WO2017086830A1 - Substituted n-{3-[4-(1-methyl-1h-indol-3-yl)pyrimidin-2-ylamino]-4-methoxy-phenyl}-amides as egfr modulators intended for treating cancer - Google Patents

Abstract

The aim of the invention is to create novel EGFR modulators for treating cancer. This is achieved with novel substituted N-{3-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino]-4-methoxy-phenyl}-amides of general formula 1, and polymorphic forms, salts, solvates and hydrates thereof, where R¹ is a radical selected from CH₂=C(R³)-, R³CH=CH- and R⁴СС-; R² is (2-dimethylaminoethyl)-methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-dimethylaminopiperidin-1-yl and 3-dimethylaminoazepan-1-yl, 4-methylpiperazin-1-yl; R³ is methyl, trifluoromethyl, fluorine, chlorine, methoxycarbonyl and dimethylcarbamoyl; R⁴ is hydrogen or methyl; or R¹ is vinyl and R² is 3-dimethylaminopyrrolidin-1-yl; R⁴ is C₁-C₄alkyl, C₃-C₆cycloalkyl.

Description

 Substituted 1CH- {3- [4- (1-methyl-Ш-indol-3-yl) pyrimidin-2-ylamino] -4-methoxyphenyl} amides as EGFR modulators for treating cancer

Technical field

 The present invention relates to substituted - {3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxy-phenyl} amides, their pharmaceutically acceptable salts, solvates and hydrates thereof, which may be useful in the treatment or prophylaxis of a disease or medical condition caused by certain mutant forms of epidermal growth factor receptor (EGFR), for example, mutants L858R, Exop19 and T790M. Such compounds and their salts may be useful in the treatment or prevention of a number of different types of cancer. The invention also relates to pharmaceutical compositions containing these compounds and their salts, solvates and hydrates, polymorphic forms of these compounds and their salts, to methods for their preparation and to methods of treating diseases caused by various forms of EGFR using these compounds and their salts.

State of the art

A number of second-generation irreversible inhibitors are known containing the aminoquinazoline fragment of Gefitinib. These inhibitors contain an acrylamide substituent that covalently binds to Cys-797, which is located in the kinase solvent channel. Afatinib, Canertinib and Docomitinib, WZ-4002, belong to this type of inhibitor. The covalent binding mechanism is believed to help overcome ATP affinity of the double mutant, as a result of which these compounds exhibit high activity in cell models. However, the Cys-797 mutant is present in all relevant forms of EGFR. These second-generation compounds possess not only increased activity towards resistant mutants, but also towards wild-type EGFR. Inhibition of wild-type EGFR does not contribute to their clinical efficacy, but is believed to reduce side effects (skin rash and diarrhea). Since these side effects tend to limit the dose in patients, the activity of these inhibitors against wild-type EGFR will limit their activity in patients against T790M mutation.

Dacomitinib

Dacomitinib

AstraZeneca recently patented 2- (2,4,5-substituted anilino) pyrimidines as EGFR modulators useful for treating cancer, including the AZD-9291 modulator [Butterworrth, S .; Raymond, M .; Finlay W. et al. 2- (2,4,5-Substituted anilino) pyrimidines as EGFR modulators useful for treating cancer. WO2013014448]. The AZD-9291 modulator is the most advanced in clinical studies and is currently undergoing several Phase III clinical trials [AstraZeneca, NCT02151981; AstraZeneca, NCT02296125].

 There remains a need for compounds that can exhibit a favorable profile of activity against wild EGFR compared with activity against mutant forms of EGFR (e.g., mutant L858R EGFR) and / or a stable mutant form of EGFR (e.g. T790M EGFR mutant). In this regard, there is a need for compounds that show higher inhibition of certain activating or mutant forms of EGFR, while at the same time showing relatively low inhibition of wild EGFR. Such compounds are expected to be more suitable as therapeutic agents, especially for the treatment of cancer, by reducing the toxicology associated with inhibition of wild EGFR. Toxicologies are known to manifest in humans, such as skin rash and / or diarrhea.

Disclosure of invention

 Applicants have unexpectedly discovered that newly substituted T - {3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxyphenyl} amides have higher efficacy against several mutant forms of EGFR compared with activity against wild-type EGFR, as well as higher solubility in aqueous solutions.

 The novel compounds may be particularly useful in the treatment of disease states in which EGFRs are involved and / or activation of EGFR mutations and / or inhibition of EGFR mutations, for example, in the treatment of cancer.

The following are definitions of terms that are used in the description of this invention. "Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" (C ₁ -C ₆ ) alkyl substituents. Preferred alkyl groups are (C ₁ -C ₆ ) alkyl, even more preferred (C ₁ -C ₃ ) alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-but, tert-boogype, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, cyclohexyl. Alkyl may have substituents.

“Substituted alkyl” - substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, heteroaryl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl alkylthio, heteroarylthio, aralkylthio, arylsulfonyl, alkylsulfonyl, heteroaralkyloxy or R _k ^a R _{k +} i ^a N-, where R _k ^a and R _{k +} j ^{a are} independently “amino substituents”, the meanings of which are defined in this section, for example water atom yes, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, or R _k ^a and R _{k +} i ^a together with the N atom to which they are bonded, form through R _k ^a and R _{k +} i ^a 4 - 7 membered heterocyclyl or heterocyclenyl . The preferred "alkyl substituents" are aryl, heteroaryl, heterocyclyl, hydroxy, C] -C ₅ alkoxy, C ₁ -S5 alkoxycarbonyl, aralkoxy, aryloxy, alkylthio, heteroarylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, geteroaralkiloksikarbonil or R _k ^a R _{k +} i N-, Rk ^a R _k + i ^a NC (= 0) -, annelated arylheterocyclenyl, annelated aryl heterocyclyl.

“Alkoxy” means a (CgC ₃ ) alkyl 0 group in which alkyl is defined in this section. Preferred alkyloxy groups are methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.

“Amino group” means an RiR ₂ N group, substituted or unsubstituted, optionally with the same substituents Ri and R ₂ . An amino group may have substituents.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial and other) origin, possessing pharmacological activity and being the active principle of the pharmaceutical composition used for the production and manufacture of a medicinal product (agent).

 “Halogen” means fluoro, chloro, bromo and iodo. Fluorine, chlorine and bromine are preferred.

 “Substituent” means a chemical radical that is attached to a molecular skeleton (scaffold, fragment), for example, “substituent alkyl”, “substituent of amino group”, “substituent of carbamoyl”, “substituent of cyclic system”, the meanings of which are defined in this section.

 “Medicinal product (preparation)” - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

"Pharmaceutical composition" means a composition comprising an active component and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving means, delivery vehicles such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial Gent, fungicides, lubricants, and prolonged delivery controllers, the choice and suitable proportions of which depend on the nature and way 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 achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be provided with the help of agents, slowing 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 also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of grinders and distributors are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal such as ointments and creams, subcutaneous , intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable 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 the compounds or prepared specially. In particular, base salts can be prepared on the basis of 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 (Detailed description of the properties of such salts is given in Berge SM, et al., "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts claimed acids can also be specially prepared by reaction of the purified acid with a suitable base, and 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 sodium and potassium salts. Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should 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, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

An object of the present invention is to provide novel EGFR modulators for the treatment of cancer.

 This goal is achieved by new substituted T - {3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxyphenyl} amides of the general formula 1, their polymorphic forms, salts solvates and hydrates.

где:

Where:

R ¹ represents a radical selected from CH ₂ = C (R ³ ) -, R ³ CH = CH— and R ⁴ C ^ C—;

R is (2-dimethylaminoethyl) methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-dimethylaminopiperidin-1-yl and 3-dimethylaminoazepan-1-yl, 4-methylpiperazin-1-yl;

R ³ represents methyl, trifluoromethyl, fluoro, chloro, methoxycarbonyl and dimethylcarbamoyl;

R ⁴ represents hydrogen or methyl;

 12

 or R is vinyl, and R is 3-dimethylaminopyrrolidin-1-yl;

R ⁴ represents C] -C ₄ alkyl, C ₃ -C ₆ cycloalkyl.

More preferred are EGFR inhibitors of the general formula 1 selected from:

 - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1 H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2- methyl acrylamide (1.1);

 - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1 H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2- fluoro acrylamide (1.2);

 K- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2- chloro-acrylamide (1.3);

 N- {2 - [(2-Dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1 H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} - 2-trifluoromethyl-acrylamide (1.4);

 K- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-yl amino] -4-methoxyphenyl} - 2-butenes d (1.5);

 - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -4,4 4-trifluorobut-2-enamide (1.6);

 (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy -phenylcarbamoyl} -acrylic acid methyl ester (1.7);

(£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy -phenylcarbamoyl} -H ^ -dimethylacrylamide (1.8); (£) - ^ -dimethyl-3- {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) - pyrimidin-2-ylamino] -4-methoxy-phenylcarbamoyl} -acrylamide (1.9);

(£) -Ν, Ν-ΛΗΜετιιπ-3 - {5- [4- (1-methyl- 1 H-indol-3-yl) -pyrimidin-2-ylamino] -2- (4-methyl-piperazin-1 -yl) -4-methoxy-phenylcarbamoyl} -acrylamide (1.10);

K- {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy-phenyl} - acrylamide (1.11);

 M- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -propinamide ( 1.12);

 - {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -propinamide (1.13 );

 - {2 - [(2-dimethylamino-ethyl) -methyl-amino] -5-5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2-butynamide (1.14)

or their pharmaceutically acceptable salts.

The present invention also includes pharmaceutically acceptable salts of compounds of general formula 1. Examples of pharmaceutically acceptable salts include, but are not limited to, salts of mineral or organic acids of compounds of formula 1, such as carboxylic acids, for example, dichloroacetic acid, as well as salts of hydrogen chloride, phosphoric acid or sulfonic acid. Pharmaceutically acceptable salts of the present invention include the usual non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic group by conventional chemical methods. Typically, such salts can be prepared by reacting the free acidic and basic forms of the compounds of general formula 1 with a stoichiometric amount of the corresponding base or acid in water or in an organic solvent or in a mixture of two solvents. Non-aqueous media are generally preferred, such as ether, ethyl acetate, ethanol, isopropanol, acetone or acetonitrile (ACN). Lists of suitable salts can be found in the pharmaceutical salts directory [R.N. Stahl, CGWermuth (Eds.). Handbook of Pharmaceutical Salts, Properties, Selection, and Use. VHCA, Verlag Helvetica Chimica Acta, Ziirich, Switzerland, and Wiley-VCH, Weinheim, Germany. 2002.].

 The compounds of general formula 1 and their pharmaceutically acceptable salts may exist in solvated and unsolvated forms. For example, in the form of a hydrate. The present invention encompasses all such solvated and unsolvated forms.

The undoubted advantage of the new kinase inhibitors of general formula 1 is, first of all, their high solubility in aqueous media, which in some cases is several orders of magnitude higher than the solubility of the known AZD-9291 (Table 1). For example, the solubility of the 1.12-2MeS0 ₃ H inhibitor in water at pH2 is more than 10 times higher than the solubility of AZD-9291, and at pH7 it is more than 10900 times.

 Table 1. The solubility of the compounds of formula 1 and the prototype AZD-9291.

Compounds of general formula 1 and their pharmaceutically acceptable salts under comparable conditions against the double mutant EGFR (L858R / T790M) have, as a rule, an inhibitory activity comparable to that of the known an inhibitor of AZD-9291. So, for example, (Table 2), new inhibitors of the general formula 1 have an inhibitory activity of 1C _{50 of} less than 10 pM (1C ₅₀ from 0.34 pM to 8.7 nM), and AZD-9291 has a corresponding 1C ₅₀ = 0.41- Z, 7 pM. At the same time, under these conditions, new inhibitors are inferior to AZD-9291 in activity against wild EGFR wt, which is their undoubted advantage, since in this case their selectivity is usually higher than the selectivity of AZD-9291 (Table 2).

Table 2. EGFR activity of compounds ll (l) MeS0 ₃ H, 1.4 MeS0 ₃ H and prototype

AZD-9291.

This invention relates to compounds of general formula 1 that inhibit one or more EGFR activating or passivating mutations, for example, the L858R mutant, Exop 19 deleted EGFR mutant, and the T790M resistant mutant. Preferably, such compounds can be used to treat cancer resistant to existing therapy. According to the present invention, the compounds of general formula 1 show higher inhibition or passivation of mutant forms of EGFR than wild EGFR.

 Such compounds are expected to be more suitable as therapeutic agents, especially for the treatment of cancer, by reducing the toxicology associated with inhibition of wild EGFR. Such toxicologies are known to manifest in humans as skin rashes and / or diarrhea.

Compounds of general formula 1 can be prepared by reaction of a compound of formula 2 in which R ² has the above meaning, or salts thereof with activated an organic acid derivative (e.g., acid chloride or the corresponding organic ester or anhydride) in a solvent such as CH ₂ Cl ₂ , tetrahydrofuran, Ν, Ν-dimethyl ormamide or Ν, Ν-dimethylacetamide.

 2

 A subject of the invention is also a pharmaceutical composition, which comprises a compound of general formula 1 or a pharmaceutically acceptable salt thereof, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.

 The compositions of the invention may be in a form suitable for oral administration (for example, in the form of tablets, tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder) or arenteralnogo administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular dosing or as a suppository for rectal dosing).

 The compositions of the invention can be prepared by conventional methods using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring agents and / or preservatives.

The compound of general formula 1 is usually administered to the patient in a single dose in the range of 5-5000 mg / m ² body area, that is, about 0.1-100 mg / kg, and this is usually provides a therapeutically effective dose. A unit dosage form, such as a tablet or capsule, usually contains, for example, 1-250 mg of the active ingredient. The daily dose will necessarily vary depending on the patient, the specific route of administration and the severity of the disease being treated. Accordingly, the doctor who treats a particular patient can determine the optimal dose.

 The compounds of general formula 1 and their pharmaceutically acceptable salts inhibiting the activity of the L858R EGFR mutant, T790M EGFR and Exop 19 EGFR are expected to be useful in the treatment of diseases or medical conditions caused in whole or in part by the activity of the EGFR mutant, for example cancer. Types of cancer that may be susceptible to treatment using a compound of general formula 1 or a pharmaceutically acceptable salt thereof include, but are not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanomas, prostate cancer, leukemia, non-Hodgkin lymphoma lymphoma, stomach cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumors (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell full-time cell lymphoma, acute myeloid leukemia (AML), multiple myelomas, melanomas and mesotheliomas.

 A method of treating the types of cancer indicated herein is to administer a compound of formula 1 to a mammal, more preferably a human.

 Similarly, the use of a compound of general formula 1 for the treatment of the types of cancer indicated herein involves administering a compound of general formula 1 to a mammal, more preferably a human.

 The subject of this invention is the use of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof as a medicine.

 The subject of the present invention is the use of a compound of general formula 1, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof for the treatment of a disease caused by a L858R mutant EGFR and / or a T790M mutant EGFR and / or an Exop mutant 19, for example, for treating cancer .

The subject of the present invention is the use of a compound of general formula 1 as defined above, or a pharmaceutically acceptable salt, hydrate or MES, for the manufacture of a medicament for the treatment of a disease caused by an L858R EGFR mutant and / or a T790M EGFR mutant and / or an Ex19 mutant, for example, for treating cancer

 The subject of this invention is the use of a compound of general formula 1 as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the treatment of cancer.

 The subject of the present invention is also a method for producing an anti-cancer effect in a warm-blooded animal, such as a person in need of such treatment, which comprises administering to it an effective amount of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

 In any of the aspects or options mentioned herein, said cancer may be selected from ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma. non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular cancer, gastrointestinal stromal tumors (GIST), thyroid cancer, bile duct cancer, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma , melanomas and mesotheliomas.

 The cancer treatment described above may be the only therapy or may include, in addition, a compound of the general formula 1 of the present invention for conventional surgery or radiation therapy or chemotherapy or immunotherapy. Chemotherapy can be used simultaneously, sequentially or separately with treatment with a compound of general formula 1 according to the invention and may include one or more antitumor agents, including antiproliferative / antitumor drugs and their combinations used in medical oncology, such as alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents and topoisomerase inhibitors; cytostatic agents such as antiestrogens, antiandrogens, LHRH antagonists or agonists, aromatase inhibitors and 5a-reductase inhibitors; growth factor function inhibitors and other drugs.

Thus, an object of the present invention is a pharmaceutical composition comprising a compound of general formula 1, as defined above, or a pharmaceutically acceptable salt, hydrate or solvate and an additional antitumor substance for the joint treatment of cancer in the form of tablets, capsules or injections. Here, where the term "co-treatment" is used in relation to combination therapy, it should be understood that this may refer to the simultaneous, separate or sequential administration of drugs.

 Thus, in one embodiment, the invention provides the use of a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof, and additionally an antitumor substance for the joint treatment of cancer.

 The subject of the present invention is a method for producing an anticancer effect in a warm-blooded animal, such as a person in need of such treatment, which comprises administering to said mammal a compound of general formula 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof and simultaneously, separately or sequentially administering an additional antitumor substance the specified mammal, where the amounts of the compounds of General formula 1 or its pharmaceutically acceptable salt and additional pr the antitumor substance together provide the production of an anti-cancer effect.

The invention is illustrated below with specific examples. The following examples are provided for purposes of illustration and are not intended to limit the invention in any way. Specialists in the art will easily understand the difference in non-critical parameters that can be changed or modified to obtain the same results.

Example 1. - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) - pyrimidin-2-ylamino] -4-methoxyphenyl} - 2-methyl-acrylamide (1.1) is obtained according to scheme 1. Scheme 1.

To a stirred solution of ¹ - [2- (dimethylamino) ethyl] - ^1- methyl- ⁴ - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1, 2 , 4-triamine (2.1, 1.0 g, 2.2 mmol), DCC (0.51 g, 2.4 mmol) and 2-methylacrylic acid (193 mg, 2.2 mmol) in CH ₂ Cl ₂ (30 ml) were added DMAP (27 mg, 0.22 mmol) at room temperature. The resulting mixture was stirred overnight. The precipitate was filtered off, the mother liquor was concentrated and purified by column chromatography using acetone as eluent. The appropriate fractions were combined and concentrated in vacuo. Received 400 mg of inhibitor 1.1. Ή-NMR (OMSO-d ₆ , 400 MHz): 2.03 (s, ЗН), 2.12 (s, 6Н), 2.20 (t, J = 5.5 Hz, 2H), 2.68 (s, 3H), 2.96 (t, J = 5.5 Hz, 2H), 3.86 (s, 3H), 3.92 (s, 3H), 5.54 (s, 1H), 5.85 (s, 1H), 7.08 (s, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.20-7.29 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 5.5 Hz, 1H), 8.71 (s, 1H), 9.19 (s, 1H), 9.96 (s, 1H).

Example 2. - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} - 2-fluoro-acrylamide (1.2) and its dichloroacetate 1.2 CHC1 ₂ C0 ₂ N are prepared according to Scheme 2.

 Scheme 2.

1.2 1.2 CHC1 ₂ C0 ₂ N To a stirred solution of ¹ - [2- (dimethylamino) ethyl] - ^1- methyl-N ⁴ - [4- (l-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1, 2,4-triamine (2.1, 0.5 g, 1.2 mmol), DCC (0.255 g, 1.2 mmol) and 2-fluoroacrylic acid (101 mg, 1.1 mmol) in CH ₂ Cl ₂ (20 ml) DMAP (14 mg, 0.11 mmol) was added at room temperature. The resulting mixture was stirred overnight. The precipitate was filtered off, the mother liquor was concentrated and purified by column chromatography using acetone as eluent. The appropriate fractions were combined and concentrated in vacuo. Received 1 17 mg of inhibitor 1.2. Ή-NMR (DMSO- / ₆ , 400 MHz): 2.14 (s, ЗН), 2.17 (t, J = 5.7 Hz, 2H), 2.69 (s, 3H), 2.97 (t, J = 5.7 Hz, 2H) , 3.88 (s, 3H), 3.90 (s, 3H), 5.42 (dd, J _! = 15.7 Hz, J ₂ = 3.3 Hz, 1H), 5.67 (dd, J, = 48.2 Hz, J ₂ = 3.3 Hz, 1H), 7.09-7.19 (m, 2H), 7.21-7.28 (m, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 8.25 (d, J = 8.3 Hz, 1H ), 8.34 (d, J = 5.3 Hz, 1H), 8.59 (s, 1H), 9.08 (s, 1H), 10.68 (s, 1H).

To a stirred solution of inhibitor 1.2 (40 mg, 0.077 mmol) in acetone (1 ml) at 25 ° С dichloroacetic acid (9.9 mg, 0.077 mmol) was added as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. Received 17 mg of an inhibitor of 1.2 CHC1 ₂ C0 ₂ N in the form of white crystals. Ή-NMR (DMS0-i 400 MHz): 2.66 (s, ЗН), 2.70 (s, 6Н), 2.96-3.11 (m, 2Н), 3.24-3.33 (m, 2Н), 3.90 (s, ЗН), 3.92 (s, ЗН), 5.48 (dd, J, = 15.5 Hz, J ₂ = 3.3 Hz, 1H), 5.75 (dd, Ji = 48.4 Hz, J ₂ = 3.3 Hz, 1H), 5.98 (s, 1H) , 7.06 (s, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.22-7.30 (m, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 8.31 ( d, J = 8.3 Hz, 1H), 8.34 (d, J = 5.3 Hz, 1H), 8.52 (s, 1H), 8.87 (s, 1H), 9.87 (s, 1H).

Example 3. - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-ΙΗ-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} - 2-butenamide (1.5) and its mesylate (I .5 CH3SO3H) are prepared according to Scheme 3.

Scheme 3.

1.2 1.2 CH ₃ S0 ₃ H

To a stirred solution of ¹ - [2- (dimethylamino) ethyl] ^ ¹ -methyl- ⁴ - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1,2 , 4-triamine (2.1, 70 mg, 1.57 mmol) and TEA (238 mg, 2.36 mmol) in CH ₂ Cl ₂ (5 ml) was added acryloyl chloride (142 mg, 1.57 mmol) in CH ₂ Cl ₂ (1 ml) at -20 ° C. The resulting mixture was warmed to room temperature, stirred for 3 hours, then washed with water (5 ml). The organic phase was concentrated and purified by column chromatography using a mixture of EtOAc and MeOH (1: 1). The appropriate fractions were combined and concentrated in vacuo. Received 200 mg of inhibitor 1.5. 'H-NMR (DMS0-400 MHz): 1.90 (d, J = 6.7 Hz, 3H), 2.22 (s, 6H), 2.31 (t, J = 5.5 Hz, 2H), 2.71 (s, 3H), 2.88 (t, J = 5.5 Hz, 2H), 3.85 (s, 3H), 3.92 (s, 3H), 6.10 (d, J = 15.3 Hz, 1H), 6.80 (dt, J, = 6.7 Hz, J ₂ = 15.3 Hz, 1H), 7.03 (s, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.20-7.27 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 7.88 (s , 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 8.68 (s, 1H), 9.14 (s, 1H), 9.97 (s, 1H).

To a stirred solution of 1.5 inhibitor (8, 55 mg, 0.1 1 mmol) in acetone (3 ml) at 25 ° С, methanesulfonic acid (10 mg, 0.1 1 mmol) was added as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. Received 36 mg of inhibitor I .5 CH3SO3H in the form of light yellow crystals. Ή-NMR (DMSO-i / ₆ , 400 MHz): 1.90 (d, J = 6.7 Hz, 3H), 2.33 (s, 3H), 2.63 (s, 3H), 2.81 (s, 6H), 3.22-3.30 (m, 4H), 3.89 (s, 3H), 3.90 (s, 3H), 6.36 (d, J = 15.3 Hz, 1H), 6.86 (dt, Ji = 6.7 Hz, J ₂ = 15.3 Hz, 1H), 7.00 (s, 1H), 7.16 (t, J = 7.1 Hz, 1H), 7.22-7.29 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 8.14 (br.s, 1H), 7.22 -7.29 (m, 2H), 8.54 (s, 1H), 8.64 (s, 1H), 9.26 (s, 1H), 9.37 (s, 1H). Example 4. N- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (l-methyl-lH-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -4,4,4-trifluorobut-2-enamide (1.6) and its dichloroacetate 1.6 CHC1 ₂ C0 ₂ N are prepared according to Scheme 4.

 Scheme 4.

1.6 1.6 CHC1 ₂ C0 ₂ N

To a stirred solution of N - [2- (dimethylamino) ethyl] - methyl-Ν - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1,2, 4-triamine (2.1, 1.0 g, 2.2 mmol), DCC (0.51 g, 2.4 mmol) and (2 £) -4,4,4-trifluorobut-2-enoic acid (314 mg , 2.2 mmol) in CH ₂ Cl ₂ (30 ml) was added at room temperature DMAP (27 mg, 0.22 mmol). The resulting mixture was stirred overnight. The precipitate was filtered off, the mother liquor was concentrated and purified by column chromatography using acetone as eluent. The appropriate fractions were combined and concentrated in vacuo. Received 233 mg of the inhibitor 1.6. Ή-NMR (DMSO-i b, 400 MHz): 2.19 (s, ЗН), 2.36 (t, J = 5.7 Hz, 2H), 2.74 (s, ЗН), 2.88 (t, J = 5.7 Hz, 2H) , 3.87 (s, 3H), 3.90 (s, 3H), 6.85-6.96 (m, 1H), 6.97-7.08 (m, 2H), 7.13 (t, J = 7.6 Hz, 1H), 7.19-7.27 (m , 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 5.3 Hz, 1H), 8.55 (s , 1H), 9.07 (s, 1H), 10.45 (s, 1H).

To a stirred solution of inhibitor 1.6 (40 mg, 0.07 mmol) in acetone (1 ml) at 25 ° C, dichloroacetic acid (9 mg, 0.07 mmol) was added as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. Received 23 mg of the inhibitor 1.6 CHC1 ₂ C0 ₂ N in the form of beige crystals. Ή-NMR (DMSO-i ₆ , 400 MHz): 2.63 (s, ЗН), 2.75 (s, 6Н), 3.1 1-3.28 (m, 4Н), 3.89 (s, ЗН), 3.90 (s, ЗН) 6.02 (s, 1H), 6.86-6.98 (m, 1H), 7.05 (s, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.19-7.27 (m, 2H), 7.43 (d, J = 14.3 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.96 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H ), 8.32 (d, J = 5.3 Hz, 1H), 8.50 (s, 1H), 9.00 (s, 1H), 9.99 (s, 1H), 10.48 (br.s, 1 H).

Example 5. (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] - 4-methoxy-phenylcarbamoyl} -acrylic acid methyl ester (1.7) and its mesylate 1.7 CH ₃ S0 ₃ H are prepared according to Scheme 5.

 Scheme 5.

 2.1 1.7 1.7 CH3SO3H

To a stirred solution of ^ - [2- (dimethylamino) ethyl] -K'-methyl- ⁴ - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1, 2,4-triamine (2.1, 300 mg, 0.67 mmol) and TEA (81 mg, 0.80 mmol) in CH ₂ Cl ₂ (5 ml) was added methyl (2g) -4-chloro-4-oxobut- 2-enoic acid (PO mg, 0.73 mmol) in CH ₂ Cl ₂ (1 ml) at 0 ° C. The resulting mixture was warmed to room temperature, stirred for 3 hours, then washed with water (5 ml). The organic phase was concentrated and purified by column chromatography using a mixture of EU Ac: MeOH 1: 1. The appropriate fractions were combined and concentrated in vacuo to give 144 mg of (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino ] -5- [4- (1-methyl-1 H-indol-3-yl) -pyrimiin-2-ylamino] -4-methoxy-phenylcarbamoyl} -acrylic acid methyl ester (1.7), Ή-NMR (DMSC fa 400 MHz): 2.24 (s, 6H), 2.36 (t, J = 5.5 Hz, 2H), 2.74 (s, 3H), 2.88 (t, J = 5.5 Hz, 2H), 3.77 (s, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 6.73 (d, J = 15.5 Hz, 1H), 7.06 (s, 1H), 7.13 (t, J = 7.1 Hz, 1H), 7.17-7.29 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 8.63 (s, 1H), 9.17 (s, 1 H), 10 .59 (s, 1H). To a stirred solution of 1.7 inhibitor (144 mg, 0.26 mmol) in acetone (6 ml) at 25 ° С was added methanesulfonic acid (20 mg, 0.21 mmol) as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight to obtain 75 mg of (E) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1 -methyl-1H-indol-3-yl) -pyrimiin-2-ylamino] -4- methoxy-phenylcarbamoyl} -acrylic acid methyl ester (I .7 CH3SO3H) as yellow crystals, NM-NMR (DMSO-i / ₆ , 400 MHz): 2.32 (s, 3H), 2.63 (s, 3H), 2.80 ( br.s, 6H), 3.29 (br.s, 4H), 3.78 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 6.78 (d, J = 15.3 Hz, 1H), 7.03 (s, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.20-7.27 (m, 2H), 7.50-7.60 (m, 2H), 7.95 (s, 1H), 8.28-8.35 (m, 2H ), 8.52 (s, 1H), 8.89 (s, 1H), 9.32 (br.s, 2H), 9.88 (br.s, 1H).

Example 6. (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] - 4-methoxy-phenylcarbamoyl} -, -dimethylacrylamide (1.8) and its bis-dichloroacetate 1.8 -2CHC1 ₂ C0 ₂ N are prepared according to Scheme 6.

 Scheme 6.

1.8 CHCI ₂ C0 ₂ H

To a stirred solution of ¹ - [2- (dimethylamino) ethyl] -K ¹ -methyl- ⁴ - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1, 2,4-triamine (2.1, 500 mg, 1.12 mmol) in dioxane (4 ml) was added furan-2,5-dione (1 10 mg, 1.12 mmol) in dioxane (1 ml) at room temperature. The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. 570 mg (93%) of (Z) -3- {2 - [(2- dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimiin-2-ylamino] -4-methoxy-phenylcarbamoyl} -acrylic acid (1.8 (1)). 1H-NMR (DMSO-i / ₆ , 400 MHz): 2.54 (s, 3H), 2.72 (s, 6H), 3.25-3.30 (m, 4H), 3.85 (s, 3H), 3.90 (s, 3H) , 5.80 (d, J = 13.1 Hz, 1H), 6.26 (d, J = 13.1 Hz, 1H), 6.92 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.90 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1 H), 8.66 (s, 1H), 9.30 (s, 1H), 12.76-13.17 (m, 3H). Ethyl chloroformate (120 mg, 1.1 mmol) in anhydrous THF (10 ml) was added to a suspension of the obtained acid 1.8 (1) (600 mg, 1.1 mmol) and triethylamine (223 mg, 2.2 mmol) in anhydrous THF ( 50 ml) at -15 ° C in a stream of nitrogen. After 30 minutes, a 20% solution of dimethylamine in THF (2.5 ml) was added and the resulting mixture was stirred overnight at room temperature. The precipitate was filtered off and the mother liquor was evaporated in vacuo. An oil was obtained which was subjected to silica gel column chromatography (acetone-MeOH, 20: 1). 73 mg of product 1.8 were obtained, which was percrystallized from diethyl ether. NM-NMR (DMSO-ifa 400 MHz): 2.29 (s, 6Н), 2.41 (br.s, 2Н), 2.73 (s, ЗН), 2.89 (br.s, 2Н), 2.95 (s, ЗН), 3.12 (s, ЗН), 3.87 (s, ЗН), 3.93 (s, ЗН), 7.01-7.1 1 (m, 2Н), 7.15 (t, J = 7.5 Hz, 1H), 7.20-7.29 (m, 2H ), 7.39 (d, J = 14.7 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.90 (s, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.68 (s, 1H), 9.22 (s, 1H), 10.51 (br.s, 1H).

To a stirred solution of 1.8 inhibitor (26 mg, 0.046 mmol) in acetone (1 ml) at 25 ° С dichloroacetic acid (5.9 mg, 0.046 mmol) was added as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. Received 24 mg of the inhibitor 1.8 ₂ CHC _{2 2} C0 ₂ N in the form of light yellow crystals. Ή-NMR (DMSO - </ ₆ , 400 MHz): 2.61 (s, ЗН), 2.78 (s, 6Н), 2.95 (s, ЗН), 3.11 (s, ЗН), 3.22-3.32 (m, 4Н) , 3.90 (s, 3H), 3.91 (s, 3H), 6.12 (s, 1H), 7.01 (s, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.20-7.27 (m, 2H), 7.40 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.94 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.57 (s, 1H), 8.96 (s, 1H), 9.81 (s, 1H), 10.10 (br.s, 1H).

Example 7. - (2- [3- (Dimethylamino) piperidin-1-yl] -5 - {[4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] amino} -4- methoxyphenyl) acrylamide (1.1 1) and its mesylate I. II CH3SO3H was prepared according to Scheme 7. Scheme 7.

To a stirred solution of 1 - (2-methoxy-5-nitrophenyl-4-fluoro) -4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-amine (1.11 (1): 2.0 g 5.1 mmol) and Ν, Ν-dimethylpiperidin-3-amine (1.2 g, 6.1 mmol) in DMF (60 ml) were added at room temperature TEA (2.1 g, 20.3 mmol). The resulting mixture was stirred at 85 ° C for 6 hours, then cooled to room temperature, water (250 ml) was added and the resulting mixture was stirred for 3 hours. The solid was collected by filtration, washed with water (50 ml) and dried in air for nights. [4- (3-Dimethylaminopiperidin-1-yl) -2-methoxy-5-nitrophenyl] - [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-yl] -amine (1.1) was obtained 1 (2): 5.6 g, 82%), Ή-NMR (DMSO-i _b , 400 MHz): 1.22-1.35 (m, W), 1.57-1.70 (m, 1H), 1.76-1.85 (m , 1H), 1.91-2.01 (m, 1H), 2.23 (s, 6H), 2.41-2.48 (m, 1H), 2.63-2.71 (m, 1H), 2.74-2.83 (m, 1H), 3.17-3.24 (m, 1H), 3.33-3.38 (m, 1H), 3.88 (s, 3H), 3.99 (s, 3H), 6.85 (s, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.23 ( d, J = 5.4 Hz, IH), 7.25 (t, J = 7.5 Hz, IH), 7.52 (d, J = 8.1 Hz, IH), 8.12 (s, IH), 8.31-8.39 (m, 3H), 8.79 (s, IH ) To a mixture of compound 1.1 1 (2) (2.1 g, 4.2 mmol), iron (1.4 g, 25.2 mmol), NH _t Cl (0.16 g, 2.9 mmol) and ethanol ( 40 ml) was added in one go water (5.5 ml). The resulting mixture was heated at 80 ° C for 3 hours, then filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography using a mixture of chloroform and methanol in a ratio of 10: 1. The appropriate fractions were combined and concentrated in vacuo. Received 4- [3- (dimethylamino) piperidin-1-yl] -6-methoxy-1CH- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] benzene-1,3- diamine (2.2: 1.7 g, 86%), Ή-NMR (DMSO-i / ₆ , 400 MHz): 1.00-1.16 (m, IH), 1.29-1.51 (m, IH), 1.52-1.74 (m , IH), 1.74-2.01 (m, IH), 2.38 (s, 6H), 2.52-2.63 (m, IH), 2.82-3.00 (m, IH), 3.12-3.28 (m, IH), 3.32-3.45 (m, IH), 3.75 (s, 3H), 3.87 (s, 3H), 6.72 (br.s, IH), 7.09-7.31 (m, 3H), 7.45-7.62 (m, 2H), 7.76 (br .s, IH), 8.22-8.34 (m, 2H), 8.43 (br.s, IH). To a stirred suspension of compound 2.2 (700 mg, 1.48 mmol) and K ₂ C0 ₃ (143 mg, 1.04 mmol) in acetone (15 ml) was added methyl-3-chloropropanoyl chloride (226 mg, 1.78 mmol) in acetone (1 ml) at -50 ° C. The resulting mixture was heated to -20 ° C and stirred for 30 minutes. Then, MeOH (2 ml) and a NaOH solution (53 mg, 1.33 mmol in 7 ml of water) were added. The resulting mixture was stirred for 3 hours at room temperature. The solid was collected by filtration and dried in air overnight. 150 mg of Y- (2- [3- (dimethylamino) piperidin-1-yl] -5 - {[4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] amino} -4 was obtained -methoxy-phenyl) acrylamide (1.1 1), Ή-NMR (DMS0- <400 MHz): 1.21-1.41 (m, Ш), 1.67-1.86 (m, 2H), 1.87-1.97 (m, IH), 2.21 (s, 6H), 2.41-2.48 (m, IH), 2.58-2.70 (m, IH), 2.90-2.99 (m, IH), 3.08-3.15 (m, IH), 3.33-3.38 (m, IH) , 3.87 (s, 3H), 3.91 (s, 3H), 5.75 (d, J = 10.5 Hz, IH), 6.24 (d, J = 17.0 Hz, IH), 6.65 (dd, Ji = 10.5 Hz, J ₂ = 17.0 Hz, IH), 6.88 (s, IH), 7.14-7.28 (m, 3H), 7.52 (d, J = 8.1 Hz, IH), 7.86 (s, IH), 8.26 (d, J = 8.1 Hz , W), 8.31 (d, J = 5.5 Hz, IH), 8.58 (s, IH), 8.84 (s, IH), 9.09 (s, IH). To a stirred solution of the inhibitor 1.1 1 (100 mg, 0.19 mmol) in acetone (4 ml) at 25 ° C was added methanesulfonic acid (18 mg, 0.19 mmol) as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The resulting solid was collected by filtration and air dried overnight. Received 80 mg of N- (2- [3- (dimethylamino) piperidin-1-yl] -5 - {[4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] amino} -4 - methoxy-phenyl) acrylamide mesylate (I .II CH ₃ SO ₃ H) in the form of light yellow crystals, Ή-NMR (DMS0-400 MHz): 1.69-1.85 (m, 2Н), 1.85-1.96 (m, IH), 1.98-2.06 (m, IH), 2.34 (s, 6H), 2.74-2.93 (m, 8H), 3.02-3.12 (m, W), 3.23-3.29 (m, 1H), 3.49-3.59 (m, 1H), 3.89 (s, 3H), 3.91 (s, 3H), 5.77 (d, J - 10.5 Hz, 1H), 6.28 (d, J = 17.0 Hz, 1H), 6.85 (dd, = 10.5 Hz, J ₂ = 17.0 Hz, 1H), 6.93 (s, 1H), 7.13-7.32 (m, 3H), 7.52 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 5.5 Hz, 1H), 8.57 (s, 1H), 8.87 (s, 1H), 9.22 (s, 1H), 9.67 (br.s, 1H).

Example 8. - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) - pyrimiin-2-ylamino] -4-methoxyphenyl} - propinamide (1.12) and its dimesylate (1.12-2CH ₃ S0 ₃ H) are prepared according to Scheme 8.

 Scheme 8.

1.11 1.11 -CH _J SO _J H

To a stirred solution of ¹ - [2- (dimethylamino) ethyl] -K ¹ -methyl-N ⁴ - [4- (l-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1 2,4-triamine (2.1: 1.0 g, 2.2 mmol), DCC (0.51 g, 2.4 mmol) and propiolic acid (157 mg, 2.2 mmol) in CH ₂ Cl ₂ ( 30 ml) was added DMAP (27 mg, 0.22 mmol) at room temperature. The resulting mixture was stirred overnight. The solid was collected by filtration, the mother liquor was concentrated and purified by column chromatography using a mixture of acetone as eluent. The appropriate fractions were combined and concentrated in vacuo. 63 mg of K- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1 H-indol-3-yl) -pyrimiin-2-ylamino] -4-methoxyphenyl were obtained } -propinamide (1.12), ¹ Н-NMR (DMS0-i 400 MHz): 2.28 (s, 8Н), 2.73 (s, ЗН), 2.85-2.93 (m, 2Н), 3.85 (s, ЗН), 3.90 (s, ЗН), 4.31 (s, 1Н), 7.07 (s, 1H), 7.16 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 5.5 Hz, 1H), 7.25 (t, J = 7.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.52 (s, 1H), 8.93 (s, 1H), 1 1.41 (s, 1H). To a solution of inhibitor 1.12 (63 mg, 0.13 mmol) in acetone (3 ml) at 25 ° C was added methanesulfonic acid (24 mg, 0.26 mmol) as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and air dried overnight. Received 31 mg - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimiin-2-ylamino] -4-methoxyphenyl} - propinamide dimesylate (1.12-2CH ₃ S0 ₃ H) in the form of light yellow crystals, ^ -NMR (DMSO-i / ₆ , 400 MHz): 2.34 (s, 6H), 2.69 (s, 3H), 2.86 (s, 6H), 3.28-3.39 (m, 2H), 3.86 (s, 3H), 3.93 (s, 3H), 4.47 (s, 1H), 7.05 (s, 1H), 7.21 (t, J = 7.3 Hz, 1H ), 7.32 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 5.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 8.16 (br.s, 1H), 8.24 (br .s, 2H), 8.72 (s, 1H), 9.13 (br.s, 1H), 9.97 (s, 1H).

Example 9. ^ {2 - [(2-dimethylamino-ethyl) -methyl-amino] -5-5- [4- (1-methyl-1 H-indol-3-yl) -pyrimidin-2-ylamino] - 4-methoxyphenyl} -2-butynamide (1.14) and its mesylate 1.14 CH ₃ S0 ₃ H are prepared according to Scheme 9.

 Scheme 9

To a stirred solution of N - [2- (dimethylamino) ethyl] - methyl-Ν - [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl] -5-methoxybenzene-1,2, 4-triamine (2.1: 1, 0 g, 2.2 mmol), DCC (0.51 g, 2.4 mmol) and but-2-new acid (189 mg, 2.2 mmol) in CH ₂ Cl ₂ (30 ml) was added at room temperature DMAP (27 mg, 0.22 mmol). The resulting mixture was stirred overnight. The precipitate was filtered off, the mother liquor was concentrated and purified by column chromatography using acetone as eluent. The appropriate fractions were combined and concentrated in vacuo. Received 440 mg of inhibitor 1.14. NM-NMR (DMSO-i / ₆ , 400 MHz): 2.05 (s, ЗН), 2.28 (s, 8Н), 2.72 (s, ЗН), 2.88 (t, J = 5.3 Hz, 2H), 3.84 (s , 3H), 3.90 (s, 3H), 7.05 (s, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 5.5 Hz, 1H), 7.25 (t, J = 7.3 Hz , 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 5.5 Hz, 1H), 8.52 (s , 1H), 8.92 (s, 1H), 1 1.08 (s, 1H).

To a stirred solution of 1.14 inhibitor (300 mg, 0.13 mmol) in acetone (5 ml) at 25 ° C was added methanesulfonic acid (48 mg, 0.11 mmol) as a solution in acetone (1 ml). The resulting mixture was stirred for 15 hours. The precipitate was filtered off and dried in air overnight. Received 245 mg of inhibitor I. H CH3SO3H in the form of light yellow crystals. ^! H-NMR (DMSO-i / ₆ , 400 MHz): 2.07 (s, ЗН), 2.33 (s, ЗН), 2.63 (s, ЗН), 2.83 (s, 6H), 3.21-3.32 (m, 4H) , 3.89 (s, 6H), 6.97 (s, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.22 (d, J = 5.5 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H) , 7.53 (d, J = 8.1 Hz, 1H), 7.95 (s, 1H), 8.28-8.38 (m, 2H), 8.43 (s, 1H), 8.57 (s, 1H), 9.08 (br.s, 1H ), 9.78 (br.s, 2H).

 Example 10. Determination of thermodynamic solubility of the compounds of formula 1 and the prototype AZD-9291. 5 mg of the test compound was mixed with 1 ml of universal buffer (pION) with a pH of 2.0, 4.0 or 7.0 for 15 min at 25 ° C. Additional amounts of substances were added until the solution became cloudy. The solution vials were incubated with stirring for 24 hours at 25 ° C to achieve equilibrium between the solution and the precipitate at saturation. After equilibration, 200 μl of the solution (in 2 repetitions) was filtered through a 96-well filter plate (Millipore) to separate the precipitate. The concentration of compounds in the filtrate was determined spectrophotometrically using a standard calibration curve. The optical absorption spectrum of the substance was measured and a calibration curve was constructed at a selected wavelength (usually corresponding to the absorption of the substance λπ χ). The concentration of the substance in the filtrate (i.e. solubility) was calculated by the formula below:

Solubility = (ODx _max filtrate - OD max blank) / Slope x 1.67 x Filtrate dilution,

 Where:

ODx _max filtrate is the optical density of the filtrate,

ODx _m ax blank - optical density of a blank solution without a substance,

 Slope - slope of the calibration curve,

 1, 67 - dilution factor of the filtrate with acetonitrile,

 Filtrate dilution - buffer dilution factor

 The results obtained are presented in Table 1.

Example 1 1. Activity analysis. The compounds of formula 1 and their salts were tested for their effect on the activity of EGFR kinases (L858R / T790M) and EGFR wt (all enzymes provided by Invitrogen Corp., catalog numbers PV3872, PV4128 and PV4803, respectively) using the платформы'-LYTE screening platform (manufactured by Life Technologies). The concentration of DMSO in the reaction mixture was 1%. 5 μl of a 2-fold substrate / kinase mixture (Tyr4 / EGFRwt or EGFR-L858R or EGFR-T790M, final concentrations 0.5 μM for substrate Tug 4 and 1000, 250, 1000 ng / ml for EGFRwt or EGFR-L858R or EGFR-T790 respectively) were added to 384-well plates (black, small volume, manufactured by Corning, Cat. # 3676). 1.5 μl of 100-fold stocks of the test substances in 100% DMSO were diluted 10 times in 13.5 μl of kinase buffer (50 mM HEPES pH 6.5, 0.01% BRIJ-35, 10 mM MgC12, 1 mM EGTA, 0.02% NaN3) and then 1 μl of diluted substances was added to the substrate / kinase mixture. The substances were preincubated with kinases for 10 min at room temperature. After that, 4 μl of a 2.5-fold ATP solution was added to start the reaction (the final concentration of ATP in the reaction mixture was 180 or 100 or 40 μM for EGFRwt, EGFR-L858R, and EGFR-T790M, respectively). After 30 seconds of incubation on a shaker, the reaction was incubated for 60 minutes at room temperature. After that, 5 μl of Reagent B (diluted 1: 500) was added and incubated for another 60 min at room temperature. Fluorescence was measured upon excitation with a wavelength of 400 nm and emission at 445 and 520 nm. The degree of phosphorylation of the peptide substrate was calculated using the formula below (if the emission ratio is low, the peptide is phosphorylated, i.e., there is no inhibition of kinase activity, if the ratio is high, the peptide is not phosphorylated, i.e., the kinase is inhibited)

% phosphorylation calculated as

 % inhibition is calculated as

% Phos Sample I

 * loo

 % Ph0S about% Inhibition Ctl

 Where:

With ioo% ⁼ average coumarin emission signal, control 100% phosphorylation,

 Co% = average coumarin emission signal control 0% phosphorylation,

Fioo% = average fluorescein emission signal control 100% phosphorylation, Fo% = average fluorescein emission signal control 0% phosphorylation.

 The concentration curve of the kinase activity versus the concentration of the tested substances was constructed using the sigmoid model. The results of a comparative analysis of the activity of some compounds of the formula (1) and the prototype AZD-9291 are presented in Table 2.

Example 12. Obtaining a drug in the form of tablets. A mixture of 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc and 1000 mg of inhibitor 1.1 (1) was pressed. The resulting bar was crushed into granules and sieved through a sieve, collecting granules with a size of 14-16 mesh. The obtained granules were tabletted into tablets of suitable forms weighing 500 mg each.

 Example 13. Obtaining a drug in the form of capsules. Inhibitor 1.1 (1) was thoroughly mixed with lactose powder in a ratio of 2: 1. The resulting powder mixture was packaged in 600 mg in a suitable size gelatin capsule.

 Example 14. Obtaining a medicinal product in the form of compositions for intramuscular, intraperitoneal or subcutaneous injection. 500 mg of the inhibitor 1.1 (1) 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water were mixed. The solution was filtered and placed in 1 ml ampoules and sealed.

 Specialists in the art will easily understand the difference in non-critical parameters that can be changed or modified to obtain the same results. Various modifications of the invention, in addition to those described herein, will become apparent to those skilled in the art from the above description.

Industrial applicability

 The invention can be used in medicine and veterinary medicine.

Claims

Claim 1. Substituted - {3- [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-ylamino] -4-methoxyphenyl} amides of the general formula 1, their pharmaceutically acceptable salts, hydrates, solvates:

 Where: R ¹ represents a radical selected from CH ₂ = C (R ³ ) -, R ³ CH = CH— and R ⁴ C = C—; R ² is (2-dimethylaminoethyl) methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-dimethylaminopiperidin-1-yl and 3-dimethylaminoazepan-1-yl, 4-methylpiperazin-1-yl; R ³ represents methyl, trifluoromethyl, fluoro, chloro, methoxycarbonyl and dimethylcarbamoyl; R ⁴ represents hydrogen or methyl;  or R 1 is vinyl, and R 2 is 3-dimethylaminopyrrolidin-1-yl; R ⁴ is C] -C ₄ alkyl, C3-C ₆ cycloalkyl. 2. The compounds according to claim 1, selected from: N- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (l-methyl-lH-indol-3-yl) -pyrimidin-2-yl amino] -4-methoxyphenyl} -2-meti l-acri lam id (1.1); - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2-fluoro acrylamide (1.2); - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2-chloro acrylamide (1.3);  - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2-trifluoromethyl acrylamide (1.4);  N- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (l-methyl-lH-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -2- butenamide (1.5);  - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -4,4 4-trifluorobut-2-enamide (1.6);  (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy -phenylcarbamoyl} -acrylic acid methyl ester (1.7); (£) -3- {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy -phenylcarbamoyl} -T, 1-dimethylacrylamide (1.8); (£) ^, -dimethyl-3- {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) - pyrimidin-2-ylamino] -4-methoxy-phenylcarbamoyl} -acrylamide (1.9); (£) -K, dimethyl-3- {5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -2- (4-methyl-piperazin-1-yl ) -4-methoxy-phenylcarbamoyl} -acrylamide (1.10); K- {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxy-phenyl} - acrylamide (1.1 1);  - {2 - [(2-dimethylaminoethyl) methyl-amino] -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamo ino] -4-methoxyphenyl} -propamine id (1.12);  - {2- (3-dimethylamino-piperidin-1-yl) -5- [4- (1-methyl-1H-indol-3-yl) -pyrimidin-2-ylamino] -4-methoxyphenyl} -propinamide (1.13 );  N- {2 - [(2-Dimethylamino-ethyl) methyl-amino] -5-5- [4- (l-methyl-lH-indol-3-yl) -pyrimidin-2-ylamo ino] -4- methoxyphenyl} -2-butynamide (1.14) or their pharmaceutically acceptable salts.  3. The active component with anticancer activity for the preparation of pharmaceutical compositions and dosage forms, which is a compound according to p. 1, 2.  4. The drug is a compound according to claims 12. 5. A pharmaceutical composition having anti-cancer activity in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable a package comprising the active ingredient according to claim 3 in a therapeutically effective amount in combination with a pharmaceutically acceptable diluent and / or carrier.  6. A method for the prevention and / or treatment of cancer, including the introduction in an effective amount of a compound according to claims 12.  7. A method for the prevention and / or treatment of cancer, comprising administering in an effective amount of an active component according to claim 3.  8. A method of preventing and / or treating cancer, comprising administering in an effective amount of a medicament according to claim 4.  9. A method for the prevention and / or treatment of cancer, comprising administering in an effective amount of a pharmaceutical composition according to claim 5.  10. The method according to any one of paragraphs. 6, 7, 8 and 9, providing for the prevention and / or treatment of small cell lung cancer.  1 1. A method for producing an anticancer effect in a mammal of an animal and a person in need of such treatment, which comprises administering to said mammal and animal an effective amount of a compound according to claims 12.  12. A method of manufacturing a medicinal product for the treatment of cancer, including the use of a compound according to claims 12.  13. A method of manufacturing a medicine according to claim 12 for the treatment of small cell lung cancer.  14. The use of compounds according to claims 1, 2 and an additional antitumor substance for the simultaneous, separate or sequential treatment of cancer. 15. A process for preparing a compound of general formula 1 by reacting a compound of formula 2 or a salt thereof with an activated derivative of an organic acid, such as an acid chloride, an ester or an anhydride of an organic acid.

 where R is (2-dimethylaminoethyl) methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-dimethylaminopiperidin-1-yl and 3-dimethylaminoazepan-1-yl, 4-methylpiperazin-1-yl.