that utilizes the principle of electrohydrodynamics to produce a fine mist may contain a suitable dose of a compound of this invention per push and the volume per push may vary from, for example, 1 µl to 100 µl.

Suitable flavoring agents such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin may be added to dosage forms of the present invention intended for inhalation/nasal administration.

Dosage forms can be made for immediate and/or modified release. Modified release dosage forms include delayed, sustained, pulsatile, controlled, targeted, and programmed release.

In one embodiment, the present invention provides a method of treating a disease or disorder mediated by EGFR activity, which comprises administering a therapeutically effective amount of any compound described above or a pharmaceutical composition of the invention to a subject in need of such treatment.

In yet another embodiment, the invention relates to a method of treatment as described above, wherein said disease or disorder is a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.

In yet another embodiment, the invention relates to a method of treatment as described above, wherein the disease or disorder mediated by EGFR activity is cancer. In yet another embodiment, the invention relates to a method of treatment as described above, wherein the cancer is selected from the group consisting of bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, biliary cancer ducts, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignancies.

In yet another embodiment, the invention relates to a method of treatment as described above, wherein the cancer is non-small cell lung cancer.

In one embodiment, the present invention relates to the use of a compound of the present invention, or a pharmaceutical composition as described above, for the treatment of a disease or disorder mediated by EGFR activity in a subject in need of such treatment.

In yet another embodiment, the present invention relates to the use described above, wherein said disease or disorder is a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.

In yet another embodiment, the present invention relates to the use described above, wherein the disease or disorder mediated by EGFR activity is an oncological disease. In yet another embodiment, the invention relates to the use described above, wherein the cancer is selected from the group consisting of bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma. , melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer (eg, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer , endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignancies.

In yet another embodiment, the invention relates to the use described above, wherein the cancer is a non-small cell lung cancer.

The compounds of the present invention may be administered alone or in combination with one or more other drugs or antibodies (or any combination thereof). Thus, pharmaceutical compositions, methods and uses of the invention also cover combinations (co-administration) embodiments with other active agents.

As used herein, the terms "co-administered", "co-administered" and "in combination with" referring to these compounds with one or more other therapeutic agents are intended to mean, refer to or include:

- simultaneous administration of such a combination of a compound of the present invention and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form from which said components are released substantially simultaneously to said patient,

- the simultaneous administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated separately in different dosage forms, the administration of which occurs at almost the same time to said patient, after which these components are released almost simultaneously to said patient

- sequential administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated separately from each other in separate dosage forms that are taken in sequential time by the specified patient with a significant time interval between each administration, after which said components are released at substantially different times to said patient; as well as

- sequential administration of such a combination of a compound of this invention and a therapeutic agent to a patient in need of treatment, when such components are formulated together in a single dosage form from which the release of these components occurs in a controlled manner, after which they are simultaneously, sequentially or jointly released into one and the same time and/or different time to the specified patient, where each part can be entered in one or different ways.

Those skilled in the art will recognize that therapeutically effective dosages may vary when drugs are used in combination therapy. Methods for experimental determination of therapeutically effective dosages of drugs and other agents for use in combination treatment regimens are described in the literature. For example, the use of uniform dosing, ie. administration of more frequent and smaller doses to minimize toxic side effects has been described in the literature. Combination treatment further includes intermittent treatment that starts and stops at different times according to the patient's treatment plan. In the combination therapy described in the present patent, the dosages of the co-administered compounds will, of course, vary depending on the type of auxiliary drug used, the specific drug used, the disease or condition being treated, and so on.

The anticancer treatment described above can be used as the sole therapy, or in combination with surgery, or radiation therapy, or drug therapy. Such therapy may be administered concurrently, simultaneously, sequentially or separately with treatment with a compound of the invention and may include one or more agents from the following categories of antitumor agents: antiproliferative/anticancer drugs and combinations thereof used in medical oncology such as alkylating agents (e.g. , cisplatin, oxaliplatin, carboplatin, cyclophosphamide, chlormethine, melphalan, chlorambucil, busulfan, treosulfan, temozolomide, bendamustine, prospidin, spirobromine, prednimustine, estramustine, pafencil, lofenal, ifosfamide, mafosfamide, trofosfamide, glufosfamide and drugs, nitrosoureas carmustine, lomustine, nimustine, fotemustine, aranose, streptozocin); antimetabolites (eg, gemcitabine, fluorouracil, floxuridine, tegafur, raltitrexide, methotrexate, trimetrexate, pemetrexed, pralatrexate, calcium levofolinate, cytosine arabinoside, hydroxyurea, azathioprine, cladribine, fludarabine, pentostatin, mercaptopurine, nelarabine, thioguanine, fludarabine, capazabinitapurine, azathioprine , cladribine, nelarabine, azathioprine, clofarabine, cytarabine, enocytabin, carmofur, gemcitabine, sapacitabine, elacytarabine, doxifluridine); anticancer antibiotics (eg bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin, dactinomycin, mithramycin, daunorubicin, carubicin, epirubicin, valrubicin, zorubicin, aclarubicin, pyrarubicin, nemorubicin, amrubicin, zinostatin, streptozocin, mitoxantrone); antimitotic agents (eg vinca alkaloids such as vincristine, vinblastine, vinflunine, vindesine and vinorelbine, taxoids such as paclitaxel and docetaxel, cabazitaxel, tezetaxel, polokinase inhibitors); and topoisomerase inhibitors (eg, epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, irinotecan, belotecan, voreloxin, amonafide, and camptothecin); cytostatic agents such as antiestrogen (eg, tamoxifen, clostilbegit, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (eg, bicalutamide, flutamide, nilutamide, topilutamide, enzalutamide, and cyproterone acetate, chlormadinone), luteinizing hormone-releasing factor antagonists (LHRH) or LHRH agonists (eg, goserelin, leuprorelin, and buserelin), progestogens (eg, chlormadinone, hestonerone caproate, medroxyprogesterone, megestrol acetate), aromatase inhibitors (eg, anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors ( e.g. finasteride, dutasteride, epristeride); anti-invasive agents (eg, c-Src kinase family inhibitors (eg, saracatinib, dasatinib, and bosutinib), metalloproteinase inhibitors (eg, marimastat), inhibitors of urokinase receptor activator function (eg, plasminogen or anti-heparanase antibodies); inhibitors of growth factor function: for example, such inhibitors include anti-growth factor antibodies and anti-growth factor receptor antibodies (e.g., trastuzumab, panitumumab, cetuximab, and any of the anti-growth factor and growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp. 11-29); such inhibitors also include tyrosine kinase inhibitors, including inhibitors of the epidermal growth factor family (eg, EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, canertinib (CI 1033), afatinib, osimertinib, rociletinib, icotinib , dacomitinib; erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the seme properties of insulin-like growth factors; platelet growth factor family inhibitors such as imatinib, nilotinib; serine/threonine kinase inhibitors (e.g. inhibitors of Ras/Raf signaling such as farnesyl transferase inhibitors such as sorafenib, tipifarnib and lonafarnib), MEK and/or AKT kinase signaling inhibitors, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (eg barasertib (AZD1152), danusertib (PHA-739358), tozasertib (VX-680), MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors such as CDK2 and/or or CDK4 inhibitors; anti-angiogenic agents, such as agents that inhibit the effects of vascular endothelial growth factor (eg, bevacizumab, vandetanib, vatalanib, sunitinib, axitinib, pazopanib, crizotinib, and cediranib (AZD2171), linomide, inhibitors of avp3 integrin function, angiostatin, endostatin, thalidomide, everolimus , sirolimus, itraconazole, suramin, semaxanib, thrombospondin, ramucirumab, tasquinimod, ranibizumab, sorafenib, compounds disclosed in international application publications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354); vasopressure agents (e.g., combretastatin A4, ombrabulin, and compounds disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; endothelin receptor antagonist (eg, bosentan, sitaxentan, ambrisentan, BQ-123, BQ-788, macitentan, tezosentan, zibotentan, atrasentan); antisense therapies (eg, which target the targets listed above, such as ISIS 2503, antisense anti-ras, antisense anti-EGFR, custirsen, apatorsen, ISIS-STAT3Rx (ISIS 481464/AZD9150), ISIS-ARRx (AZD5312), Trabedersen (AP 12009), EZN-2968, LErafAON-ETU); gene therapy approaches, including, for example, approaches for aberrant gene substitutions (eg, aberrant p53 or aberrant BRCA1 or BRCA2), GDEPT approaches (gene directed enzyme prodrug therapy, such as approaches using cytosine deaminase, thymidine kinase, or the bacterial enzyme nitroreductase), and approaches to increase patient tolerance to chi myotherapy or radiotherapy (eg, multidrug resistance gene therapy); and immunotherapeutic approaches, including, for example, checkpoint inhibitors such as PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, pidilizumab, and others), as well as drugs that act on CTLA-4 (including ipilimumab, tremelimumab), OX-40, VISTA, ICOS, TIGIT, LAG-3, 4-1BB, GITR, CD40, CCR4 and others; other ex-vivo and in-vivo approaches to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4, interleukin 15, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, approaches using anti-idiotypic antibodies, approaches to reduce the function of immunosuppressive cells such as regulatory T cells, myeloid suppressor cells, or IDO (indolamine-2 ,3,-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines composed of proteins or peptides derived from tumor-associated antigens such as NY-ESO-1, MAGE-3, WT1 or Her2/neu.

Thus, in yet another embodiment of the invention, a pharmaceutical product is described comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, as defined above, in combination with an antitumor agent, as defined above, for the co-treatment of cancer.

Drug regimens can be adjusted to provide the optimal desired response. For example, a single dose may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased depending on the severity of the therapeutic situation. It is particularly useful to formulate oral compositions in unit dosage form for ease of administration and dosage uniformity. Unit dosage form, as used herein, refers to physically discrete units suitable as unit doses for patients/subjects to be treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. The specification for unit dosage forms of the present invention is generally dictated by and directly dependent on (a) the unique characteristics of the therapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for sensitivity treatment in subjects.

Thus, those skilled in the art will appreciate from the disclosure provided herein that doses and dosing regimens are adjusted in accordance with methods well known in the therapeutic field. This means that the maximum tolerated dose can be easily set and the effective amount that provides a detectable therapeutic effect for the patient can also be determined, as well as the time requirements for the administration of each agent to achieve a visible therapeutic effect for the patient. Thus, although some doses and regimens are given as examples herein, these examples do not in any way limit the doses and regimens that a patient may need in the practice of the present invention.

It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated and may include one or more doses. In addition, it should be understood that for any particular patient, specific administration schedules will need to be adjusted over time according to individual need and at the discretion of the healthcare professional who administers or supervises the administration of the compositions, and that the concentration ranges given in this specification are only by way of example and are not intended to limit the scope or practice of the claimed compositions. In addition, the dosage regimen with the compositions of this invention may be based on various factors, including the type of disease, age, weight, sex, health conditions of the patient, severity of the condition, route of administration, and the particular compound of the present invention used. Thus, the dosing regimen may vary widely, but may be determined regularly using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses individual dose escalation as determined by the skilled artisan. Determination of the required dose and modes are well known in the relevant field of technology and will be clear to a person skilled in the art after reading the ideas disclosed in this document.

Typically, doses used to treat an adult human are typically in the range of 0.02-5000 mg per day, or about 1-1500 mg per day.

When the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which relief of the disease, disorder, or condition is maintained. Patients may, however, require intermittent treatment over time for any recurrence of symptoms.

The above spectrum is only suggestive, as the number of variables in relation to an individual treatment regimen is large, and significant deviations from these recommended values are not uncommon. These dosages may be varied depending on a variety of variables, not limited to the activity of the compound being used, the disease or condition being treated, the route of administration, the needs of the individual subject, the severity of the disease or condition being treated, and the judgment of the attending physician.

For a better understanding of the invention, the following examples are given. These examples are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any form.

All publications, patents, and patent applications referenced in this specification are incorporated herein by reference. Although the above invention has been described in some detail by way of illustration and example in order to avoid ambiguity, it will be quite clear to those skilled in the art based on the ideas disclosed in this invention that certain changes and modifications can be made without deviating from the essence and scope of the attached options. implementation of the invention.

Examples

Example 1. Method for obtaining compound 4b.

Stage 1. Preparation of compound 4_2.

To a solution of 4-fluoro-2-methoxy-5-nitroaniline 4_1 (10.0 g, 53.7 mmol) and DMAP (0.33 g, 2.66 mmol) in dichloromethane (100 mL) at 0 tert-butyl dicarbonate (16.2 g, 74.3 mmol) in 30 ml dichloromethane. The reaction mixture was brought to room temperature and stirred for 24 hours. The resulting mixture was concentrated in vacuo, the product was isolated by column chromatography on silica gel using dichloromethane/hexane eluent (1:1 to 1:0 gradient). The yield of compound 4_2 was 6.40 g (42%).

Stage 2. Preparation of compound 4_3.

To a solution of aniline 4_2 (6.10 g, 20.9 mmol) in DMF (10 mL) was added N,N,N'-trimethylethylenediamine (3.59 mL, 27.2 mmol) and DIPEA (5.24 mL, 31.3 mmol) at room temperature. The reaction mixture was stirred for 2 h at 60°C. The resulting mixture was poured into water, the product was extracted with ethyl acetate. The combined organic fractions were washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The yield of compound 4_3 was 7.62 g (99%).

Stage 3. Obtaining compound 4_4.

Pd/C (1.30 g, 3.02 mmol) was added to a solution of compound 4_3 (7.50 g, 20.2 mmol) in methanol (90 mL) and reduced under hydrogen pressure (2 atm) for 1 h. The reaction mixture was filtered and concentrated in vacuo . The yield of compound 4_4 was 6.69 g (98%).

Stage 4. Preparation of compound 4_5.

To a mixture of compound 4_4 (6.69 g, 19.8 mmol) and DIPEA (3.59 ml, 27.2 mmol) in dichloromethane (150 ml) at 0°C dichloromethane (80 ml). The resulting mixture was stirred at room temperature. After 3.5 h additional amounts of acroloyl chloride (0.38 ml, 4.60 mmol) and DIPEA (0.80 ml, 4.60 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Saturated Na ₂ CO ₃ solution was added to the resulting mixture, the organic layer was washed with saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane/triethylamine eluent (8:2:0 to 8:2:0.05 gradient). The yield of compound 4_5 was 5.04 g (65%).

Step 5: Preparation of Compound 4b.

Compound 4_5 (5.04 g, 12.8 mmol) was dissolved in trifluoroacetic acid (30 ml) and stirred at room temperature for 1 h. The reaction mixture was added dropwise to a saturated solution of Na ₂ CO ₃ , the product was extracted with ethyl acetate. The combined organic fractions were washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane/triethylamine eluent (8:2:0 to 8:2:0.07 gradient). The yield of compound 4b was 3.23 g (85%).

Пример 2. Способ получения соединений EGFR_3365_3, EGFR_3365_4, EGFR_3365_50, EGFR_3365_51, EGFR_3365_52, EGFR_3365_54, EGFR_3365_56, EGFR_3365_57, EGFR_3365_77, EGFR_3365_85, EGFR_3365_87, EGFR_3365_88, EGFR_3365_93.

Stage 1. Preparation of compound 3a.

To a solution of iodobenzene 1a (8.35 g, 39.7 mmol) in 350 mL of diethyl ether was added dropwise a 2.5 M solution of n-butyllithium in hexane (15.9 mL, 39.7 mmol) over 15 min at –78°C under nitrogen atmosphere. The temperature of the reaction mixture was then brought to 0° C. and stirred at this temperature for 30 minutes. Next, the reaction mixture was again cooled to -78°C and a solution of nitrile 2a (5.00 g, 36.1 mmol) in 50 ml of diethyl ether was slowly added. The resulting mixture was stirred for 1 hour at -78°C, then the temperature of the mixture was brought to -30°C and 100 ml of 2M HCl was added. The reaction mixture was stirred for 1 h, then neutralized with 1M NaOH solution, the product was extracted with ethyl acetate. The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane (1:4) as eluent. The yield of compound 3a was 7.04 g (90%).

Compound 3b was prepared similarly from the corresponding starting reagent 1b.

Stage 2. Preparation of compound 5a.

Cs ₂ CO ₃ (0.300 g, 0.92 mmol), BINAP (0.057 g, 0.09 mmol) and aniline 4а (0.094 g, 0.51 mmol) were added to a solution of compound 3a (0.100 g, 0.46 mmol) in 2 ml of 1,4-dioxane. at room temperature. The resulting solution was degassed with nitrogen for 10 min. Then, Pd(OAc) ₂ (0.010 g, 0.05 mmol) was added to the reaction mixture with stirring. The resulting mixture was refluxed for 3 h under a nitrogen atmosphere. The mixture was then diluted with 10 ml dichloromethane and filtered through celite. The filtrate was concentrated in vacuo and the product was isolated by silica gel column chromatography using dichloromethane as eluent. The yield of compound 5a was 0.112 g (66%).

Compound 5b was prepared similarly from the corresponding intermediate 3b.

Stage 3. Preparation of compound 6a.

To a solution of compound 5а (0.110 g, 0.3 mmol) in 3 mL of dimethylformamide was added N,N,N'-trimethylethane-1,2-diamine (0.034 g, 0.33 mmol) and DIPEA (0.077 g, 0.6 mmol). The reaction mixture was stirred for 12 hours at room temperature. The resulting mixture was concentrated and the product was isolated by silica gel column chromatography using dichloromethane/ethyl acetate (8:1) with a triethylamine gradient (0% _v/v to 10% _v /v) as eluent. The yield of compound 6a was 0.127 g (95%).

Compound 6b was prepared similarly from the corresponding intermediate 5b.

Step 4. Preparation of compound 7a.

NaHCO ₃ (0.214 g, 2.54 mmol) was added to a solution of compound 6а (0.127 g, 0.28 mmol) in 9 ml of a mixture of tetrahydrofuran/methanol/water (3:1:5). Na ₂ S ₂ O ₄ (0.442 g, 2.54 mmol) was added to the resulting mixture in portions over 30 min at 0°C. The resulting mixture was stirred for 15 min at room temperature. The mixture was then diluted with water, the product was extracted with ethyl acetate. The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using dichloromethane/ethyl acetate (3:1) with a triethylamine gradient (0.5% _v/v to 5% _v /v) as eluent. The yield of compound 7a was 0.107 g (90%).

Compound 7b was prepared similarly from the corresponding intermediate 6b.

Step 5: Preparation of compound EGFR_3365_3.

DIPEA (0.035 g, 0.27 mmol) was added to a solution of compound 7a (0.107 g, 0.26 mmol) in 5 mL of dichloromethane. A solution of acryloyl chloride (0.024 g, 0.26 mmol) in 3 ml of dichloromethane was added dropwise to the resulting mixture at -70°C over 1 h. The temperature of the reaction mixture was brought to -30°C and stirred at this temperature for 30 min. A saturated solution of NaHCO ₃ was added to the resulting mixture, the product was extracted with dichloromethane. The combined organic fractions were washed with saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using dichloromethane/hexane/ethyl acetate (3:1:1) with a triethylamine gradient (0.5% _v/v to 3% _v /v) as eluent. The yield of compound EGFR_3365_3 was 0.055 g (45%).

The compound EGFR_3365_4 was prepared similarly from the corresponding intermediate 7b (the product was further purified by preparative chromatography). Connection EGFR_3365_4a was obtained by repeated lyophilization of the connection EGFR_3365_4.

Аналогично соединению 5а получены кандидаты EGFR_3365_50, EGFR_3365_51, EGFR_3365_52, EGFR_3365_54, EGFR_3365_56, EGFR_3365_57, EGFR_3365_77, EGFR_3365_85, EGFR_3365_87, EGFR_3365_88, EGFR_3365_93 с использованием анилина 4b вместо 4a из соответствующих исходных реагентов через соответствующие промежуточные соединения, указанные в таблице 1.

Example 3 Method for preparing the compound EGFR_3365_5, EGFR_3365_15, EGFR_3365_26, EGFR_3365_73, EGFR_3365_101, EGFR_3365_102, EGFR_3365_103, EGFR_3365_104, EGFR_3365_116, EGFR_2365

Stage 1. Preparation of compound 3c.

Aryl bromide 1с (0.5 g, 2.06 mmol) and a catalytic amount of dibromoethane were added to a suspension of magnesium (0.061 g, 2.52 mmol) in 20 mL of tetrahydrofuran. The resulting suspension was refluxed for 2.5 h, then cooled to room temperature, and nitrile 2а (0.277 g, 2.0 mmol) was added. The reaction mixture was stirred at room temperature for two days, then diluted with a saturated solution of NH ₄ Cl, the organic layer was separated and concentrated. The residue was dissolved in 10 ml of diethyl ether, 40 ml of 1M HCl was added to the solution, and the resulting mixture was stirred for 30 minutes at room temperature. The aqueous layer was separated and neutralized with saturated NaHCO ₃ solution, the product was extracted with dichloromethane, the combined organic layers were washed with saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane (1:4) as eluent. The yield of compound 3 с was 0.407 g (65%).

Stage 2. Obtaining compound EGFR_3365_5.

Compound EGFR_3365_5 was prepared analogously to compound 5a (step 2) using compound 3c instead of compound 3a and aniline 4b instead of aniline 4a. Connection EGFR_3365_5a was obtained by repeated lyophilization of the connection EGFR_3365_5.

Compounds EGFR_3365_15, EGFR_3365_26, EGFR_3365_73, EGFR_3365_101, EGFR_3365_102, EGFR_3365_103, EGFR_3365_104, EGFR_3365_116, EGFR_3365_124 were obtained similarly from the corresponding intermediates indicated in Table 2 via the corresponding intermediates indicated in Table 2.

Пример 4. Способ получения соединения EGFR_3365_10, EGFR_3365_11, EGFR_3365_12, EGFR_3365_13, EGFR_3365_14, EGFR_3365_14a, EGFR_3365_16, EGFR_3365_17, EGFR_3365_28, EGFR_3365_29, EGFR_3365_30, EGFR_3365_31, EGFR_3365_32, EGFR_3365_33, EGFR_3365_34, EGFR_3365_36, EGFR_3365, EGFR_3365_64, EGFR_3365_66, EGFR_3365_67, EGFR_3365_68, EGFR_3365_69, EGFR_3365_70, EGFR_3365_71, EGFR_3365_78, EGFR_3365_86, EGFR_3365_91, EGFR_3365_92, EGFR_3365_94.

Stage 1. Preparation of compound 3d.

To a solution of aldehyde 1d (0.478 g, 3.85 mmol) in 10 mL of DMF was added 2,4-dichloropyrimidine 2b (0.500 g, 3.35 mmol) and N,N'-dimethylimidazolium iodide (0.375 g, 1.67 mmol) at room temperature. The resulting solution was degassed with nitrogen for 10 min, then NaH (60% wt., 0.201 g, 5.02 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. The resulting mixture was poured into cold water, the product was extracted with ethyl acetate. The combined organic fractions were washed with water and saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane (1:4) as eluent. The yield of compound 3d was 0.166 g (21%).

Compounds 3e - 3u were obtained similarly (shown in Table 2). For the synthesis of compounds 3f and 3g, a mixture of 1,4-dioxane and DMSO in a ratio of 10:1 was used as a solvent.

Step 2. Preparation of compound EGFR_3365_10.

Aniline 4b (0.115 g, 0.53 mmol) and trifluoroacetic acid (0.185 ml, 2.64 mmol) were added to a solution of compound 3d (0.114 g, 0.48 mmol) in 2 mL of isopropanol at room temperature. The reaction mixture was boiled for 24 hours. To the resulting mixture was added a saturated solution of NaHCO ₃ and dichloromethane. The organic layer was washed with saturated NaCl solution, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using dichloromethane/hexane/ethyl acetate (3:1:1) with a triethylamine gradient (0.5% _v/v to 3% _v /v) as eluent. The yield of the EGFR_3365_10 compound was 54 mg (23%). The product was further purified by preparative chromatography.

Аналогично были получены соединения EGFR_3365_11, EGFR_3365_12, EGFR_3365_13, EGFR_3365_14, EGFR_3365_14a, EGFR_3365_16, EGFR_3365_17, EGFR_3365_28, EGFR_3365_29, EGFR_3365_30, EGFR_3365_31, EGFR_3365_32, EGFR_3365_33, EGFR_3365_34, EGFR_3365_36, EGFR_3365, EGFR_3365_64, EGFR_3365_66, EGFR_3365_67, EGFR_3365_68, EGFR_3365_69, EGFR_3365_70, EGFR_3365_71, EGFR_3365_78, EGFR_3365_86, EGFR_3365_91, EGFR_3365_92, EGFR_3365_94 from the respective starting reagents via the respective intermediates listed in Table 3.

Example 5. Method for obtaining the compound EGFR_3365_31a, EGFR_3365_30a.

Step 1. Preparation of compound 5c.

Compound 5c was prepared analogously to EGFR_3365_10, using compound 3p instead of compound 3d and aniline 4a instead of aniline 4b.

Compound 5d was prepared similarly from the corresponding starting 3о.

Step 2: Preparation of compound 6c.

Compound 6c was prepared analogously to compound 6a, using compound 5c instead of compound 5a.

Compound 6d was prepared similarly from the corresponding intermediate 5d.

Step 3. Preparation of compound 7aa.

Na ₂ S ₂ O ₄ (13.75 g, 78.2 mmol) was added to a solution of compound 6с (4.1 g, 7.82 mmol) in 120 ml of methanol/water (1:2) mixture. The reaction mixture was stirred for 1 hour at 40°C. The resulting mixture was concentrated, the product was extracted with dichloromethane, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using dichloromethane/methanol eluent (9:1 to 1:1 gradient). Yield of compound 7аа was 3.6 g (96%), brown oily substance.

Compound 7ab was prepared similarly from the corresponding intermediate 6d.

Stage 4. Method for obtaining the compound EGFR_3365_31a.

To a solution of compound 7аа (2.0 g, 4.03 mmol) in 40 mL of dichloromethane at –70°C under nitrogen was added dropwise a solution of N,N-diisopropylethylamine (0.63 g, 4.84 mmol) in 5 mL of dichloromethane, then a solution of acryloyl chloride (0.33 g , 3.63 mmol) in 5 ml of dichloromethane. The reaction mixture was stirred for 2 h at -40°C, then water was added at the same temperature, the product was extracted with dichloromethane, the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using dichloromethane/methanol eluent (99:1 to 90:1 gradient). The yield of compound EGFR_3365_31a was 0.81 g (37%), white powder.

Similarly, compound EGFR_3365_30a was prepared from the corresponding intermediate 7ab.

Пример 6. Способ получения соединения EGFR_3365_63, EGFR_3365_58, EGFR_3365_61, EGFR_3365_62, EGFR_3365_62a, EGFR_3365_72, EGFR_3365_90, EGFR_3365_97, EGFR_3365_98, EGFR_3365_105, EGFR_3365_106, EGFR_3365_106a, EGFR_3365_108, EGFR_3365_109, EGFR_3365_110, EGFR_3365_111, EGFR_3365_112, EGFR_3365_112a, EGFR_3365_113, EGFR_3365_114, EGFR_3365_115, EGFR_3365_121a.

K2CO3 (36 mg, _0.258 mmol, 1.25 eq.) was added to a solution _of compound EGFR_3365_10 (102 mg, 0.21 mmol) and pyrrolidine (17 μl, 0.21 mmol, 1 equiv.) in DMF (1 ml). The resulting suspension was stirred at 80°C for 12 hours. The reaction mass was poured into water, the product was extracted with ethyl acetate. The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/triethylamine (1/0.075) eluent. The yield of compound EGFR_3365_63 was 72 mg. The product was further purified by preparative HPLC to give 48 mg (43%).

Аналогично были получены соединения EGFR_3365_58, EGFR_3365_61, EGFR_3365_62, EGFR_3365_62a, EGFR_3365_72, EGFR_3365_90, EGFR_3365_97, EGFR_3365_98, EGFR_3365_105, EGFR_3365_106, EGFR_3365_106a, EGFR_3365_108, EGFR_3365_109, EGFR_3365_110, EGFR_3365_111, EGFR_3365_112, EGFR_3365_112a, EGFR_3365_113, EGFR_3365_114, EGFR_3365_115, EGFR_3365_121a из соответствующих исходных реагентов, indicated in table 4.

Example 7. Method for obtaining the compound EGFR_3365_120, EGFR_3365_122, EGFR_3365_123, EGFR_3365_127.

Stage 1. Preparation of compound 5.

4-Fluoro-2-methoxyaniline (2.50 g, 17.5 mmol) was dissolved in 14 ml _{conc. HCl.} , cooled to 0°C, then added with stirring a solution of NaNO ₂ (1.45 g, 21.0 mmol) in 13 ml of water. Stirring was continued for 40 min, the resulting solution was added dropwise to a solution of KI (8.73 g, 52.6 mmol) in 30 ml of water at room temperature. The resulting mixture was stirred at 35-40°C for 1 h, the product was extracted with ethyl acetate (3×70 ml), the extract was washed with Na ₂ S ₂ O ₃ solution, dried over Na ₂ SO ₄ . The product was isolated by silica gel chromatography using hexane as eluent. 3.46 g (78%) of 2-iodo-5-fluoroanisole 5 was obtained as a colorless solid.

Stage 2. Preparation of compound 6.

2-Iodo-5-fluoroanisole 5 (3.46 g, 13.0 mmol) was dissolved in 70 ml of THF, the reaction mixture was cooled in a nitrogen atmosphere to -10°C, a 2 M solution of isopropylmagnesium chloride in THF (8.50 ml, 17.0 mol) was added, continued stirring for 30 min, DMF (2.89 g, 39.1 mmol) was added, stirring was continued for 30 min, the reaction mass was heated to room temperature, 20 ml of a saturated aqueous solution of NH ₄ Cl was added. The resulting mixture was extracted with ethyl acetate (3×70 ml), the extract was washed with water (5×20 ml), dried over Na ₂ SO ₄ . The product was isolated by chromatography on silica gel, eluent ethyl acetate-hexane (1:9). 1.9 g (94%) of 2-methoxy-4-fluorobenzaldehyde 6 was obtained.

Stage 3. Preparation of compound 7.

2-Methoxy-4-fluorobenzaldehyde (0.40 g, 2.60 mmol), 2,4-dichloropyrimidine (0.59 g, 3.89 mmol), 1,3-dimethylimidazolium iodide (0.31 g, 1.30 mmol) was dissolved in 9 ml of DMF, nitrogen was passed through through the reaction mass for 2 min, NaH was added in the form of a 60% suspension in paraffin (0.13 g, 2.24 mmol), the resulting mixture was stirred in a nitrogen atmosphere at 75°C for 4 h. Then 2,4-dichloropyrimidine was added to the reaction mass (0.3 g, 1.95 mmol), 1,3-dimethylimidazolium iodide (0.16 g, 0.65 mmol) and NaH (0.065 g, 1.12 mmol) and continued heating with stirring for 1 h, added NaH (0.065 g, 1.12 mmol) and continued heating for another 2 hours To the resulting mixture was added 20 ml of water, the product was extracted with ethyl acetate (3×50 ml), the extract was washed with water (4×10 ml), dried over Na ₂ SO ₄ . The product was isolated by chromatography on silica gel, eluent ethyl acetate-hexane (1:9). 0.21 g (30%) of compound 7 was obtained.

Step 4 Preparation of Compound 9

Compound 7 (0.12 g, 0.45 mmol), aniline 8 (0.28 g, 0.90 mmol), BINAP (0.057 g, 0.09 mmol), Cs ₂ CO ₃ (0.44 g, 1.35 mmol) and Pd(OAc) ₂ (10 mg, 0.05 mmol, 10 mol %) was dissolved in 3.6 ml of dioxane and placed in a screw cap vial. The reaction mass was degassed with a stream of nitrogen for 5 min, stirred under nitrogen at 90°C for 4 h. The product was isolated by chromatography on silica gel, eluent triethylamine-ethyl acetate-hexane (2:40:10). 0.18 g (69%) of compound 9 was obtained.

Step 5. Preparation of compound EGFR_3365_120.

Compound 9 (0.10 g, 0.17 mmol), K ₂ CO ₃ (0.029 g, 0.21 mmol), 1 mL of DMSO, and N-methylpiperazine (0.019 g, 0.19 mmol) were placed into a vessel with a screw cap in the indicated order. The reaction mass was stirred at 80°C for 5 hours To the resulting mixture was added 5 ml of water, the product was extracted with ethyl acetate (3×30 ml), the extract was washed with water (3×5 ml), dried over Na ₂ SO ₄ . The product was isolated by chromatography on silica gel, eluent - methanol, then methanol-triethylamine (100:1). Received 0.054 g (52%) compound EGFR_3365_120.

Compounds EGFR_3365_122, EGFR_3365_123, and EGFR_3365_127 were prepared similarly from the corresponding starting reagents listed in Table 5.

Example 8. Method for obtaining the compound EGFR_3365_121, EGFR_3365_126.

Stage 1. Preparation of compound 10.

Compound 10 was prepared analogously to EGFR_3365_63, using tert-butyl-piperidin-4-ylcarbamate instead of pyrrolidine.

Step 2. Preparation of compound EGFR_3365_121.

Trifluoroacetic acid (1.8 ml) was added to a solution of compound 9 (0.051 g, 0.07 mmol) in dichloromethane (7 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was carefully poured into a saturated solution of Na ₂ CO ₃ (degassed). The product was extracted with ethyl acetate (3×15 ml), the combined organic fractions were washed with water (2×10 ml), saturated NaCl solution (1×10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting substance (0.032 g, 80%) was purified by preparative HPLC. The resulting sample was treated with saturated Na ₂ CO ₃ solution (degassed) until slightly basic, the product was extracted with ethyl acetate (degassed) (3×15 ml). The combined organic fractions were washed with brine (1×10 ml). The extract obtained was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. After lyophilization, 0.03 g (75%) of a yellow crystalline substance was obtained.

Similarly, compound EGFR_3365_126 was prepared from the corresponding intermediate 9 and tert-butyl-piperidin-4-ylcarbamate.

Example 9. Method for obtaining the compound EGFR_3365_53.

Stage 1. Preparation of compound 11.

To a mixture containing ketone 4d (200 mg, 0.65 mmol), 3-methoxyazetidine hydrochloride (74 mg, 0.58 mmol, 0.9 eq), rac-BINAP (82 mg, 0.013 mmol, 0.2 eq), Cs ₂ CO ₃ (646 mg , 1.96 mmol, 3 equiv) Pd(OAc) ₂ (15 mg, 0.06 mmol, 0.1 equiv) was added in dry 1,4-dioxane (14 ml) under argon flow. The reaction mixture was stirred for 3 hours at 90°C. To the resulting mixture was added water (45 ml), the product was extracted with ethyl acetate (3×15 ml). The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/hexane (10/90) eluent. The yield of compound 7 was 110 mg (45%), yellow powder.

Step 2. Preparation of compound EGFR_3365_53.

To a mixture containing compound 11 (100 mg, 0.29 mmol), block 5 (79 mg, 0.27 mmol, 0.9 equiv), rac-BINAP (37 mg, 0.059 mmol, 0.2 equiv), Cs ₂ CO ₃ (293 mg, 0.89 mmol, 3 equiv) Pd(OAc) ₂ (7 mg, 0.03 mmol, 0.1 equiv) was added in dry 1,4-dioxane (7 ml) under argon flow. The reaction mixture was stirred for 4 hours at 90°C. Water (30 ml) was added to the resulting mixture, the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was isolated by silica gel column chromatography using ethyl acetate/triethylamine (98/2) eluent. The yield of EGFR_3365_53 was 40 mg (24%), yellow powder.

Example 10. Analysis of the obtained compounds.

The purity and structure of the obtained compounds were confirmed by LC/MS chromatography-mass spectrometry and 1H NMR spectroscopy (Table 6).

Equipment data:

Example 11. Determination of chemical stability in artificial biological environments.

1) Determination of chemical stability in artificial intestinal juice, artificial gastric juice and human blood plasma.

SGF without enzymes concentrate, pH=1.4 (Sigma Ireland, cat#01651) was used as artificial gastric juice. The candidate stock solution (10 mM in DMSO) was diluted with SGF working solution to a concentration of 10 μM (test solution). The test solution was kept in a solid state thermostat for 2 hours at a temperature of 37°C. SIF without enzymes concentrate, pH=6.5 (Sigma Ireland, cat#55331) was used as artificial intestinal juice. The candidate stock solution (10 mM in DMSO) was diluted with SIF working solution to a concentration of 10 μM (test solution). The test solution was kept in a solid state thermostat for 2 hours at a temperature of 37°C. The HPLC method using an Agilent1200 chromatograph (Agilent, USA) was used to determine the peak areas of the compounds in the tested samples corresponding to the initial test time (before holding) and the final test time (after holding in a solid state thermostat for 2 hours at a temperature of 37°C). Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. The amount of substance in the sample was determined in % after thermostating.

The stability of the compounds was evaluated. The compounds described in the present invention had chemical stability values in artificial biological media greater than 80% (see Table 9), i.e. are chemically stable in the acidic environment of artificial gastric juice and the slightly acidic environment of artificial intestinal juice.

2) Determination of chemical stability in human plasma.

The determination of stability in human plasma was performed using pooled human plasma taken from ten healthy donors. The candidate stock solution (10 mM in DMSO) was diluted with pooled blood plasma to a concentration of 10 μM (test solution). The test solution was kept in a solid-state thermostat for 4 hours at a temperature of 37°C. The HPLC method using an Agilent1200 chromatograph (Agilent, USA) was used to determine the peak areas of the compounds in the test samples corresponding to the initial test time (before exposure) and the final test time (after exposure in a solid-state thermostat for 4 hours at a temperature of 37°C) with preliminary precipitation of proteins with acetonitrile . Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. The amount of substance in the sample was determined in % after thermostating.

The stability of the compounds was evaluated. The compounds described in the present invention had chemical stability values in human plasma greater than 60% (see Table 10).

Thus, from example 11 it can be seen that the claimed compounds of formula I are quite stable in the acidic environment of artificial gastric juice, in the slightly acidic environment of artificial intestinal juice and in human blood plasma.

Example 12 Determination of enzymatic stability.

Determination of the enzymatic stability of candidates made it possible to evaluate the resistance of the compounds to the action of liver enzymes.

The rate of enzymatic degradation of the compound was determined by keeping the reaction mixture containing 0.5 mg/ml pooled S9 human liver fractions (XenoTech, USA, cat# H0610), 10 μm of the compound, 2 mM β-nicotinamide adenine dinucleotide ( Carbosynth, UK, cat#NN10871) and 4 mM magnesium chloride in 0.1 M sodium phosphate buffer pH=7.4. The reaction was stopped with acetonitrile at the rate of 100 μl of acetonitrile per 100 μl of the reaction mixture. After stopping the reaction, the samples were centrifuged for 10 minutes at 10,000 rpm. The supernatant was analyzed by chromatography using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. We plotted the dependence of the logarithm of the peak area of the substance on time. The dependent coefficient of this straight line corresponded to the elimination constant k, on the basis of which the half-life of the drug T1 / 2 and the decomposition rate CLint were calculated:

Elimination rate constant (k)=(-gradient)

Based on the data obtained, a conclusion was made about the enzymatic stability of candidates in the S9 human liver fractions (see Table 11).

Thus, from example 12 it can be seen that the claimed compounds of formula I showed sufficient resistance to the action of liver enzymes and had a Clint enzymatic degradation rate of less than 24 μl/min/mg.

Example 13 - Determination of the permeability of compounds.

1) Determination of passive permeability through an artificial membrane.

Passive permeability was determined using an artificial membrane, where the role of the lipid bilayer is performed by a membrane of L-α-phosphatidylcholine.

5 µl of a solution of soybean L-α-phosphatidylcholine (Sigma, Ireland, cat#8002-43-5) at a concentration of 20 mg/ml in DMSO was applied to the membrane of the acceptor filter plate, 150 µl of 0.01 M sodium were added to the wells of the acceptor filter plate -phosphate buffer pH=7.4. 300 μl of the test compound solution (10 mM in DMSO) was added to the wells of the donor plate. The assembled system was kept for 20 hours at room temperature. Samples from donor and acceptor plates were analyzed by chromatography using an Agilent1200 chromatograph (Agilent, USA). Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. The peak areas of the analytes in the donor and acceptor were determined on the chromatograms, and the concentrations of the compound were calculated. Passive permeability through the artificial membrane Pe was calculated by the formula:

P _e - effective permeability constant, m/s

V _D - volume of donor solution (0.3 ml), ml

V _A - volume of acceptor solution (0.15 ml), ml

Area - membrane surface area (0.24 cm ² ), cm ²

t ₁ - holding time (72000 sec), sec

t ₀ - the time required to fill the membrane (1140 sec), sec

C _d(0) - concentration of the acceptor solution at the initial time, μM

C _d(0) - concentration of the donor solution at the initial time, μM

C _d(t) - concentration of the acceptor solution after 20 hours, μM

C _d(t) - concentration of the donor solution after 20 hours, μM

The compounds showed a high rate of passive transport (see Table 12), i.e. compounds are able to enter the cell through the membrane.

2) Determination of permeability through a monolayer of Caco-2 cells.

Determination of the permeability through the monolayer of Caco-2 cells made it possible to evaluate the ability of substances to penetrate biological membranes through both active and passive transport.

Caco-2 intestinal epithelial cells were cultured in inserts with filters (0.4 µm pores, BD Falcon with High Density) for 21 days, after which the integrity of the monolayer was checked using Lucifer Yellow dye (Sigma-Aldrich, USA) according to a standard protocol. . When setting up the transfer A->B (transfer "intestinal lumen" - "blood flow"), solutions of the studied substances were added in buffer pH 6.5 (HBSS, 10 mM HEPES, 15 mM p-p Glucose) at a concentration of 10 μM into the upper chamber; the lower chamber was filled with pH 7.4 buffer (HBSS, 10 mM HEPES, 15 mM p-p Glucose, 1% BSA). When setting up the B->A transfer (transfer "blood flow" - "intestinal lumen"), the upper chamber was filled with buffer pH 6.5, and solutions of the studied substances were added in buffer pH 7.4 at a concentration of 10 μM to the lower chamber. Propranolol was used as a control as a high permeability substance.

After incubation for 2 h at 37°C in an atmosphere with 5% CO2, the amounts of the studied substances in the upper and lower chambers _were determined by HPLC using an Agilent 1200 chromatograph (Agilent, USA) with preliminary precipitation of proteins with acetonitrile. Chromatographic analysis was carried out in a gradient elution mode at a flow rate of 1 ml/min. The peak areas corresponding to the compounds were determined on the chromatograms. Based on the peak area values of the compounds in the calibration standards, the concentration of the compound in the stock solution and in the samples from the wells of the upper and lower chambers was determined.

The permeability through the layer of Papp cells was calculated by the formula:

Papp=(C _(t) *V)/(C ₍₀₎ *t*Area), where

Papp - effective permeability constant, m/s

V is the volume of the solution (in the A->B test - 0.8 ml, in the B->A test - 0.2 ml), ml

Area - membrane surface area (0.33 cm ² ), cm ²

t - holding time (7200 sec), sec

C ₍₀₎ - concentration of the initial solution, µM

C _(t) - concentration of the solution after 2 hours (in the test A->B - the concentration in the sample from the well of the lower chamber; in the test B->A - the concentration in the sample from the well of the upper chamber), μM

The efflux coefficient showed the ability of cells to eliminate a substance from the bloodstream. The value was calculated by the formula:

P _{app AB} - direct analysis permeability value A->B;

P _{app BA} - the value of the reverse analysis permeability B->A.

The compounds showed a high rate of direct transport "intestinal lumen" - "blood flow", while the efflux coefficient did not exceed 2 (see Table 13), which indicates that the Pgp transporter does not impose restrictions on the bioavailability of the tested compounds.

Thus, from example 13 it is seen that the claimed compounds of formula I have a sufficiently high rate of passive and active transport, from which it follows that the compounds of the present invention potentially have good bioavailability.

Example 14 EGFR inhibitory activity in vitro.

The IC ₅₀ values of the compounds described in the present invention were determined using a biochemical test for inhibition of kinase activity in a non-cellular system and using a functional cellular antiproliferative test.

Inhibition of the activity of WT EGFR (Wild-TypeEGFR), DM EGFR (DoubleMutantEGFR, L828R/T790M) kinases was determined using the SignalChem kinase system and the ADP-Glo™ Kinase Assay detection kit (V9102, Promega).

Measurements were performed in a 96-well format in a reaction volume of 25 μl. The enzyme and inhibitor were preincubated for 10 minutes in a reaction buffer containing 25 mM MOPS, pH 7.2, 12.5 mM B-glycerol phosphate, 27 mM MgCl2, 2 mM MnCl2 5 mM EGTA, 2 mM EDTA, 0.3 mM DTT, 1.2 mg/ml bovine serum albumin. Staurosporine (S4400, Sigma) was used as a control inhibitor, and 0.1% DMSO solution in reaction buffer was used as a negative control. A solution of the peptide substrate 0.5 mg/ml and 50 μM ATP in the same buffer was added, incubated for 180 minutes at 37°C, the amount of ATP consumed in the kinase reaction was detected using the ADP-Glo™ detection system (V9102, Promega). The luminescence signal was measured on an Infinite M200Pro plate spectrophotometer (Tecan, Switzerland). The IC ₅₀ value was determined using the Magellan 7.2 program (Tecan, Switzerland), approximating the experimental points using a four-parameter model with Levenberg-Markart optimization (Table 14).

The antiproliferative activity of EGFR inhibitors (Tables 15 and 16) was measured in a cell assay on continuous cultures of epithelial cells A549 (lung adenocarcinoma, ATCC® CRM-CCL-185™ - WT), HCC827 (lung adenocarcinoma, ATCC® CRL-2868™ - SM ( SingleMutantEGFR, exon19delE746-A750)) and H1975 (lung adenocarcinoma, ATCC® CRL-5908™ - DM (DoubleMutantEGFR, L828R/T790M)) using Alamar Blue (ThermoFisher, #DAL1100) lifetime dye. Cells were subcultured in RPMI-1640 medium (PanEco, C330p) supplemented with 10% FBS (Gibco, #16140071) for at least 1 passage after thawing, washed, and re-plated in 96-well culture plates (3599, Corning) in RPMI- 1640 supplemented with 2% FBS at 5*10 ³ cells/well for A549, 10*10 ³ cells/well for HCC827 and 15*10 ³ cells/well for H1975 in 100 µl. Incubated for 16-18 hours in a CO ₂ incubator (Thermo Forma, USA) at 37°C with an atmosphere of 5% CO ₂ for cell attachment.

The test compounds were dissolved in DMSO in the selected concentration ranges and transferred to RPMI-1640 medium (PanEco, S330p) supplemented with 2% FBS. After adding 50 µl of the prepared dilutions to the cells, the incubation mixture contained the final concentrations of the test substances and no more than 1% DMSO. The contents of the plates were incubated at 37°C for 72 h, after which 15 µl of Alamar Blue vital dye (ThermoFisher, #DAL1100) were added to the wells, mixed on an orbital shaker (Biosan, Latvia) and incubated for 3-5 hours at 37°C. C in CO ₂ incubator (Thermo Forma, USA). The number of living cells was detected on an Infinite M200Pro plate spectrophotometer (Tecan, Switzerland), measuring the fluorescent signal at an excitation wavelength (λEx) of 540 nm and a detection wavelength (ΔEm) of 590 nm.

The IC50 value was determined using the Magellan 7.2 program ( _Tecan , Switzerland), approximating the experimental points using a four-parameter model with Levenberg-Markart optimization.

Total cytotoxicity (CC ₅₀ ) was determined in a HepG2 cell assay (hepatocellular carcinoma, ATCC® HB-8065™) (Table 16). Cells were subcultured in DMEM medium (PanEco, C420p) supplemented with 10% FBS (Gibco, #16140071) for at least 1 passage after thawing, washed and re-plated in 96-well culture plates (3599, Corning) at a concentration of 2*10 ⁴ cells / 100 µl per well. Incubated 16-18 hours. The test substances were titrated in DMSO and transferred to DMEM medium (PanEco, С420p) with 2% FBS, added to the cells and incubated at 37°C for 72 hours, after which cell viability was detected using Alamar Blue vital dye (ThermoFisher, # DAL1100). The CC ₅₀ value was determined similarly to the IC ₅₀ .

Therapeutic Index (TI) was defined as the ratio of CC ₅₀ on the HepG2 line to IC ₅₀ on the HI975 cell line:

Selectivity Index (SI) was defined as the ratio of IC ₅₀ for lines containing wild-type EGFR (A549) to IC ₅₀ for lines with the target mutation L828R/T790M (HI975):

The compounds of the present invention showed effective inhibition of kinase activity with a target EGFR mutation (L828R/T790M) and also showed low activity against wild-type EGFR. The compounds of the present invention showed high selectivity for mutated EGFR.

In cell tests, the compounds of the present invention showed high antiproliferative activity against target cell lines (EGFR with mutation L828R/T790M and deletion in exon 19).

According to the results of the test for total cytotoxicity, the compounds of the present invention showed low toxicity.

* After the ">" and "<" signs, IC ₅₀ values are given that are above the limit of the range of concentrations studied.

** After the "<" and ">" signs are indicative values calculated on the basis of an IC ₅₀ value that is outside the range of the studied concentrations.

* After the ">" sign, IC ₅₀ values are given that are above the limit of the range of concentrations studied.

** After the “>” sign, guide values are given, calculated on the basis of an IC ₅₀ value that is outside the range of concentrations studied.

* After the ">" sign, IC ₅₀ values are given that are above the limit of the range of concentrations studied.

** After the “>” sign, guide values are given, calculated on the basis of an IC ₅₀ value that is outside the range of concentrations studied.

Claims (139)

1. Compound of formula I:

or a pharmaceutically acceptable salt thereof, where L represents -C(O)-; X ₁ represents CH or N; A represents

where X ₂ , X ₃ , X ₄ , X ₅ , X ₆ are each independently C, CH or N, R ₁ is each independently hydrogen; Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from hydroxy, C ₁ -C ₆ alkyloxy, C ₆ -C ₁₀ aryl; phenoxy; C ₃ -C ₆ cycloalkyloxy; -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from C ₁ -C ₆ alkyl; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, -NR ₂ R ₃ ; R ₂ or R ₃ - each independently represents hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals selected from the hydroxy group, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3; Hal represents a fluorine, bromine or chlorine atom. 2. The compound according to claim 1, where the fragment

selected from the group consisting of:

where R ₁ each independently represents Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from hydroxy, C ₁ -C ₆ alkyloxy, C ₆ -C ₁₀ aryl; phenoxy; C ₃ -C ₆ cycloalkyloxy; -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from C ₁ -C ₆ alkyl; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, -NR ₂ R ₃ ; R ₂ or R ₃ - each independently represents hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals selected from the hydroxy group, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3; Hal represents a fluorine, bromine or chlorine atom. 3. The compound according to claim 1, where the fragment

selected from the group consisting of:

where R ₁ each independently represents Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from Hal, C ₁ -C ₆ alkyloxy, C ₆ -C ₁₀ aryl; phenoxy; C ₃ -C ₆ cycloalkyloxy; -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from C ₁ -C ₆ alkyl; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, -NR ₂ R ₃ ; R ₂ or R ₃ - each independently represents hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals selected from the hydroxy group, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3; Hal represents a fluorine, bromine or chlorine atom. 4. The compound according to claim 1, where the fragment

selected from the group consisting of:

where R ₁ each independently represents Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from hydroxy, C ₁ -C ₆ alkyloxy, C ₆ -C ₁₀ aryl; phenoxy; C ₃ -C ₆ cycloalkyloxy; -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from C ₁ -C ₆ alkyl; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, -NR ₂ R ₃ ; R ₂ or R ₃ - each independently represents hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals selected from the hydroxy group, C ₁ -C ₆ alkyloxy; k is 0, 1, 2 or 3; Hal represents a fluorine, bromine or chlorine atom. 5. The compound according to claim 1, where the fragment

selected from the group consisting of:

where R ₁ each independently represents Hal; cyano; nitro; a hydroxy group; C ₁ -C ₆ alkyl, unsubstituted or substituted with one or more radicals selected from Hal, hydroxy; C ₁ -C ₆ alkyloxy unsubstituted or substituted with one or more radicals selected from hydroxy, C ₁ -C ₆ alkyloxy, C ₆ -C ₁₀ aryl; phenoxy; C ₃ -C ₆ cycloalkyloxy; -NR ₂ R ₃ ; 5-6 membered heteroaryl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from C ₁ -C ₆ alkyl; 4-7 membered heterocyclyl with 1-2 heteroatoms selected from N and/or O, unsubstituted or substituted with one or more substituents selected from cyano, hydroxy, oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, -NR ₂ R ₃ ; R ₂ or R ₃ - each independently represents hydrogen, C ₁ -C ₆ alkyl, unsubstituted or substituted by one or more radicals selected from the hydroxy group, C ₁ -C ₆ alkyloxy; Hal represents a fluorine, bromine or chlorine atom. 6. Connections according to paragraphs. 1-5, which are: N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-(trifluoromethyl)benzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide ( EGFR_3365); N-(5-((4-benzoylpyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_3); N-(5-((4-(dimethylamino)benzoyl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide 2,2,2 -trifluoroacetate (EGFR_3365_4); N-(5-((4-(dimethylamino)benzoyl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_4a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-morpholinobenzoyl)pyridin-2-yl)amino)phenyl)acrylamide 2,2, 2-trifluoroacetate (EGFR_3365_5); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-morpholinobenzoyl)pyridin-2-yl)amino)phenyl)acrylamide (EGFR_3365_5a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-fluorobenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_10); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3-fluorobenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_11); N-(5-((4-(2-bromobenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide ( EGFR_3365_12); N-(5-((4-(4-bromobenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide ( EGFR_3365_13); N-(5-((4-(4-cyanobenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide 2 ,2,2-trifluoroacetate (EGFR_3365_14); N-(5-((4-(4-cyanobenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)prop-2-enamide (EGFR_3365_14a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)amino)-4-methoxy-5-((4-(pyridine-3-carbonyl)pyrimidin-2-yl)amino)phenyl)prop -2-enamide (EGFR_3365_15); N-(5-((4-(4-(benzyloxy)benzoyl)pyrimidin-2-yl)amino)-2-((2-dimethylamino)ethyl)methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_16) ; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-phenoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_17); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(5-methylpyridine)-3-carbonyl)pyrimidin-2-yl)amino)phenyl) prop-2-enamide (EGFR_3365_26); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_28); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-ethoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_29); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-propoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_30); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(hydroxy(4-propoxyphenyl)methyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ( EGFR_3365_30a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-isopropoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_31); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_32); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_33); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(3-nitrobenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_34); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-nitrobenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_36); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-propoxybenzoyl)pyridin-2-yl)amino)phenyl)acrylamide (EGFR_3365_50); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxybenzoyl)pyridin-2-yl)amino)phenyl)acrylamide (EGFR_3365_51); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-ethoxybenzoyl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_52); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxyazetidin-1-yl)benzoyl)pyridin-2-yl) amino)phenyl)acrylamide (EGFR_3365_53); N-(5-((4-(4-diethylamino)benzoyl)pyridin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_54) ; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(4-methylpiperazin-1-yl)benzoyl)pyridin-2-yl) amino)phenyl)acrylamide (EGFR_3365_55); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(pyrrolidin-1-yl)benzoyl)pyridin-2-yl)amino) phenyl)acrylamide (EGFR_3365_56); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methylbenzoyl)pyridin-2-yl)amino)phenyl)acrylamide (EGFR_3365_57); N-(5-((4-(4-(azetidin-1-yl)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl )acrylamide (EGFR_3365_58); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxyazetidin-1-yl)benzoyl)pyrimidin-2-yl) amino)phenyl)acrylamide (EGFR_3365_61); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(4-methylpiperazin-1-yl)benzoyl)pyrimidin-2-yl) amino)phenyl)acrylamide (EGFR_3365_62); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(4-methylpiperazin-1-yl)benzoyl)pyrimidin-2-yl) amino)phenyl)acrylamide (EGFR_3365_62a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(pyrrolidin-1-yl)benzoyl)pyrimidin-2-yl)amino) phenyl)acrylamide (EGFR_3365_63); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methylbenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_64); N-(5-((4-(4-butoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_66); N-(5-((4-(4-(cyclohexyloxy)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_67 ); N-(5-((4-(2,4-diethoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_68) ; N-(5-((4-(2,4-dimethoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_69) ; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2,4-dipropoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_70) ; N-(5-((4-(2,4-diisopropoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_71) ; N-(5-((4-(4-(diethylamino)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_72 ); N-(5-((4-(4-(dimethylamino)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_73 ); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-isobutoxybenzoyl)pyridin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_77); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-isobutoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_78); N-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(1-methyl-1H-pyrazol-4-yl)benzoyl)pyridine-2 -yl)amino)phenyl)acrylamide (EGFR_3365_85); N-(5-((4-(4-(1H-imidazol-1-yl)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -methoxyphenyl)acrylamide (EGFR_3365_86); N-(5-((4-(2,4-dimethoxybenzoyl)pyridin-2-yl)amino)-2-((2-dimethylamino)ethyl)(methyl)amino-4-methoxyphenyl)acrylamide (EGFR_3365_87); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxybenzoyl)pyridin-2-yl)amino)phenyl)acrylamide (EGFR_3365_88); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(piperidin-1-yl)benzoyl)pyrimidin-2-yl)amino) phenyl)acrylamide (EGFR_3365_90); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(2-oxopyrrolidin-1-yl)benzoyl)pyrimidin-2-yl) amino)phenyl)acrylamide (EGFR_3365_91); N-[2-{[2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-({4-[4-(2-methoxyethoxy)benzoyl]pyridin-2-yl}amino)phenyl] prop-2-enamide (EGFR_3365_92); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(2-methoxyethoxy)benzoyl)pyridin-2-yl)amino)phenyl) acrylamide (EGFR_3365_93); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indole-2-carbonyl)pyrimidin-2-yl)amino )phenyl)acrylamide (EGFR_3365_94); N-(5-((4-(4-(4-cyanopiperidin-1-yl)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -methoxyphenyl)acrylamide (EGFR_3365_97); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(4-methoxypiperidin-1-yl)benzoyl)pyrimidin-2-yl) amino)phenyl)acrylamide (EGFR_3365_98); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxy-4-propoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_101); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-methoxy-2-propoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_102); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-isopropoxy-2-methoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ( EGFR_3365_103); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(2-isopropoxy-4-methoxybenzoyl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ( EGFR_3365_104); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-((2-methoxyethyl)amino)benzoyl)pyrimidin-2-yl)amino )phenyl)acrylamide (EGFR_3365_105); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-((2-hydroxyethyl)amino)benzoyl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide formate (EGFR_3365_106); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-((2-hydroxyethyl)amino)benzoyl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide (EGFR_3365_106a); (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(3-hydroxypiperidin-1-yl)benzoyl)pyrimidin-2-yl) amino)-4-methoxyphenyl)acrylamide (EGFR_3365_108); (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(3-hydroxypiperidin-1-yl)benzoyl)pyrimidin-2-yl) amino)-4-methoxyphenyl)acrylamide (EGFR_3365_109); (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxypiperidin-1-yl)benzoyl)pyrimidin- 2-yl)amino)phenyl)acrylamide (EGFR_3365_110); (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxypiperidin-1-yl)benzoyl)pyrimidin- 2-yl)amino)phenyl)acrylamide (EGFR_3365_111); (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(3-hydroxypyrrolidin-1-yl)benzoyl)pyrimidin-2-yl) amino)-4-methoxyphenyl)acrylamide formate (EGFR_3365_112); (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(3-hydroxypyrrolidin-1-yl)benzoyl)pyrimidin-2-yl) amino)-4-methoxyphenyl)acrylamide (EGFR_3365_112a); (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(3-hydroxypyrrolidin-1-yl)benzoyl)pyrimidin-2-yl) amino)-4-methoxyphenyl)acrylamide (EGFR_3365_113); (S)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxypyrrolidin-1-yl)benzoyl)pyrimidin- 2-yl)amino)phenyl)acrylamide (EGFR_3365_114); (R)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(4-(3-methoxypyrrolidin-1-yl)benzoyl)pyrimidin- 2-yl)amino)phenyl)acrylamide (EGFR_3365_115); N-(5-((4-(4-cyclopropoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide (EGFR_3365_116); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxy-4-(4-methylpiperazin-1-yl)benzoyl)pyrimidin- 2-yl)amino)phenyl)acrylamide (EGFR_3365_120); N-(5-((4-(4-(4-aminopiperidin-1-yl)benzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4 -methoxyphenyl)acrylamide (EGFR_3365_121); N-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-dimethylaminopiperidin-1-yl)benzoyl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide (EGFR_3365_121a); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxy-4-(piperidin-1-yl)benzoyl)pyrimidin-2- yl)amino)phenyl)acrylamide (EGFR_3365_122); N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(2-methoxy-4-(pyrrolidin-1-yl)benzoyl)pyrimidin-2- yl)amino)phenyl)acrylamide (EGFR_3365_123); N-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-(5-((4-(2,4,6-trimethoxybenzoyl)pyrimidin-2-yl)amino)phenyl)acrylamide (EGFR_3365_124); N-(5-((4-(4-(4-aminopiperidin-1-yl)-2-methoxybenzoyl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino )-4-methoxyphenyl)acrylamide (EGFR_3365_126); N-2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(4-(4-dimethylaminopiperidin-1-yl)-2-methoxybenzoyl)pyrimidin-2-yl)amino) -4-methoxyphenyl)acrylamide (EGFR_3365_127). 7. A method of inhibiting the biological activity of the epidermal growth factor receptor (EGFR) in a subject, which consists in contacting EGFR with a compound according to any one of paragraphs. 1-6. 8. Pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-6 and one or more pharmaceutically acceptable excipients and intended for the prevention or treatment of a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation and/or a deletion in exon 19 and/or a C797S mutation. 9. A method of treating a disease or disorder mediated by EGFR activity, comprising administering a therapeutically effective amount of a compound according to any one of paragraphs. 1-6 or a pharmaceutical composition according to claim 8 to a subject in need of such treatment, where said disease or disorder is a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation and/or a deletion in exon 19 and/or a mutation C797S. 10. The method of claim 9 wherein the disease or disorder mediated by EGFR activity is a cancer. 11. The method of claim 10 wherein the disease or disorder is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer , leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma , acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors. 12. The method of claim 11 wherein the cancer is non-small cell lung cancer. 13. The use of a compound according to any one of paragraphs. 1-6 or the pharmaceutical composition of claim 8 for treating a disease or disorder mediated by EGFR activity in a subject in need of such treatment, wherein said disease or disorder is a disease or disorder mediated by EGFR activity with an L858R mutation and/or a T790M mutation, and /or a deletion in exon 19 and/or a C797S mutation. 14. The use of claim 13 wherein the disease or disorder mediated by EGFR activity is a cancer. 15. The use of claim 14 wherein the disease or disorder is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer , leukemia, lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, liver cancer, anaplastic large cell lymphoma , acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors. 16. Use according to claim 15, wherein the cancer is non-small cell lung cancer.