WO2022146201A1

WO2022146201A1 - Epidermal growth factor receptor inhibitors

Info

Publication number: WO2022146201A1
Application number: PCT/RU2021/050459
Authority: WO
Inventors: Kirill Vadimovich ZAVIALOV; Georgii Viktorovich IAKOBSON; Shamil Dinarovich KADYROV; Adel Ravilevich KHAIDAROV; Daria Dmitrievna BEKETOVA; Daniel Evgenevich POLIANCZYK; Ilia Alexeevich SMETANIN; Ramilia Rinadovna STARODUBTSEVA; Polina Olegovna SUNTSOVA; Dmitry Alekseevich KHALABUDIN; Artsiom Evgenievich SHEKHAUTSOU; Dmitry Valentinovich MOROZOV
Original assignee: Joint Stock Company "Biocad"
Priority date: 2020-12-30
Filing date: 2021-12-30
Publication date: 2022-07-07
Also published as: TW202241890A; UY39600A

Abstract

The present invention relates to novel compounds of formula I: I or pharmaceutically acceptable salt, solvate or stereoisomer thereof, which have EGFR inhibitor properties, to pharmaceutical compositions containing said compounds, to methods of treating diseases or disorders and the use of said compounds as pharmaceutical products for treating diseases or disorders

Description

Epidermal growth factor receptor inhibitors

Field of the invention

The present invention relates to novel epidermal growth factor receptor (EGFR) inhibitors, also to pharmaceutically acceptable salts, solvates or stereoisomers thereof, to pharmaceutical compositions comprising the present compounds, to methods for treating diseases or disorders and use of the present compounds as pharmaceutical products for treating diseases or disorders.

Background of the invention

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 external ligand-binding domain (621 residues) and a cytoplasmic domain (542 residues) bound by a short 23-amino-acid transmembrane linker. The extracellular portion of EGFR contains 25 disulfide bonds and 12 N-linked glycosylation sites, and is generally considered to consist of four subdomains. X-ray crystal structures of EGFR suggest that the receptor may adopt both an autoinhibited tethered-conformation that cannot bind epidermal growth factor (EGF) (Ferguson et al., Mol Cell, 2003, vol 11 :507-517) and an active conformation that may mediate EGF ligand binding and receptor dimerisation (Garrett et al., Cell 2002, vol 110:763-773; Ogiso et al., Cell, 2002, vol 110:775-787). Upon binding of a growth factor ligand such as epidermal growth factor (EGF), the receptor can homo-dimerise with another EGFR molecule or hetero-dimerise with another family member such as erbB2 (FIER2), erbB3 (HER3), or erbB4 (HER4). Homo- and/or hetero-dimerisation of erbB receptors results in the phosphorylation of key tyrosine residues in the intracellular domain and leads to the stimulation of numerous intracellular signal transduction pathways involved in cell proliferation and survival. Detailed reviews of erbB receptor signalling and its involvement in tumourigenesis have been provided 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 link of EGFR to oncological diseases was first recognized when the transforming v- ErbB oncogene of the avian erythroblatosis virus was found to be a mutant homolog of human EGFR (Downward J. Nature. 1984; 307:521-527). The v-erbB oncogene was found to contain recombinations of the transmembrane and cytoplasmic domains of EGFR (Olofsson B. Eur. J. Biochem. 1986; 160:261-266), resulting in EGFR oncogenic aberrations. In addition to mutations, overexpression of EGFR was then determined, promoting the progression of a number of malignant tumours (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). It is currently known that EGFR regulates numerous cellular processes via tyrosine-kinase mediated signal transduction pathways, including, but not limited to, control of cell proliferation, differentiation, cell 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). Overexpression of EGFR has been confirmed in numerous human malignant tumors, including cancers of the bladder, brain, head and neck, pancreas, lung, breast, ovary, colon, prostate, and kidney (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 the cells of normal tissues, particularly the epithelial tissues of the skin, liver, and gastrointestinal tract, although typically at lower levels than in malignant cells (Herbst R. S. Cancer. 2002; 94: 1593-1611).

Low 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).

Frequent mutations and EGFR hyperexpression are observed in many oncological diseases (Lu X. Med Res Rev. 2018 Sep; 38(5): 1550-1581), therefore, there remains a need for new effective and safe drugs directed to inhibiting EGFR activity.

Description of the invention

The terms used in the description of this invention appear below.

Optionally substituted in one, two, three, four or several positions means the specified group can be substituted by a radical or any combination of radicals in one, two, three, four or from one to six positions.

An "annelated compound" or "condensed compound" is a polycyclic compound that has two neighboring atoms in common. Examples of condensed compounds include, but are not limited to, naphthalene, quinoline, /.w-qui noline, quinoxaline, indole, 1H-pyrrolo[2,3-b]pyridine, 77/-pyrrolo[2,3-d/]pyrimidine.

“Alkyl” means an aliphatic straight chain or branched chain hydrocarbon group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms. Branched chain means alkyl chain having one or more “lower alkyl” substituents. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, Ao-propyl, n-butyl, Ao-butyl, ec-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, neo- pentyl, n-hexyl. Alkyl may have substituents which may be same or different structure.

“Cycloalkyl” means a fully saturated carbocyclic ring that contains from 3 to 10 carbon ring atoms. Cycloalkyl may have substituents which may be same or different structure. Cycloalkyl may be annelated with aril, heteroaryl, heterocyclyl. 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.

“Alkenyl” means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms that contains one or more carboncarbon double bound. Alkenyl may have substituents which may be same or different structure.

“Alkynyl” means a straight chain or branched chain hydrocarbon group having from 2 to 12 carbon atoms, more preferably from 2 to 6 carbon atoms that contains one or more carboncarbon triple bound. Alkynyl may have substituents which may be same or different structure.

“Aryl” means an aromatic monocyclic or polycyclic system having from 6 to 14 carbon atoms, more 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 substituents which may be same or different structure. Aryl can be annelated with a heterocycle, cycloalkyl, or heteroaryl.

“Alkyloxy”, “Alkoxy” or “alkyloxy group“ means an alkyl-O- group, wherein alkyl is defined in this section. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, //-propoxy,iso-propoxy, //-butoxy, tert-butoxy, Ao-butoxy.

“Aryloxy” or “aryloxy group” means an aryl-O- group, wherein aryl is defined in this section. An example of aryloxy group is, without limitation, phenoxy group.

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

“Amino group” means R'R"N-group.

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

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

"Alkylsulfonyl" (-S(O)₂-(C₁-C₆)alkyl), or (-S(0)₂-(C₃-C₁₀)cycloalkyl) means "alkyl" or "cycloalkyl", as defined above, linked to the corresponding fragment of a molecule via a sulfonyl group, -SO₂-. Examples of alkyl sulfonyls include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, cyclopropylsulfonyl, etc.

"Alkylsulfonamide" (-NH-S(O)₂-(C₁-C₆)alkyl), or (-NH-S(0)₂-(C₃-C₁₀)cycloalkyl) means "alkyl" or "cycloalkyl", as defined above, linked to the corresponding fragment of a molecule via a sulfonamide group, -NH-SO₂-. Examples of alkylsulfonamides include, but are not limited to, methylsulfonamide, ethylsulfonamide, propylsulfonamide, cyclopropylsulfonamide, etc.

"Dialkylphosphine oxide" or "dialkylphosphoryl" (-P(O)((C₁-C₆ )alkyl)₂) or (-P(O)((C 3- Cio)cycloalkyl)₂) means "alkyl" or "cycloalkyl" as defined above, linked to the corresponding fragment of the molecule via a phosphoryl group

. Examples of dialkylphosphine oxide include, but are not limited to, dimethylphosphine oxide, diethylphosphine oxide, methylethylphosphine oxide, dipropylphosphine oxide, dicyclopropylphosphine oxide, etc.

The term “oxo” as used herein relates to the radical =0.

“Lower alkyl” means a straight chain or branched chain alkyl having from 1 to 4 carbon atoms.

“Halo” or “Halogen” (Hal) means fluoro, chloro, bromo and iodo.

“Heterocycle”, “heterocyclyl”, “heterocyclic ring” means a monocyclic or polycyclic system having from 3 to 11 carbon atoms, of which one or more carbon atoms are substituted by a heteroatom, such as nitrogen, oxygen, sulfur. Heterocycle may have one or more substituents which may be same or different structure. Nitrogen and sulfur atoms of heterocycle could be oxidized to N-oxide, S-oxide or S-dioxide. Heterocycle may be saturated, partially saturated or unsaturated. Heterocycle may be annelated with cycloalkyl, aryl or heteroaryl. Examples of heterocycles include, but are not limited to, azetidine, pyrrolidine, piperidine, 2,8- diazaspiro[4.5]decane, piperazine, morpholine, diazepane, azepane, azabicycloheptane, and others.

“Heteroaryl”, "heteroarylyl", "heteroaryl ring" means an aromatic monocyclic or polycyclic system having from 5 to 11 carbon atoms, preferably from 5 to 10, of which one or more carbon atoms are substituted by one or more heteroatoms, such as nitrogen, sulfur or oxygen. Nitrogen atom of heteroaryl may be oxidized to N-oxide. Heteroaryl may have one or more substituents which may be same or different structure. Examples of heteroaryls include, but are not limited to, 1H-pyrrolo[2,3-b]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, pyrrole, furan, pyridine, pyrazine, pyrimidine, pyridazine, isooxazole, isothiazole, tetrazole, oxazole, thiazole, pyrazole, furazan, 1,2,4-triazole, 1,2, 3 -triazole, 1,2,4-thiadiazol, quinoxaline, imidazo[l,2-a]pyridine, indole, benzimidazole, quinoline, imidazole, pyrazole, thienopyridine, quinazoline, naphthyridine, thienopyrimidine, imidazopyridine, isoquinoline, etc.

"Heteroalkyl" means an linear chain or branched chain aliphatic hydrocarbon group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbon atoms, of which one or more carbon atoms are substituted by heteroatom, such as nitrogen, sulfur or oxygen. Branched chain means heteroalkyl chain having one or more “lower alkyl” substituents. Heteroalkyl may have one or more substituents which may be same or different structure. Nitrogen and sulfur atoms of heteroalkyl may be oxidized to N-oxide, S-oxide or S-dioxide. Examples of heteroalkyls include, but are not limited to, methoxymethyl, (2-(dimethylamino)ethyl)amino, (2- (thiomethyl)ethyl)amino, (2-methoxyethyl)amino.

“Substituent” means a chemical radical attached to a scaffold (fragment).

“Solvate” is a molecular aggregate that consists of the compound of the present invention, including its pharmaceutically acceptable salts, with one or more solvent molecules. The solvent molecules are molecules of common pharmaceutical solvents, known to be safe for recipients, e.g. water, ethanol, ethylene glycol, and the like. Other solvents, such as MeOH, methyl -tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butanediol, and the like, can be used as intermediate solvates for obtaining more desirable solvates.

The term “hydrate” refers to a complex, wherein the solvent molecule is water.

Solvates and/or hydrates preferably exist in crystalline form.

The terms “bond”, “chemical bond”, or “single bond” refer to a chemical bond of two atoms or two moi eties (i.e. groups, fragments) when the atoms joined by the bond are considered to be part of 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 their 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, carboxyl group or hydroxy group. Examples of protecting groups include, but are not limited to, tert-butyl oxy carbonyl (Boc), benzyl oxy carbonyl (Cbz), 2-(trimethylsilyl)ethoxy)methyl acetal (SEM), trialkyl silyl, alkyl(diaryl)silyl or alkyl.

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

“Pharmaceutical composition” means a composition comprising a compound of the invention and at least one excipient. The excipient may be selected from a group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary, distributing and sensing agents, delivery agents, such as preservatives, stabilizers, fillers, disintegrators, moisteners, emulsifiers, suspending agents, thickeners, sweeteners, flavouring agents, aromatizing agents, antibacterial agents, fungicides, lubricants, and prolonged delivery controllers, the choice and proportions of which depend on the nature and route of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacant and their mixtures as well. Protection against action of microorganisms can be provided by various antibacterial and antifungal agents, such as, for example, parabens, chlorobutanole, sorbic acid, and similar compounds. The composition may also contain isotonic agents, for example, sugars, sodium chloride, and similar compounds. Prolonged action of the composition may be achieved by agents slowing down absorption of active ingredient, for example, aluminum monostearate and gelatine. Examples of suitable carriers, solvents, diluents and delivery agents are water, ethanol, polyalcohols and their mixtures, natural oils (such as olive oil) and organic esters (such as ethyl oleate) for injections. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of disintegrators and distributors are starch, alginic acid and its salts, silicates, and the like. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and polyethylene glycol of high molecular weight as well. The pharmaceutical composition for peroral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of active ingredient, alone or in combination with another active ingredient may be administered to animals and human in a standard administration form, in a mixture with traditional pharmaceutical carriers. Suitable standard administration forms include peroral forms such as tablets, gelatin capsules, pills, powders, granules, chewing-gums and peroral solutions or suspensions; sublingual and transbuccal administration forms; aerosols; implants; local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

“Pharmaceutically acceptable salt” means relatively nontoxic both organic and inorganic salts of acids and bases disclosed in the present invention. These salts may be prepared in situ in the processes of synthesis, isolation or purification of compounds or they may be prepared specially. In particular, salts of bases may be prepared specially from purified base of the disclosed compound and suitable organic or inorganic acid. Examples of salts prepared in this manner are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosilates, citrates, maleates, fumarates, succinates, tartrates, mesilates, malonates, salicylates, propionates, ethane sulphonates, benzene sulfonates, sulfamates and the like (Detailed description of such salts properties is given in: Berge S.M., et al., “Pharmaceutical Salts” J. Pharm. Sci. 1977, 66: 1-19). Salts of disclosed acids may be prepared by reaction of a purified acid with suitable base; furthermore, metal salts and amine salts may be synthesized as well. Metal salts are salts of sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum; sodium and potassium salts are most preferred. Suitable inorganic bases from which metal salts may be prepared are: sodium hydroxide, carbonate, bicarbonate and hydride; potassium hydroxide and bicarbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. Organic bases from which salts of disclosed acids may be prepared are amines and amino acids, the basicity of which is sufficient enough to produce a stable salt, and which are suitable for use in medical purposes (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. Besides, salts can be prepared using tetraalkylammonium hydroxides, such as holine, tetramethylammonium, tetraethylammonium, and the like. Basic aminoacids, i.e. lysine, ornithine and arginine, may be used as aminoacids.

“Medicament (drug product, medicinal product)” - is a compound (or a mixture of compounds as a pharmaceutical composition) in the form of tablets, granules, capsules, injections, ointments and other ready forms intended for restoration, improvement or modification of physiological functions in humans and animals, as well as for treatment and prophylaxis of diseases, for diagnostics, anesthesia, contraception, cosmetology and others.

“Treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a biological disorder and/or at least one of its attendant symptoms. The term “to alleviate” a disease, disorder or condition means reducing the severity and/or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to "treatment" include references to curative, palliative treatment.

“Prophylaxis”, “prophylactic therapy” refers to a set of measures aimed at preventing the onset, eliminating risk factors, or early detecting a disease or disorder, its exacerbation, relapse, complications or other consequences.

In one aspect, the patient, or subject of treatment, or prophylaxis, is a mammal. Examples of the patients include, but are not limited to, a human subject. Said subject may be either male or female, of any age.

The term "disorder" means any condition that would benefit from treatment according to the present invention. The definition of this term includes chronic and acute disorders or pathological conditions that predispose the mammal to the onset of diseases in question. Nonlimiting examples of diseases to be treated include benign and malignant neoplasms, or neoplasms of unspecified nature, including tumors originating from blood cells and lymphoid cells. The example can be: bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leucosis, lymphoma, non-Hodgkin lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular cancer, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large-cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

“Therapeutically effective amount” refers to that amount of the therapeutic agent being administered in the course of treatment which will relieve the severity or eliminate the symptoms of the disease being treated.

As used in the present description and claims that follow, unless otherwise dictated by the context, the words "have", "include," and "comprise" or variations thereof such as "has", "having," "includes", "including", "comprises," or "comprising," will be understood to imply the inclusion of a stated 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 to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Li is a chemical bond or -NH-;

Xi is -CH-, -N- or -C(Re)-; each n, m is independently 0, 1, 2, 3 or 4; each Ri is independently -H; -Hal; - C(Hal)₃; -CN; -NR₇R₈; -C(0)NR₉Rio; -C(O)ORu; - C(O)Ri2; -ORB; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ru; -(C₃- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4_a;

R2 is -P(O)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; - P(O)((C₃-Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; - P(O)(O(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15c; -P(O)(O(C₃- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R_15e; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several _{radicals R15; -P(O)(O(C3-C6)cycloalkyl)((C3-C6)cycloalkyl), unsubstituted or substituted by one} _{or several radicals R15; -SO2(C1-C6)alkyl, unsubstituted or substituted by one or several radicals} _{R15f; or -SO2(C3-C6)cycloalkyl, unsubstituted or substituted by one or several radicals R15g;} _{R3 is -H; -Hal; -CN; -C(Hal)3; -NR7aRsa; -C(0)NR9aRioa; -C(O)ORua; -C(O)Ri2a; -ORi3a;} _{-(C1-C6)alkyl, unsubstituted or substituted by one or several radicals R16a; -(C3-C6)cycloalkyl,} _{unsubstituted or substituted by one or several radicals Ri6t>; -(Ce-Ci2)aryl, unsubstituted or} _{substituted by one or several radicals R16C; 4-10-membered heteroaryl with 1 or 2 heteroatoms} _{selected from N, S or O, unsubstituted or substituted by one or several radicals R16d;} _{each R4 is independently -H; -Hal; -CN; -NR7bR8b; -C(Hal)3; -C(0)NR9bR10b; -C(O)OR11b;} _{-C(O)R12b; -OR13b; -(C1-C6)alkyl, unsubstituted or substituted by one or several radicals R17a; -} _{(C3-C6)cycloalkyl, unsubstituted or substituted by one or several radicals R17b; 4-10 membered} _{heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one} _{or several radicals RI7C; or -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals} _Riva; _{R5 is:} _{-NR7CRIS; -NR7dRi9; -Wi; -OW2; -NRaW3; -C(0)W4; or -(CH2)W5;} _{wherein each Wi, W2, W3, W4 or W5 is independently -(C3-C6)cycloalkyl, unsubstituted or} _{substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms} _{selected from N, S or O, unsubstituted or substituted by one or several radicals R20,} _{Rs is -Hal, -CN, -C(Hal)3, CH(Hal)2, OHhHal, -NR7eR8c; -(C1-C6)alkyl, unsubstituted or} _{substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0);} _{each R7, R7a, R7b, R7e, Rs, Rsa, Rsb, Rsc, R9, R9a, R9b, Rio, Rioa, Riob is independently -H, -} _{(C1-C6)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -} _{OH, (=0); -(C3-C6)cycloalkyl, unsubstituted or substituted by one or several radicals selected from} _{-Hal, -NH2, -OH, (=0);} _{each R7C, R7d, RB is independently -H, -(C1-C6)alkyl;} _{Ris is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected} _{from -Hal, -OH, -N02, -NR23R24, (=0);} _{R19 is 2- 10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O,} _{unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO2, -} _{NR23R24, (=0);} _{each Rn, R12, R13, Riia, Ri2a, Rua, Rub, Rub, Rub is independently -H, -(C1-C6)alkyl,} _{unsubstituted or substituted by one or several radicals R21, -(C3-C6)cycloalkyl, unsubstituted or} _{substituted by one or several radicals R2ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or} several radicals R_21b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each R₁₄, R_14a, R₁₅, R_15a, R₁₅, R_15a, R_15b, R_15C, R_15d, R_15e, R_15f, R_15g, R₁₆, R_16a, R_16b, R_16C, R_16d, R₁₇, R_17a, R_17b, R_17c, R_17d is independently -Hal, -H, -OH, -NO₂, -NR₂₃R₂₄, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R₂₀ is independently (=0), -NR_7fR_8d, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₂₂, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R_22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_22b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R_7f, R_8d is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R₂₁, R_21a, R_21b, R_21C, R₂₂, R_22a, R_22b R_22C is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -O(C₁-C₆)alkyl, -OH, (=0); each R₂₃, R₂₄ is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR₂₅R₂₆; -(C₂-C₆)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R₂₅, R₂₆, R_25a, R_26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula I, wherein Li is a chemical bond, R₂ is -P(0)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; -P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((C₁-C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅t,; -P(0)(0(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15c; -P(O)(O(C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; - P(O)(O(C₁-C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R_15e; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or

Li is -NH-, R₂ is -SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅f; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g, wherein each R₁₅, R_15a, R₁₅, R_15a, R_15b, R_15e, R_15d, R₁₅e, R₁₅f, R₁₅g is independently -Hal, -H, -OH, - NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl,

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

In another embodiment, the present invention relates to a compound of Formula I:

Xi is -CH-, -N- or -C(Re)-; each n, m is independently 0, 1, 2, 3 or 4; each Ri is independently -H; -Hal; - C(Hal)₃; -CN; -NR₇R₈; -C(0)NR₉Rio; -C(0)0Ru; - C(O)Ri2; -OR13; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R14; -(C3- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals R_14a;

R2 is -P(0)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; - P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; - P(0)(0(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15C; -P(O)(O(C3- C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R_15e; - SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R_15r; P(O)(O(Ci- C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g;

R₃ is -H; -Hal; -CN; -C(Hal)₃; -NR_7aRs_a; -C(0)NR_9aRio_a; -C(O)ORu_a; -C(O)Ri_2a; -ORi_3a; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6t>; -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Ri6_C; 4-10-membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals Riea; each R4 is independently -H; -Hal; -CN; -NR?bRsb; -C(Hal)3; -C(0)NR9bRiob; -C(O)ORub; -C(O)Ri2b; -ORi3b; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a; - (C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Rnb; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals RI_7C; or -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Riva;

R5 is:

-NR₇CRIS; -NR_7dRi9; -Wi; -OW₂; -NR_aW₃; -C(0)W₄; or -(CH₂)W₅; wherein each Wi, W₂, W3, W₄ or W5 is independently -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20;

Rs is -Hal, -CN, -C(Hal)3, CH(Hal)₂, CH₂Hal, -NR_7eR8c; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R₇, R_7a, R₇b, R_7e, Rs, Rs_a, Rsb, Rsc, R9, R_9a, R₉b, Rio, Rioa, Riob is independently -H, - (C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, - OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R_7C, R₇d, Ra is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -N0₂, -NR23R₂₄, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R₂₄, (=0); each Rn, R12, R13, Riia, Ri2a, Ri3a, Rub, Ri2b, Ri3b is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Riia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each R14, R14a, R₁₅, R₁₅a, R₁₅, R₁₅a, R₁₅b, R₁₅C, R₁₅d, R₁₅e, R₁₅f, R₁₅g, R16, R16a, R16b, R16c, Ried, R17, Ri7a, Ri7b, Ri7c, Rnd is independently -Hal, -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R21, R2ia, R2ib, R21C, R22, R22a, R22 R22C is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -O(C₁-C₆)alkyl, (=0), -OH; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula I, wherein Li is a chemical bond, R2 is -P(0)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; -P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((C₁-C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; -P(0)(0(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅e; -P(O)(O(C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; - P(O)(O(C₁-C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅e; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or

Li is -NH-, R2 is -SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅f; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g, wherein each R₁₅, R_15a, R₁₅, R₁₅a, R₁₅b, R₁₅e, R₁₅d, R₁₅e, R₁₅f, R₁₅g is independently -Hal, -H, -OH, - NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl.

In another embodiment, the present invention relates to a compound of Formula 1.1

Xi is -CH-, -N- or -C(Re)-; m is 0, 1, 2, 3 or 4; each Ria, Rib, Ric, Rid is independently -H; -Hal; - C(Hal)3; -CN; -NR?Rs; -C(0)NR9RIO; - C(0)0Rn; -C(O)Ri2; -OR13; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R14; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4_a;

R2 is -P(0)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; - P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; - P(0)(0(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15C; -P(O)(O(C3- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅e; - SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅r; P(O)(O(Ci- C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g;

R5 is:

Rs is -Hal, -CN, -C(Hal)3, CH(Hal)₂, CH₂Hal, -NR_7eR8c; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R₇, R_7a, R₇b, R_7e, Rs, Rs_a, Rsb, Rsc, R9, R_9a, R₉b, Rio, Rioa, Riob is independently -H, - (C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, - OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R_7C, R₇d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -N0₂, -NR23R₂₄, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R2U (=0); each Rn, R12, R13, Riia, Ri_2a, Rua, Rub, Rub, Rub is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R.2i_a, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R.2ib, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each R14, R14a, R₁₅, R₁₅a, R₁₅, R₁₅a, R₁₅b, R₁₅C, R₁₅d, R₁₅e, R₁₅f, R₁₅g, R16, R16a, R16b, R16C, Ried, Ri7, Ri7a, Ri7b, Ri7c, Rnd is independently -Hal, -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R21, R2ia, R2ib, R21C, R22, R22a, R22 R22C is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -O(C₁-C₆)alkyl, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula 1.2

Xi is -CH-, -N- or -C(Re)-; n is 0, 1, 2, 3 or 4; each Ri is independently -H; -Hal; - C(Hal)₃; -CN; -NR₇R₈; -C(0)NR₉Rio; -C(O)ORu; - C(O)Ri2; -OR13; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R14; -(C3- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4_a;

R2 is -P(O)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; - P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅t,; - P(O)(O(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15C; -P(O)(O(C3- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅e; - SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅r; -P(O)(O(Ci- C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g;

R₃ is -H; -Hal; -CN; -C(Hal)₃; -NR_7aR_8a; -C(0)NR_9aRio_a; -C(O)ORu_a; -C(O)Ri_2a; -ORi_3a; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6t>; -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Ri6_C; 4-10-membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals Rir.ci; each R_4a, R4b, R4c, R4d is independently -H; -Hal; -CN; -NR^Rsb; -C(Hal)₃; -C(0)NR₉bRiob; -C(O)ORnb; -C(O)Ri2b; -ORnb; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri₇b; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals RI_7C; or -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Rna;

Rs is:

-NR_7CRI₈; -NR_7dRi₉; -Wi; -OW₂; -NR_aW₃; -C(0)W₄; or -(CH₂)W₅; wherein each Wi, W2, W3, W4 or W5 is independently -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20;

Rs is -Hal, -CN, -C(Hal)₃, CH(Hal)₂, OHhHal, -NR_7eR_8c; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R7, R?a, R?b, R?e, Rs, Rsa, Rsb, Rsc, R9, R9a, R%, Rio, Rioa, Riob is independently -H, - (C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, - OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R?_c, R?d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -N0₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R24, (=0), -(C₁-C₆)alkyl; each Rn, R12, R13, Riia, Ri2a, Ri3a, Rub, Ri2b, Ri3b is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R₂ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R₂ib, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R₂I_C; each R14, R14a, R₁₅, R₁₅a, R₁₅, R₁₅a, R₁₅b, R₁₅C, R₁₅d, R₁₅e, R₁₅f, R₁₅g, R16, R16a, R16b, R16c, Ried, R17, Ri7a, Ri7b, Ri7c, Rnd is independently -Hal, -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R₂2a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R₂2b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R₂2_C; each R?f, Rxd is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R21, R₂ia, R2ib, R21C, R22, R₂2a, R22b, R22C is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, -O(C₁-C₆)alkyl, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R₂5a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula 1.3

or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Li is a chemical bond, -NH-;

Xi is -CH-, -N-, -C(R₆)-; each Ria, Rib, Ric, Rid is independently -H; -Hal; - C(Hal)3; -CN; -NR₇R₈; -C(0)NR9RIO; - C(O)ORn; -C(O)Ri2; -ORr,; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ru; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4_a;

R2 is -P(O)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; - P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; - P(O)(O(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15C; -P(O)(O(C3- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅e; - SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅r; P(O)(O(Ci- C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; - P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g;

R₃ is -H; -Hal; -CN; -C(Hal)₃; -NR_7aR_8a; -C(0)NR_9aRio_a; -C(O)ORu_a; -C(O)Ri_2a; -ORi_3a; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6t>; -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Ri6_C; 4-10-membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals ir.ci; each R_4a, R4b, R4c, R4d is independently -H; -Hal; -CN; -NR^Rsb; -C(Hal)3; -C(0)NR9bRiob; -C(O)ORnb; -C(O)Ri2b; -ORnb; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri₇b; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals RI_7C; or -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Rna;

Rs is:

-NR_7CRIS; -NR₇dRi9; -Wi; -OW₂; -NR_aW₃; -C(O)W₄; or -(CH₂)W₅; wherein each Wi, W2, W₃, W₄ or W5 is independently -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20;

Rs is -Hal, -CN, -C(Hal)₃, CH(Hal)₂, CHiHal, -NR_7eRsc; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R₇, R_7a, R₇b, R_7e, Rs, Rs_a, Rsb, Rsc, R9, Rg_a, R9b, Rio, Rioa, Riob is independently -H, - (C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, - OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R_7C, R₇d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -N0₂, -NR₂₃R₂₄, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR₂₃R₂₄, (=0), -(C₁-C₆)alkyl; each Rn, R12, RI₃, Rn_a, Ri2a, Ri_3a, Rub, Rub, Rub is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2i_a, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each RI₄, R_44a, R₁₅, R_15a, R₁₅, R₁₅a, R₁₅b, R₁₅e, R₁₅a, R₁₅e, R₁₅f, R₁₅g, Rie, Ri6a, Ri6b, Ri6c, Ried, R17, Ri_7a, Ri-zb, R17C, Ri7d is independently -Hal, -H, -OH, -NO₂, -NR2₃R2₄, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R20 is independently (=0), -NR₇fRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22_a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R21, R2ia, R2ib, R21C, R22, R22a, R22b, R22C is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, -O(C₁-C₆)alkyl, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C₂-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In one embodiment, the present invention relates to a compound of Formula I, wherein Re is -Hal, -CN, -C(Hal)₃, CH(Hal)₂, CH₂Hal.

In one embodiment, the present invention relates to a compound of Formula I, wherein Re is -Hal, -CN, -CF3, CHF₂, CHCh, CHBr₂, CH₂F.

In another embodiment, the present invention relates to a compound of Formula I, wherein each Ri is independently Hal; -C(Hal)3, -O(CHah); -CN; -O(C₁-C₆)alkyl, -O(CH₂)₂O-(CI- Ce)alkyl.

In another embodiment, the present invention relates to a compound of Formula I, wherein each Ri is independently -F, -Cl, -Br, -CF₃, -CCI3, -O(CF₃), -O(CC1₃), -OCH3, -OCH2CH3, - O(CH₂)₂O-CH3, -O(CH₂)₂O-CH2-CH3.

In another embodiment, the present invention relates to a compound of Formula I, wherein R₂ is -P(O)((C₁-C₆)alkyl)₂, -P(O)((C3-C₆)cycloalkyl)₂, -P(O)((C₁-C₆)alkyl))((C3-C₆)cycloalkyl)), -P(O)(O(C₁-C₆)alkyl)₂, -P(O)(O(C3-C₆)cycloalkyl)₂, -P(O)(O(C₁-C₆)alkyl)((C3-C₆)cycloalkyl), P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), P(O)(O(C₃- C₆)cycloalkyl)((C₃-C₆)cycloalkyl), -SO₂(C₁-C₆)alkyl.

In one embodiment of the invention, R₂ is -P(O)(CH3)₂, P(O)(CH₂CH3)₂, - P(O)(CH3)(CH₂CH3), -P(O)(cyclopropyl)₂, -P(O)(CH3)(cyclopropyl),

P(O)(CH₂CH₃)(cyclopropyl), -P(O)(OCH₃)₂, -P(O)(OCH₂CH₃)₂, -P(O)(OCH3)(OCH₂CH₃), - P(O)(OCH3)(CH₃), -P(O)(OCH3)(CH₂CH₃), -P(O)(OCH₂CH3)(CH₃),

P(O)(OCH₂CH3)(CH₂CH₃), -P(O)(OCH₃)(cyclopropyl), -P(O)(OCH₂CH₃)(cyclopropyl), - SO₂CH₃, SO₂CH₂CH₃.

In another embodiment, the present invention relates to a compound of Formula I, wherein R₃ is -H; -Hal; -C(Hal)₃, -CN; -NR₇aRsa; -C(0)NR₉aRioa; -C0(0)Ru_a; -C(O)Ri_2a; -ORi_3a; -(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6t>; phenyl, unsubstituted or substituted by one or several radicals Ri6c, wherein each R_7a, Rsa, R9a, Rioa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rua, Ri2a, Ri3a, is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2i_a, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each Ri6a, Ri6b, Ri6c, R21, R2ia, R2ib, R21C is independently -H, -OH, - NO₂, -NR23R24, -(C 1- Ce)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0), -O(C₁-C₆)alkyl; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula I, wherein R₃ is -H; -Hal; -C(Hal)₃, -CN; -NR_7aRsa; -C(0)NR_9aRio_a; -C0(0)Ru_a; -C(O)Ri_2a; -ORi_3a; -(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6b; phenyl, unsubstituted or substituted by one or several radicals Ri6c, wherein each R_7a, Rsa, R_9a, Rioa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rua, Ri2a, Ri3a, is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2i_a, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each R^a, Ri6b, Ri6c, R21, R2ia, R2ib, R21C is independently -H, -OH, - NO₂, -NR23R24, -(C 1- Ce)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0), -O(C₁-C₆)alkyl; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In one embodiment of the invention, R3 is -CN; phenyl, unsubstituted or substituted by one radical Ri6c, selected from prop-2-enamidyl], 3-hydroxypropanamidyl, 3- (dimethylamino)propanamidyl, wherein Ri6_C is -Hal, -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0).

In another embodiment, the present invention relates to a compound of Formula I, each R4 is independently -H; -Hal; -C(Hal)₃; -CN; -NR_7bRx_b; -C(0)NR₉bRiob; -C(O)Ru_b; -C(O)ORi2b; - ORi3b; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a, wherein each R_7b, Rsb, R%, Riob is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rub, Ri2b, Rob is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each Ri7a, R21, Riia, R2ib, R21C is independently -H, -OH, -NO₂, -Hal, -NR23R24, -(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0), -O(C₁-C₆)alkyl; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula I, each R4 is independently -H; -Hal; -C(Hal)₃; -CN; -NR_7bR_xb; -C(0)NR₉bRiob; -C(0)Ru_b; -C(0)0Ri2b; - 0Ri3b; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a, wherein each R₇b, Rsb, R%, Riob is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rub, Ri2b, Rob is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each Rna, R21, R2ia, R2ib, R21C is independently -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, -O(Ci- C₆)alkyl, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl.

In one embodiment of the invention, each R4 is independently -H; -(C₁-C₆)alkyl, -O(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -OH, - NO₂, - NH₂.

In another embodiment, the present invention relates to a compound of Formula I, wherein R5 is:

-NR_7CRIS; -NR₇dRi9; -Wi; -0W₂; -NR_aW₃; -C(0)W₄; or -(CH₂)W₅; wherein each Wi, W2, W3, W4 or W5 is independently

-(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20, selected from

5-7 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20, selected from

w ere n p s , , or ; each Yi, Y2 is independently CH2, CHR20, C(R2o)₂, NH, NR20, S or O; each R?_c, R?d Ra is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R24, (=O); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsd is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R22, R22a, R22b, R22C is independently -H, -OH, - NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

wherein q is selected from 0,1 or 2, the total number of cyclic system substituents being selected from 0,1,2 or 3; each Yi, Y2 is independently CH2, CHR20, C(R2o)₂, NH, NR20, S or O; each R_7c, R₇d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R24, (=O); each R20 is independently (=0), -NR₇fRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rxd is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R22, R22a, R22b, R22C is independently -H, -OH, - NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl.

wherein p is 0, 1, 2 or 3; each R?_c, R?d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R24, (=O); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R₂₂a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R₂₂b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R_22c; each R?f, Rsd, Ra is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R22, R₂2a, R₂2b, R22C is independently -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R₂₃, R₂₄ is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR₂₃R₂6; -(C₂-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR₂5aR₂6_a; each R₂5, R₂6, R₂s_a, R₂6_a is independently -H, -(C₁-C₆)alkyl;

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

In another embodiment, the present invention relates to a compound of Formula I, wherein Rs is:

-NR_7CRIS; -NR₇dRi9; -Wi; -0W₂; -NR_aW₃; -C(O)W₄; or -(CH₂)W₅; wherein each Wi, W₂, W₃, W₄ or W5 is independently

wherein q is selected from 0,1 or 2, the total number of cyclic system substituents being selected from 0,1,2 or 3; each R?_c, R?d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, - NR23R24, (=O), -(C₁-C₆)alkyl; each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R₂₂a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R₂₂b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R_22c; each R?f, Rxd is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R22, R₂2a, R₂2b, R22C is independently -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R₂5a, R₂6a is independently -H, -(C₁-C₆)alkyl.

In one embodiment of the invention, R5 is

[2-(dimethylamino)ethyl](methyl)amino, 4-(4-methylpiperazine- 1 -yl)piperidine- 1 -yl, 4- methylpiperazine-l-yl, 4-(dimethylamino)piperidine-l-yl, 4-morpholine-l-yl, 4-m ethyl- 1,4- diazepan-l-yl, l-isopropylpiperidine-4-yl, (l-methylpiperidine-4-yl)oxy, (l-methylpiperidine-3- yl)amino, (l-methylpiperidine-4-yl)amino, methyl(l-methylpiperidine-4-yl)amino, (4- methylpiperazine- 1 -yl)methanone, (4-m ethylpiperazine- 1 -yl)m ethyl, (2-methyl-2- azabicyclo[2.2.1]heptane-5-yl)oxy, (l-methylpyrrolidine-3-yl)oxy, (l-methylpipiridine-4-yl)oxy, 1 -acetylpiperidine- 1-yl, piperidine- 1-yl, l-(2-(dimethylamino)-2-oxoethyl)piperidine.

Compounds, described in the present invention, may be obtained as, and/or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 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-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-3-hydroxy-2-ene-l-carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tert-butyl acetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

The corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described in the present patent can be conveniently prepared or formed during the processes described in the present invention. In addition, the compounds provided in the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided in the present invention. Compounds described in the present invention may be provided in various forms, including but not limited to, amorphous forms, milled forms and nano-particulate forms. In addition, compounds described in the present invention include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, different density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause one crystal form to dominate.

The screening and characterization of the pharmaceutically acceptable salts, polymorphs and/or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address to analysis of thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, to determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravi -metric and infrared analysis (TG/IR). Crystallographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman (combinational scattering), FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive x-ray analysis (EDX), environmental scanning electron microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

In another embodiment of the present invention relates to the compounds selected from the group including:

The present invention also relates to a method for inhibiting of biological activity of epidermal growth factor receptor (EGFR) in a subject, comprising contacting the EGFR kinase domain with the compound described herein.

EGFR-inhibiting compounds may be used to manufacture drug products intended for treating 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, alone or partially, by EGFR activity, for example, oncological diseases. Examples of oncological diseases that may be amenable to treatment using the above compounds include, but are not limited to, bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leucosis, lymphoma, non-Hodgkin lymphoma, Hodgkin's lymphoma, lung cancer (for example, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large-cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

In one embodiment, the present invention relates to a pharmaceutical composition that comprises at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition that comprises a therapeutically effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat a disease or disorder mediated by the activation of EGFR.

In another one embodiment, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat a disease or disorder mediated by the activation of EGFR with a L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.

In another one embodiment of the present invention, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat oncological diseases including bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leucosis, lymphoma, non-Hodgkin lymphoma, Hodgkin's lymphoma, lung cancer (for example, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large-cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

In another one embodiment of the present invention, the pharmaceutical composition comprising compounds of the present invention is intended to prevent or treat an oncological disease, wherein the oncological disease is non-small cell lung cancer.

The pharmaceutical composition of the present invention comprises, by way of example, from about 5 wt% to about 100 wt% of active ingredients, preferably from about 10 wt% to about 60 wt% of active ingredients. It is to be understood that each dosage unit may not comprise an effective amount of an active ingredient or ingredients, because the sufficient effective amount may be achieved by administering multiple dosage unit forms. A typical composition is prepared by mixing the compound of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal. In general, safe solvents are aqueous solvents such as water and other solvents that are soluble or miscible in water. Suitable aqueous solvents include water, as the main ingredient, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The compositions may also include one or more buffers, stabilizing agents, surfactants, wefting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug product (i.e., compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e. drug product). The pharmaceutical compositions should preferably be manufactured in compliance with the GMP (Good Manufacturing Practice) requirements.

The pharmaceutical compositions also include solvates and hydrates of compounds of the present invention, or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent).

The pharmaceutical compositions of the invention may be formulated for an oral route administration. Oral administration may involve swallowing, so that the compound enters the -gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; granules; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches. More preferred formulations for oral administration comprise tablets, granules, and capsules.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, made of gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet. The pharmaceutical compositions of the invention may also be administered parenterally. As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, inter alia, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intrasynovial injection or infusions; and kidney dialytic infusion techniques. Intratumoral delivery, e.g. intratumoral injection, may also be advantageous. Regional perfusion is also contemplated.

Formulations of pharmaceutical compositions suitable for parenteral administration typically comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, inter alia, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and the like.

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, or as a mixed component particle, for example, mixed with a suitable pharmaceutically acceptable excipient) from a dry powder inhaler, as an aerosol pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, or as nasal drops.

The pressurized container, pump, spray, atomizer, or nebuliser typically contains a solution or suspension of the compound of the present invention comprising, for example, a suitable agent for dispersing, solubilising, or extending release of the active ingredient, a propellant as solvent.

Prior to use as dry powder or suspension, the drug product is typically micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying. Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the present invention, a suitable powder base and a performance modifier.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain a suitable dose of the compound of the present invention per actuation and the actuation volume may for example vary from 1 pL to 100 pL.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, may be added to those formulations of the present invention intended for inhaled/intranasal admini strati on.

Formulations may be formulated to be immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

In one embodiment, the present invention relates to a method for treating diseases or disorders mediated by the activity of EGFR that comprises administering, in a therapeutically effective amount, any compound described above, or a pharmaceutical composition of the present invention to a subject in need of such treatment.

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

In another one embodiment, the invention relates to the method for treating described above, wherein the disease or disorder mediated by the activit7 of EGFR is oncological diseases. In another one embodiment, the invention relates to the method for treating described above, wherein the oncological diseases are selected from the group comprising bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leucosis, lymphoma, non-Hodgkin lymphoma, Hodgkin's lymphoma, lung cancer (for example, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large-cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

In another one embodiment, the invention relates to the method for treating described above, wherein the oncological disease is non-small cell lung cancer.

In one embodiment, the present invention relates to use of the compound of the present invention or the pharmaceutical composition described above for the treatment of a disease or disorder mediated by the activity of EGFR in a subject in need of such treatment. In another one embodiment, the present invention relates to the use described above, wherein said disease or disorder is the disease or disorder mediated by the activity of EGFR with a L858R mutation and/or a T790M mutation and/or an exon 19 deletion and/or a C797S mutation.

In another one embodiment, the present invention relates to the use described above, wherein the disease or disorder mediated by the activit7 of EGFR is oncological diseases. In another one embodiment, the invention relates to the use described above, wherein the oncological diseases are selected from the group comprising bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leucosis, lymphoma, non-Hodgkin lymphoma, Hodgkin's lymphoma, lung cancer (for example, non-small cell lung cancer), hepatocellular cancer, esophageal cancer, stomach cancer, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, endometrial cancer, renal cancer, liver cancer, anaplastic large-cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, hematological malignant tumors.

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

The compounds of the invention may be administered alone or in combination with one or more other drug products or antibodies (or in any combination thereof). The pharmaceutical compositions, methods and use of the invention thus also encompass embodiments of combinations (co-admini strati on) with other active agents.

As used herein, the terms “co-administration”, “co-administered” and “in combination with” referring to the compounds with one or more other therapeutic agents, is intended to mean, and does refer to and include the following:

• simultaneous administration of such combination of the compound of the invention and therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,

• simultaneous administration of such combination of the compound of the invention and therapeutic agent to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,

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

• sequential administration of such combination of the compound of the invention and therapeutic agent to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlappingly released at the same and/or different times to said patient, wherein each part may be administered by either the same or a different route.

As well known to those skilled in the art, therapeutically effective dosages may vary when the drug products are used in combination treatment. Methods for experimentally determining therapeutically effective dosages of drug products and other agents for use in combination treatment regimens have been described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described in the literature. Combination treatment further includes periodic treatments that start and stop at various times in accordance with the patient treatment plan. For combination therapy described in the present patent, dosages of co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition or disorder being treated and so forth.

The antitumor treatment described above can be used either as a stand-alone therapy, or in combination with surgery, or radiotherapy, or drug therapy. Such therapy may be administered concurrently, simultaneously, sequentially or separately with treatment with the compound of the invention and may include one or more agents of the following categories of anti-tumour agents: antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, chlormethine, melphalan, chlorambucil, busulfan, treosulfan, temozolomide, bendamustine, prospidine, spirobromine, prednimustine, estramustine, paphencyl, lofenal, ifosfamide, mafosfamide, trofosfamide, glufosfamide, and nitrosoureas, including carmustine, lomustine, nimustine, fotemustine, aranose, streptozocin); antimetabolites (for example, gemcitabine, fluorouracil, floxuridine, tegafur, raltitrexed, methotrexate, trimetrexate, pemetrexed, pralatrexate, calcium levofolinate, cytosine arabinoside, hydroxyurea, azathioprine, cladribine, fludarabine, pentostatin, mercaptopurine, nelarabine, thioguanine, fopurin, azacitidine, capecitabine, fludarabine, cladribine, nelarabine, azathioprine, clofarabine, cytarabine, enocitabine, carmofur, gemcitabine, sapacitabine, elacytarabine, doxifiuridine); antitumor antibiotics (for example, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin, dactinomycin, mitramycin, daunurobicin, carubicin, epirubicin, valrubicin, zorubicin, aclarubicin, pirarubicin, nemorubicin, amrubicin, zinostatin, streptozocin, mitoxantrone); antimitotic agents (for example, vinca alkaloids, such as vincristine, vinblastine, vinflunine, vindesine and vinorelbine, taxoids, such as paclitaxel and docetaxel, cabazitaxel, tezetaxel, polo kinase inhibitors); and topoisomerase inhibitors (for example, epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan, belotecan, voreloxin, amonafide and camptothecin); cytostatic agents such as anti-estrogens (for example, tamoxifen, clostilbegyt, fulvestrant, toremifene, raloxifene, droloxifene and iodoxifen), antiandrogens (for example, bicalutamide, flutamide, nilutamide, topilutamide, enzalutamide and cyproterone acetate, chlormadinone), luteinizing hormone- releasing hormone (LHRH) antagonists or LHRH agonists (for example, goserelin, leuprorelin and buserelin), progestogens (for example, chlormadinone, gestonorone caproate, medroxyprogesterone, megestrol acetate), aromatase inhibitors (for example, anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase (for example, finasteride, dutasteride, epristeride); anti-invasive agents (for example, c-Src family kinase inhibitors (for example, saracatinib, dasatinib and bosutinib), metalloproteinase inhibitors (for example, marimastat), inhibitors of urokinase activator receptor function (for example, plasminogen or anti- heparanase antibodies); growth factor inhibitors: for example, such inhibitors include anti -growth factor antibodies and anti-growth factor receptor antibodies (for example, trastuzumab, panitumumab, cetuximab, and any anti-growth factor/anti-growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology /haematology, 2005, Vol. 54, p. 11-29); such inhibitors also include tyrosine kinase inhibitors, including inhibitors of the epidermal growth factor family (for example, 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 insulin-like growth factor family; inhibitors of the platelet-derived growth factor family, such as imatinib, nilotinib; serine/threonine-kinase inhibitors (for example, Ras/Raf pathway inhibitors, such as farnesyl transferase inhibitors, for example sorafenib, tipifamib, and lonafarnib), MEK- and/or AKT-kinase pathway 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 (for example, barasertib (AZDI 152), danusertib (PHA- 739358), tozasertib (VX-680), MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example, bevacizumab, vandetanib, vatalanib, sunitinib, axitinib, pazopanib, crizotinib and cediranib (AZD2171), linomide, integrin avp3 function inhibitors, angiostatin, endostatin, thalidomide, everolimus, sirolimus, itraconazole, suramin, semaxanib, thrombospondin, ramucirumab, tasquinimod, ranibizumab, sorafenib, compounds disclosed in international applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354); vascular-damaging agents (for example, combretastatin A4, ombrabulin, and compounds disclosed in international applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; an endothelin receptor antagonist (for example, bosentan, sitaxentan, ambrisentan, BQ-123, BQ- 788, macitentan, tezosentan, zibotentan, atrasentan); antisense therapies (for example, those which are directed to the targets listed above, such as ISIS 2503, anti-ras antisense, anti-EGFR antisense, custirsen, apatorsen, ISIS-STAT3Rx (ISIS 481464/ AZD9150), ISIS-ARRx (AZD5312), Trabedersen (AP 12009), EZN-2968, LErafAON-ETU); gene therapy approaches, including, for example, approaches to replace aberrant genes (for example, aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme), and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including, for example, checkpoint inhibitors, such as PD-1/PD-L1 (nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, pidilizumab, etc.), and drugs that target CTLA-4 (including ipilimumab, tremelimumab), OX-40, VISTA, ICOS, TIGIT, LAG-3, 4-1BB, GITR, CD40, CCR4, etc.; other ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4, interleukin 15 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine- transfected dendritic cells, approaches using cytokine-transfected tumour cell lines, approaches using anti -idiotypic antibodies, approaches to reduce functions of immunosuppressive cell, such as regulatory T-cells, myeloid suppressor cells or IDO (indoleamine 2,3-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines consisting of proteins or peptides derived from tumour-associated antigens such as NY-ESO-1, MAGE-3, WT1 or Her2/neu.

Thus, in another embodiment of the invention, there is described a pharmaceutical product comprising a compound of formula (I) or pharmaceutically acceptable salt, solvate or stereoisomer thereof as defined hereinbefore, in combination with an anti-tumour agent as defined hereinbefore, intended for the conjoint treatment of cancer.

Dosage regimens may be adjusted to provide the optimum 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 as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate peroral compositions in a unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients/subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Specification for the unit dosage forms of the invention is typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.

Thus, a skilled artisan would appreciate, based upon the disclosure provided herein, that the doses and dosage regimen are adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient. Thus, while certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.

It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Furthermore, it is to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the compositions, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed compositions. Furthermore, the dosage regimen with the compositions of the present invention may be based on a variety of factors, including the type of disease, age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound of the present invention employed. Thus, the dosage regimen may vary widely, but can be determined routinely 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 intra-patient dose-escalation as determined by a qualified specialist. Methods for determining appropriate dosage and regimen are well-known in the art and would be understood by a skilled artisan once provided the ideas disclosed herein.

As a rule, standard daily dosage for an adult human is typically in the range from 0.02 mg to 5000 mg or from about 1 mg to about 1500 mg.

Once improvement of the patient’s conditions has occurred, a maintenance dose is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients may be however required periodic treatment on a long-term basis upon any relapse of symptoms.

The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. These dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disorder or condition to be treated, the method of administration, the requirements of the individual subject, the severity of the disorder or condition being treated, and the judgment of the physician.

The following examples are provided for better understanding of the invention. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

All publications, patents, and patent applications cited in this specification are incorporated herein by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments.

Examples

List of abbreviations:

2-MeTHF - 2-methyltetrahydrofuran

THF - tetrahydrofuran

PTSA - para-toluenesulfonic acid

Pd(dppf)C12 - [1,1 '-Bis(diphenylphosphino)ferrocene]palladium(II)chloride

XPhos - 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Pd2(dba)3 - tris(dibenzylideneacetone)dipalladium(0)

XantPhos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

DIPEA - diisopropylethylamine

TEA - triethylamine

TBAF - tetrabutylammonium fluoride

//-BuLi - //-butyllithium

TMEDA - A¹, A¹, A², A² -tetramethylethylenediamine

NIS - A-iodosuccinimide

NBS - A-bromosuccinimide

LiHMDS - lithium hexamethyldisilazane

DCM - dichloromethane NMP - A-methylpyrrolidone

DMF - dimethylformamide

RM - reaction mass

R.t. - room temperature

DBU - l,8-diazabicyclo[5.4.0]undec-7-ene

LDA - lithium diisopropylamide

Rac-BINAP - ([l,l'-binaphthalene-2,2'-diyl)bis(diphenylphosphine)

EtO Ac - ethyl acetate

TFA - trifluoroacetic acid

STAB - sodium triacetoxyborohydride

MeOH - methanol

MTBE - tert-butyl methyl ether

HBTU - 3-[bis(dimethylamino)methyliumyl]-3J/-benzotriazol-l-oxide hexafluorophosphate

B2pin2 - bis(pinacolato)diborane

MeCN - acetonitrile

EtOH - ethanol

AcOH - acetic acid

KOAc - potassium acetate

Example 1. Method for preparation of compound la.

_

Solution of la_l (10.0 g, 0.069 mol) in 2-MeTHF (33 ml) was added at 20 °C for 20 min to a solution of methylmagnesium iodide in 2-MeTHF (40 ml, 0.213 mol) obtained from Mg (5.85 g, 0.241 mol) and iodomethane (14 ml, 0.213 mol). After 1 hour, a glacial solution of K2CO3 was added to the reaction mass. The resulting suspension was left to mix overnight. The precipitate was filtered, washed with MeOH and the resulting solution was concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using DCM/MeOH as eluent. Yield of 1 was 4.5 g (84%).

Example 1.1 Method for preparation of compound lb.

lb_l Compound lb was prepared similarly to Example 1 from lb_l and ethylmagnesium bromide, with a yield of 3.4 g (91%).

Example 1.2 Method for preparation of compound Id.

Id 1 Id

Compound Id was prepared similarly to Example 1 from ld_l and cyclopropylmagnesium bromide, with a yield of 2.4 g (52%).

Example 2. Method for preparation of compound 2.

Step 1. Preparation of compound 2_2.

N¹, N¹ ,N² -trimethylethane- 1,2-diamine (7.68 g, 0.07 mol) was added to a solution of 2_1 (10 g, 0.07 mol). The resulting mixture was mixed at a temperature of 80° C for 10 h. Hexane was added to the reaction mixture, the precipitate was filtered and dried. Yield of 2_2 was 15.6 g (99%).

Step 2. Preparation of compound 2_3.

Aqueous suspension of Ni-Raney (8 ml) was added to a solution of 2_2 (15.6 g, 0.06 mol) and hydrazine hydrate (33.2 g, 0.66 mol) in EtOH (100 ml). RM was stirred overnight. RM was filtered, washed with EtOH and concentrated on a rotary evaporator. Yield of 2_3 was 12.8 g (99%).

Step 3. Preparation of compound 2.

Tert-butyl nitrite (4.36 g, 0.04 mol) was slowly added at -10 °C to a solution _Of 2_3 (7.78 g, 0.04 mol) and HBF4 (25.5 g, 0.14 mol) in THF (120 ml). After 1 hour, the precipitate was filtered, washed with EtOAc and dried. The resulting compound was dissolved in MeCN (120 ml), Ehpi (9.39 g, 0.04 mol) and pyridine (11.6 g, 0.14 mol) were added for 1 min at -25°C. RM was brought to r.t. and left to stir overnight. The resulting solution was concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/EtsN as eluent. Yield of 2 was 6.85 g (62%).

Example 3. Method for preparation of compound 3b.

Step 1. Preparation of compound 3b_2.

DIPEA (15.5 ml, 0.10 mol) was added in a nitrogen atmosphere to a solution of 2_1 (5.46 g, 0.04 mol) and piperidin-4-one (7.21 g, 0.05 mol) in DMF (30 ml). RM was stirred at 80°C for 5 hours and poured into water. Precipitate was filtered, washed with water (50 ml), diethyl ether, and dried. Yield of 3b_2 was 7.72 g (92%).

Step 2. Preparation of compound 3b_3.

Solution of 3b_2 (3.72 g, 0.02 mol), 1 -methylpiperazine (3.59 ml, 0.03 mol), AcOH (1 ml, 0.02 mol) in DCM (56 ml) was mixed at r.t. for 1 h. STAB (7.12 g, 0.03 mol) was added, and the mixture was stirred for 16 h. STAB (7.12 g, 0.03 mol) was added portionwise for 4 h. Saturated NH4CI solution was added to the suspension. The resulting suspension was washed with DCM, the water layer was neutralized, and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The yield of 3b_3 was 4.88 g (99%).

Step 3. Preparation of compound 3b_4.

Solution of 3b_3 (0.91 g, 2.94 mmol) in MeOH (20 ml) in the presence of 5% Pd/C (5 mol%) was mixed for 1 h in a hydrogen atmosphere (5 atm). RM was filtered, washed with MeOH and concentrated on a rotary evaporator. The yield of 3b_4 was 0.8 g (99%).

Step 4. Preparation of compound 3b.

PTS A in AcOH (21 ml, 0.07 mol) was added to a solution of 3b_4 (3.00 g, 9.84 mmol) in MeCN (10 ml). Solution of tert-butyl nitrite (2.15 ml, 0.2 mol) in MeCN (10 ml) was added at 0°C to the resulting solution. After 3 hours, a solution of KI (12.2 g, 0.07 mol) in water (15 ml) was added. RM was stirred at 70 °C for 5 hours, poured into an aqueous solution of ISfeCCE, then brought to pH 9 with an aqueous solution of NaOH. Product was extracted using DCM. The combined organic phases were washed with a saturated solution of ISfeSCh, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 3b was 2.7 g (71%).

Example 3.1 Method for preparation of compound 3a.

Compound 3a was prepared similarly to Example 3, step 4 from 3a_l, with a yield of 3.1 g (69%).

Example 3.2 Method for preparation of compound 3c.

Compound 3c was prepared similarly to Example 3, step 4, from 3c_l, with a yield of 1.29 g (59%).

Example 3.3 Method of preparation of compound 3d.

3d_l 3d

Compound 3d was prepared in a similar manner to Example 3, step 4, from 3d_l, yield was 1.38 g (94%).

Example 3.4 Method of preparation of compound 3e.

3e_l 3e

Compound 3e was prepared in a similar manner to Example 3, step 4, from 3e_l, yield of

3e was 0.36 g (40%).

Example 3.5 Method of preparation of compound 3f.

Compound 3f was prepared in a similar manner to Example 3, step 4, from 3f_l, yield was 1.02 g (75%).

Example 3.6 Method of preparation of compound 3n.

3n_4 3n_5 3n

Step 1. Preparation of compound 3n_2.

Compound 3n_2 was prepared in a similar manner to Example 3, step 1, from tert-butyl 5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate, yield was 1.4 g (94%).

Step 2. Preparation of compound 3n_3.

Solution of 4N HC1 in methanol (15 ml) was added to a solution of 3n_2 (1.4 g, 0.004 mol) in 1,4-di oxane (7 ml). RM was mixed at r.t. for 1 h. The resulting solution was concentrated, brought to pH 9-10 with a saturated NazCOs solution, and the product was extracted using DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 3n_3 was 1.0 g (117%). The product was used in the next step without additional purification steps.

Step 3. Preparation of compound 3n_4.

Sodium cyanoborohydride (0.73 g, 3.28 mmol) and AcOH (0.2 ml) were added to a mixture of an aqueous solution of formaldehyde (0.50 ml, 6.7 mmol) and 3n_3 (0.87 g, 3.3 mmol) inMeOH (20 ml), the resulting RM was mixed at 25°C for 3 h. RM was adjusted to pH 12 with an aqueous solution of 3N NaOH, then washed with DCM. The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 3n_4 was 0.68 g (82%).

Step 4. Preparation of compound 3n_5.

Compound 3n_5 was prepared in a similar manner to Example 3, step 3, from 3n_4, yield was 0.66 g (99%).

Step 5. Preparation of compound 3n.

Compound 3n was prepared in a similar manner to Example 3, step 4, from 3n_5, yield was 0.32 g (34%).

Example 3.7 Method of preparation of compound 3o.

Step 1. Preparation of compound 3o_2.

Compound 3o_2 was prepared in a similar manner to Example 3.6, step 1, from tert-butyl (R)-3 -hydroxypyrrolidine- 1 -carboxylate, yield was 8.5 g (79%).

Step 2. Preparation of compound 3o_3.

Compound 3o_3 was prepared in a similar manner to Example 3.6, step 2, from 3o_2, yield was 2.3 g (117%).

Step 3. Preparation of compound 3o_4.

Compound 3o_4 was prepared in a similar manner to Example 3.6, step 3, from 3o_3, yield was 2.2 g (99%).

Step 4. Preparation of compound 3o_5.

Compound 3o_5 was prepared in a similar manner to Example 3, step 3, from 3o_4, yield was 1.5 g (90%).

Step 5. Preparation of compound 3o

Compound 3o was prepared in a similar manner to Example 3, step 4, from 3o_5, yield was 0.91 g (86%).

Example 3.8 Method of preparation of compound 3p.

Step 1. Preparation of compound 3p_2.

Compound 3p_2 was prepared in a similar manner to Example 3.6, step 1, from tert-butyl (S)-3 -hydroxypyrrolidine- 1 -carboxylate, yield of 3p_2 was 6.3 g (77%).

Step 2. Preparation of compound 3p_3.

Compound 3p_3 was prepared in a similar manner to Example 3.6, step 2, from 3p_2, yield was 2.0 g (104%).

Step 3. Preparation of compound 3p_4.

Compound 3p_4 was prepared in a similar manner to Example 3.6, step 3, from 3p_3, yield 3p_4 was 1.7 g (84%).

Step 4. Preparation of compound 3p_5.

Compound 3p_5 was prepared in a similar manner to Example 3, step 3, from 3p_4, yield was 1.5 g (108%).

Step 5. Preparation of compound 3o.

Compound 3o was prepared in a similar manner to Example 3, step 4, from 3p_5, yield was 1.13 g (94%).

Example 3.9 Method of preparation of compound 3q

Step 1. Preparation of compound 3q_2.

HBTU (3.14 g, 8.2 mmol) was added portionwise at r.t. to a solution of 3q_l (1.2 g, 5.1 mmol), AcOH (0.6 ml, 10 mmol), DIPEA (4.5 ml, 26 mmol) in DMF (20 ml). After 3 hours, water was added (150 ml). RM was mixed at r.t. for 1 h. Product was extracted using EtOAc. The combined organic layers were washed with water and a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using DCM as eluent. Yield of 3q_2 was 2.34 g (173%). Product was used in the next step without additional purification steps.

Step 2. Preparation of compound 3q_3.

Compound 3q_3 was prepared in a similar manner to Example 3, step 3, from 3q_2. Product was dissolved in aqueous IM HC1 and washed with DCM. Water layer was adjusted to pH 11 with a solution of 3N NaOH, then washed with DCM. The combined organic layers were washed with a saturated solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 3q_3 1.05 g (101%).

Step 3. Preparation of compound 3q.

Compound 3q was prepared in a similar manner to Example 3, step 3, from 3q_3, yield was 1.1 g (94%).

Example 3.10 Method of preparation of compound 3r.

Step 1. Preparation of compound 3r_2.

Suspension of 3q_l (0.39 g, 2.0 mmol), A,A-dimethyl-2-chloroacetamide (0.50 g, 2.6 mmol) and K2CO3 (1.13 g, 8.0 mmol) in DMA (5 ml) was mixed at r.t. for 16 h. RM was poured into a saturated aqueous solution of NaCl, and the product was extracted using EtOAc. The combined organic layers were washed with water, a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 3r_2 was 0.92 g (149%). Product was used in the next step without additional purification steps.

Step 2. Preparation of compound 3r_3.

Compound 3r_3 was prepared in a similar manner to Example 3, step 3, from 3r_2, yield was 0.36 g (62%).

Step 3. Preparation of compound 3r.

Compound 3r was prepared in a similar manner to Example 3, step 3, from 3r_3, yield was 0.4 g (86%).

Example 4. Method of preparation of compound 3g.

Step 1. Preparation of compound 3g_2.

Pd2(dba)3 (72 mg, 0.07 mmol) and Rac-BINAP (0.14 g, 0.22 mmol) were added in an argon atmosphere to a solution of 3g 1(0.70 g, 3.4 mmol), 1,4-dibromobenzene (2.5 g, 10 mmol) and DBU (0.94 ml, 6.3 mmol) in toluene (7.5 ml). The mixture was mixed at 100 °C for 1 h, sodium tert-butylate (0.85 g, 8.6 mmol) was added, the mixture was mixed at 100 °C for 2 h. The resulting RM was concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using hexane/MTBE as eluent. Yield of 3g was 0.82 g (67%).

Step 2. Preparation of compound 3g_3.

Solution of 3g 2 (0.3 g, 0.8 mmol) in TFA (3 ml) was mixed at 25 °C for 16 h. RM was neutralized with a saturated solution of Na2CO3 and washed with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 3g_3 was 0.2 g (99%).

Step 3. Preparation of compound 3g.

STAB (0.73 g, 3.28 mmol) and MeOH (1 ml) were added to a mixture of an aqueous solution of formaldehyde (0.15 ml, 2.0 mmol) and 3g 3 (0.22 g, 0.82 mmol) in THF (5 ml), the resulting RM was mixed at 25°C for 16 h. RM was adjusted to pH 12 with an aqueous solution of 3N NaOH, then washed with DCM. The combined organic layers were washed with a saturated aqueous solution ofNaCl, the organic layer was dried over lSfeSCU, filtered and concentrated on a rotary evaporator. Yield of 3g was 0.19 g (87%).

Example 4.1. Method of preparation of compound 3h.

Step 1. Preparation of compound 3h_2.

Compound 3h_2 was prepared in a similar manner to Example 4, step 1 from 3h_l, yield was 0.75 g (62%). Step 2. Preparation of compound 3h_3.

Compound 3h_3 was prepared in a similar manner to Example 4, step 2 from 3h_2, yield was 0.20 g (98%).

Step 3. Preparation of compound 3h.

Compound 3h was prepared in a similar manner to Example 4, step 3 from 3h_3, yield was 0.20 g (87%).

Example 4.2. Method of preparation of compound 3i.

_

Compound 3i was prepared in a similar manner to Example 4, step 1 from 3i_l , yield was 0.22 g (33%).

Example 4.3. Method of preparation of compound 3j.

Compound 3j was prepared in a similar manner to Example 4, step 1 from 3j_l, yield was 0.42 g (53%).

Example 5. Method of preparation of compound 4a.

Solution of 4a_l (0.47 g, 1.69 mmol), 2 (0.79 g, 2.45 mmol) and Cs 2CO3 (2.42 g, 7.35 mmol) in a mixture of 1,4-dioxane/water (25 ml, 20: 1) was degassed with argon. Pd(dppf)C12 (0.18 g, 0.2 mmol) was added in an argon atmosphere. The mixture was stirred at 80 °C for 2 h. 4a_l (0.25 g, 0.8 mmol) was added. The mixture was stirred at 80 °C for 4 h. EtOAc was added to the reaction mixture, the organic layer was washed with an aqueous solution of IN HC1. The water layer was neutralized with a saturated solution of Na2CO₃ and washed with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using DCM/MeOH as eluent. Yield of 4a was 0.44 g (55%).

Example 6. Method of preparation of compound 5a.

Step 1. Preparation of compound 5a_2.

NIS (1.75 g, 7.60 mmol) was added to a solution of 5a_l (0.68 g, 5.07 mmol) in DMF (4 ml). RM was stirred at 100 °C for 3 h. Water and a saturated solution of Na2S2C>4 were added to RM while stirring. Precipitate was filtered off, washed with water and dried. Yield of 5a_2 was 0.83 g (64%).

Step 2. Preparation of compound 5a_3.

Solution of 5a_2 (1.73 g, 6.43 mmol), trimethylsilylacetylene (0.98 g, 9.65 mmol) and DIPEA (1.68 g, 12.9 mmol) in THF (30 ml) was degassed with argon. Cui (0.25 g, 1.29 mmol) and Pd(Pph₃)₂Cl₂ (0.46 g, 0.64 mmol) were added in an argon atmosphere. RM was stirred at 70 °C for 3 h and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/hexane as eluent. Yield of 5a_3 was 1.29 g (89%).

Step 3. Preparation of compound 5a_4.

5a_3 (0.30 g, 1.26 mmol) was added to a solution of IM TBAF in THF (2.5 ml, 2.5 mmol), the mixture was mixed at r.t. for 2.5 h. The reaction mass was diluted with water and extracted with EtOAc. The organic phase was washed with 10% Na2CO₃, a saturated solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 5a_4 was 0.19 g (98%).

Step 4. Preparation of compound 5a_5.

Solution of 5a_4 (0.31 g, 0.89 mmol), 3a (0.45 g, 1.18 mmol), DIPEA (0.31 g, 2.36 mmol), Cui (0.02 g, 0.12 mmol) in THF (5 ml) was degassed with argon. Pd(PPH ₃)₂Ch (0.42 g, 0.06 mmol) was added in an argon atmosphere. RM was stirred at r.t. overnight, diluted with water, and extracted with EtOAc. Organic phase was washed with a saturated aqueous solution of NaCl and extracted with an aqueous solution of IM HC1. Combined aqueous phases were neutralized with a saturated solution of NaHCOs, the precipitate was filtered off and dried. Yield of 5a_5 was 0.33 g (84%).

Step 5. Preparation of compound 5a.

Solution of 5a_5 (0.15 g, 0.45 mmol), Cui (0.07 g, 0.36 mmol) and DBU (0.55 ml, 3.6 mmol) in DMF (10 ml) was mixed at 100 °C for 24 h. RM was diluted with water and DCM, filtered off, and an aqueous solution of IM HC1 was added. Organic layer was extracted with an aqueous solution of IM HC1. Combined aqueous phases were neutralized with a saturated solution of NaHCO, and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. Yield of 5a was 0.08 g (57%).

Example 6.1. Method of preparation of compound 5b

a

Step 1. Preparation of compound 5b_l.

Compound 5b_l was prepared in a similar manner to Example 6, step 4, from 5a_4 and 3b, yield was 0.65 g (80%).

Step 2. Preparation of compound 5b.

Suspension of 5b_l (0.51 g, 1.4 mmol) and Cs 2CO3 (1.8 g, 5.2 mmol) in NMP (5 ml) was mixed at 87 °C for 2 h. Product was isolated by column chromatography on silica gel using CHCh/MeOH/TEA as eluent. Yield of 5b was 0.35 g (65%).

Example 7. Method of preparation of compound 6a

Step 1. Preparation of compound 6a_2. NaH (0.10 g, 2.53 mmol) was added portionwise at 0 °C to a solution of 6a_l (0.42 g, 2.11 mmol) in THF (10 ml), the mixture was stirred for 10 min. Tosyl chloride (0.42 g, 2.22 mmol) was added at 0 °C portionwise. The mixture was stirred at r.t. for 2 h, neutralized with a saturated aqueous solution of NH4CI. Product was extracted using EtOAc. Combined organic phases were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/hexane as eluent. Yield of 6a_2 was 0.72 g (99%).

Step 2. Preparation of compound 6a_3.

Solution of 2M LDA in THF/heptane/ethylbenzene (1.15 ml, 2.29 mmol) was slowly added at -30 °C in an argon atmosphere to a solution of 6a_2 (0.55 g, 1.53 mmol) in THF (10 ml). Tributyltinchloride (0.43 ml, 1.53 mmol) was added after 1 h. Mixture was heated to r.t. for 1 hour, an aqueous solution of 20% NH4CI was added. Product was extracted using EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/hexane as eluent. Yield of 6a_2 was 0.62 g (64%).

Step 3. Preparation of compound 6a_4.

Pd(PPh₃)₂C12 (0.11 g, 0.09 mmol) was added in an argon atmosphere to a suspension of 6a_3 (0.62 g, 0.92 mmol), 3a (0.23 g, 0.61 mmol), CsF (0.19 g, 1.23 mmol), Cui (0.04 g, 0.18 mmol) in DMF (10 ml). RM was stirred at 80 °C for 1 h and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/TEA as eluent. Yield of 6a_4 was 0.18 g (57%).

Step 4. Preparation of compound 6a.

Aqueous solution of 3NNaOH (2 ml) was added to a solution of 6a_4 (100 mg, 0.18 mmol) in MeOH (4 ml), the resulting RM was mixed at 70 °C for 1 h. RM was concentrated on a rotary evaporator, DMF was added, RM was filled with water, the precipitate was filtered off and dried. Yield of 6a was 0.05 g (72%).

Example 7.1 Method of preparation of compound 6b

Step 1. Preparation of compound 6b_2.

Compound 6b_2 was prepared in a similar manner to Example 7, step 3, from 6a_3 and 3b, yield was 0.89 g (63%).

Step 2. Preparation of compound 6b. Compound 6b was prepared in a similar manner to Example 7, step 4, from 6b_2, yield was 0.46 g (99%).

Example 8. Method of preparation of compound 4b

Step 1 Preparation of compound 4b_2.

Compound 4b_2 was prepared in a similar manner to Example 7, step 1, from 4b_l, yield was 3.7 g (97%).

Step 2. Preparation of compound 4b_3.

Compound 4b_3 was prepared in a similar manner to Example 7, step 2, from 4b_2, yield was 1.76 g (30%).

Step 3. Preparation of compound 4b_4.

Compound 4b_4 was prepared in a similar manner to Example 7, step 3 from 4b_3, and 3b yield was 0.11 g (78%).

Step 4. Preparation of compound 4b.

Compound 4b was prepared in a similar manner to Example 7, step 4 from 4b_4, yield was 0.06 g (76%).

Example 8.1. Method of preparation of compound 4c.

Compound 4c was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3i via 4c_l (Table 1). Yield of 4c_l was 0.26 g (52%). Yield of 4c was 0.09 g (64%).

Example 8.2. Method of preparation of compound 4d.

Compound 4d was prepared in a similar manner to Example 7, step 3 from 4b_3 and 3j (table 1). Compound 4d_l was not isolated from RM. CS2CO3 (0.68 g, 2.1 mmol) and methanol (3 ml) were added to RM, the mixture was mixed at 60 °C for 1 hour. RM was concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 4d was 0.32 g (82%, yield over 2 steps).

Example 8.3. Method of preparation of compound 4e.

Compound 4e was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3c via 4e_l (Table 1). Yield of 4e_l was 0.36 g (20%). Yield of 4e was 0.14 g (83%).

Example 8.4. Method of preparation of compound 4f. Compound 4f was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3d via 4f_l (table 1). Yield of 4f_l was 0.10 g (24%). Yield of 4f was 0.15 g (57%).

Example 8.5. Method of preparation of compound 4g.

Compound 4g was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3k via 4g_l (table 1). Yield of 4g_l was 0.17 g (48%). Yield of 4g was 0.07 g (66%).

Example 8.6. Method of preparation of compound 4h.

Compound 4h was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3e via 4h_l (table 1). Yield of 4h_l was 0.23 g (63%). Yield of 4h was 0.14 g (94%).

Example 8.7. Method of preparation of compound 4i.

Compound 4i was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 31 via 4i_l (table 1). Yield of 4i_l was 0.36 g (89%). Yield of 4i was 0.14 g (75%).

Example 8.8. Method of preparation of compound 4j.

Compound 4j was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3m via 4j_l (table 1). Yield of 4j_l was 0.29 g (67%). Yield of 4j was 0.20 g (99%).

Example 8.9. Method of preparation of compound 4k.

Compound 4k was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3g via 4k_l (table 1). Yield of 4k_l was 0.14 g (50%). Yield of 4k was 0.04 g (44%).

Example 8.10. Method of preparation of compound 41.

Compound 41 was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3h via 41 1 (table 1). Yield of 41 1 was 0.20 g (55%). Yield of 41 was 0.06 g (55%).

Example 8.11. Method of preparation of compound 4m.

Compound 4m was prepared in a similar manner to Example 7, step 3, step 4 from 4b_3 and 3f via 4m_l (table 1). Yield of 4m_l was 0.67 g (93%). Yield of 4m was 0.09 g (23%).

Example 8.12. Method of preparation of compound 4n.

Compound 4n was prepared in a similar manner to Example 7, step 3 from 4b_3 and 3n via 4n_l (table 1). The compound 4n_l was not isolated from RM. CS2CO3 (0.68 g, 2.1 mmol) and methanol (3 ml) were added to RM, the mixture was mixed at 60 °C for 1 hour. RM was concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 4n was 0.14 g (83%, yield over 2 steps).

Example 8.13. Method of preparation of compound 4o.

Step 1 Preparation of compound 4o_l.

Compound 4o_lwas prepared in a similar manner to Example 7, step 3, from 3o, yield was 0.45 g (92%).

Step 2. Preparation of compound 4o. Compound 4o was prepared in a similar manner to Example 7, step 4, from 4o_l, yield was 0.15 g (54%).

Example 8.14. Method of preparation of compound 4p.

Compound 4p was prepared in a similar manner to Example 7, step 3 from 4b_3 and 3p via 4p_l (table 1). The compound 4p_l was not isolated from RM. CS2CO3 (1.3 g, 4.0 mmol) and methanol (5 ml) were added to RM, the mixture was mixed at r.t. for 16 h. RM was concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 4p was 0.12 g (47%, yield over 2 steps).

Example 8.15. Method of preparation of compound 4q.

Compound 4q was prepared in a similar manner to Example 7, step 3 from 4b_3 and 3q via 4q_l (table 1). Compound 4q_l was not isolated from PM. CS2CO3 (1.3 g, 4.0 mmol) and methanol (5 ml) were added to RM, the mixture was mixed at r.t. for 16 h. RM was concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using DCM/MeOH/TEA as eluent. Yield of 4q was 0.13 g (42%, yield over 2 steps).

Example 8.16. Method of preparation of compound 4r.

Compound 4r was prepared in a similar manner to Example 7, step 3 from 4b_3 and 3r via 4r_l (table 1). Yield of 4r_l was 0.36 g (78%). Yield of 4r was 0.03 g (35%).

Example 8.12 Method of preparation of compound 4s.

Step 1. Preparation of compound 4s_2.

Pd(dppf)C12 (0.06 g, 0.07 mmol) was added in an argon atmosphere to a suspension of 4s_l (0.40 g, 1.57 mmol), KOAc (0.40 g, 3.92 mmol) and fhpi (0.61 g, 2.35 mmol) in 1,4-dioxane (8 ml). The mixture was stirred at 100 °C for 1 h. 4b_3 (0.40 g, 1.57 mmol), ISfeCCh (0.42 g, 3.92 mmol) and water (1 ml) were added to RM, the mixture was mixed at 100 °C for 3 h. RM was concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/hexane as eluent. Yield of 4s_2 was 0.47 g (77%).

Step 2. Preparation of compound 4s.

Solution of NaOH (0.36 g, 9.0 mmol) in water (2.5 ml) was added dropwise to a solution of 4s_2 (0.47 g, 0.90 mmol) in MeOH (5 ml). The mixture was stirred at 60 °C for 2 h. Water was added (10 ml), the precipitate was filtered off and dried in air. Yield of 4s was 0.2 g (71%).

Example 8.13 Method of preparation of compound 4t.

Step 1. Preparation of compound 4t_2.

Compound 4t_2 was prepared in a similar manner to Example 8.12, step 1, from 4t_l, yield was 0.72 g (58%).

Step 2. Preparation of compound 4t.

Compound 4t was prepared in a similar manner to Example 8.12, step 2, from 4t_2, yield was 0.22 g (52%).

Example 8.14 Method of preparation of compound 4u.

Step 1. Preparation of compound 4u_2.

Compound 4u_2 was prepared in a similar manner to Example 8.12, step 1, from 4u_l, yield was 0.32 g (50%).

Step 2. Preparation of compound 4u.

Compound 4u was prepared in a similar manner to Example 8.12, step 2, from 4u_2, yield was 0.40 g (21%).

Example 8.15 Method of preparation of compound 4v

Step 1 Preparation of compound 4v_2.

Compound 4v_2 was prepared in a similar manner to Example 7, step 1, from 4v_l, yield was 1.8 g (91%).

Step 2. Preparation of compound 4v_3.

Compound 4v_3 was prepared in a similar manner to Example 7, step 2, from 4v_2, yield was 1.21 g (37%).

Step 3. Preparation of compound 4v_4.

Compound 4v_4 was prepared in a similar manner to Example 7, step 3 from 4v_3, yield was 0.11 g (34%).

Step 4. Preparation of compound 4v.

Compound 4v was prepared in a similar manner to Example 7, step 4 from 4v_4, yield was 0.06 g (84%).

Example 8.16 Method of preparation of compound 4w

Step 1 Preparation of compound 4w_2.

Compound 4w_2 was prepared in a similar manner to Example 7, step 1, from 4w_l, yield of 4w_2 was 1.1 g (36%).

Step 2. Preparation of compound 4w_3.

Compound 4w_3 was prepared in a similar manner to Example 7, step 2, from 4w_2, yield was 0.10 g (38%).

Step 3. Preparation of compound 4w_4.

Compound 4w_4 was prepared in a similar manner to Example 7, step 3 from 4w_3, yield was 0.05 g (33%).

Step 4. Preparation of compound 4w.

Compound 4w was prepared in a similar manner to Example 7, step 4 from 4w_4, yield was 0.01 g (3%).

Example 9. Method of preparation of compound EGFR_48.

7a_l 7a_2 EGFR 48

Step 1 Preparation of compound 7a_2.

Pd(OAc)₂ (100 mg, 0.50 mmol) and XantPhos (540 mg, 0.90 mmol) were added in an argon atmosphere to a suspension of 7a_l (2.04 g, 0.09 mol), la (0.90 g, 0.01 mol), CS2CO3 (3.25 g, 0.01 mol) in 1,4-dioxane (20 ml). RM was stirred at 110 °C for 3 h, diluted with a mixture of DCM/MeOH, filtered off, washed with a mixture of DCM/MeOH and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using DCM/MeOH as eluent. Yield of 7a_2 was 1.29 g (83%). Step 2. Preparation of candidate EGFR_48.

Pd(OAc)₂ (3 mg, 0.02 mmol) and XPhos (14 mg, 0.02 mmol) were added in an argon atmosphere to a suspension of 7a_2 (30 mg, 0.17 mmol), 4a (50 mg, 0.14 mmol), K2CO3 (59 mg, 0.42 mmol) in a mixture of /c/V-butanol/DMF (3 ml). RM was stirred at 100 °C for 5 hours and concentrated. Product was isolated by column chromatography on silica gel using DCM/MeOH/NHs as eluent. The isolated product was further purified by preparative chromatography. Yield of EGFR 48 was 9 mg (14%).

Example 9.1 Method of preparation of candidate EGFR_58.

Candidate EGFR_58 was prepared in a similar manner to Example 9, from 7d_l, la and 4a (Table 2), yield was 40 mg (18%).

Example 9.2 Method of preparation of candidate EGFR_65.

Candidate EGFR_65 was prepared in a similar manner to Example 9, from 7c_l, la and 4a (Table 2), yield was 20 mg (9%).

Example 9.3 Method of preparation of candidate EGFR_66

Candidate EGFR_66 was prepared in a similar manner to Example 9, from 7b_l, la and 4a (Table 2), yield was 10 mg (9%).

Example 9.4 Method of preparation of candidate EGFR_68

Candidate EGFR_68 was prepared in a similar manner to Example 9, from 7e_l, la and 4a (Table 2), yield was 40 mg (26%).

Example 9.5 Method of preparation of candidate EGFR_69

Candidate EGFR_69 was prepared in a similar manner to Example 9, from 7a_l, la and 5a (Table 2), yield was 10 mg (14%).

Example 9.6 Method of preparation of candidate EGFR_79

Candidate EGFR_79 was prepared in a similar manner to Example 9, step 2, from 8 and 4a (Table 2), yield was 70 mg (61%).

Example 9.7 Method of preparation of candidate EGFR_440

Candidate EGFR_440 was prepared in a similar manner to Example 9, from 7a_l, la and 5b (Table 2), yield was 40 mg (40%).

Example 9.8 Method of preparation of candidate EGFR_441

Candidate EGFR_441 was prepared in a similar manner to Example 9, from 7d_l, la and 5b (Table 2), yield was 25 mg (25%).

Example 9.9 Method of preparation of candidate EGFR_483

Candidate EGFR_483 was prepared in a similar manner to Example 9, from 7b_l, la and 5b (Table 2), yield was 90 mg (54%).

Example 9.10 Method of preparation of candidate EGFR_774 Candidate EGFR_774 was prepared in a similar manner to Example 9, from 7f_l, la and 4a (Table 2), yield was 90 mg (54%).

Example 9.11 Method of preparation of candidate EGFR_74

Candidate EGFR_74 was prepared in a similar manner to Example 9, from 7a_l, lb and 4a (Table 2), yield was 40 mg (69%).

Example 9.12 Method of preparation of candidate EGFR_76

Candidate EGFR_76 was prepared in a similar manner to Example 9, from 7a_l, dimethylphosphite and 4a (Table 2), yield was 10 mg (11%).

Example 9.13 Method of preparation of candidate EGFR_656

Candidate EGFR_656 was prepared in a similar manner to Example 9, from 7a_l, la and 4s (Table 2), yield was 70 mg (55%).

Example 9.14 Method of preparation of candidate EGFR_667

Candidate EGFR_667 was prepared in a similar manner to Example 9, from 7a_l, la and 4t (Table 2), yield was 40 mg (34%).

Example 9.15 Method of preparation of candidate EGFR_668

Candidate EGFR_668 was prepared in a similar manner to Example 9, from 7a_l, la and 4c (Table 2), yield was 40 mg (49%).

Example 9.16 Method of preparation of candidate EGFR_743

Candidate EGFR_743 was prepared in a similar manner to Example 9, from 7a_l, la and 4e (Table 2), yield was 40 mg (49%).

Example 9.17 Method of preparation of candidate EGFR_752

Candidate EGFR_752 was prepared in a similar manner to Example 9, from 7a_l, la and 4f (Table 2), yield was 80 mg (77%).

Example 9.18 Method of preparation of candidate EGFR_796

Candidate EGFR_796 was prepared in a similar manner to Example 9, from 7a_l, la and 4h (Table 2), yield was 80 mg (68%).

Example 9.19 Method of preparation of candidate EGFR_797

Candidate EGFR_797 was prepared in a similar manner to Example 9, from 7a_l, la and 4i (Table 2), yield was 20 mg (27%).

Example 9.20 Method of preparation of candidate EGFR_798

Candidate EGFR_798 was prepared in a similar manner to Example 9, from 7a_l, la and 4j (Table 2), yield was 10 mg (10%).

Example 9.21 Method of preparation of candidate EGFR_853 Candidate EGFR_853 was prepared in a similar manner to Example 9, from 7i_l, la and 4e (Table 2), using at the first step Pd(dppf)C12 and KO Ac instead of Pd(OAc)₂ and CS2CO3, yield was 10 mg (12%).

Example 9.22 Method of preparation of candidate EGFR_854

Candidate EGFR_854 was prepared in a similar manner to Example 9, from 7j_l, la and 4e (Table 2), using at the first step Pd(dppf)C12 and KO Ac instead of Pd(OAc)₂ and CS2CO3, yield was 10 mg (14%).

Example 9.23 Method of preparation of candidate EGFR_855

Candidate EGFR_855 was prepared in a similar manner to Example 9, from 7k_l, la and 4e (Table 2), using at the first step Pd(dppf)C12 and KO Ac instead of Pd(OAc)₂ and CS2CO3, yield was 40 mg (42%).

Example 9.23 Method of preparation of candidate EGFR_856

Candidate EGFR_856 was prepared in a similar manner to Example 9, from 71 1, la and 4e (Table 2), using at the first step Pd(dppf)C12 instead of Pd(OAc)₂, yield was 4 mg (5%).

Example 9.24 Method of preparation of candidate EGFR_857

Candidate EGFR_857 was prepared in a similar manner to Example 9, from 7m_l, la and 4e (Table 2), using at the first step Pd(dppf)C12 instead of Pd(OAc)₂, yield was 20 mg (28%).

Example 9.25 Method of preparation of candidate EGFR_858

Candidate EGFR_858 was prepared in a similar manner to Example 9, from 7n_l, la and 4e (Table 2), using at the first step Pd(dppf)C12 and KO Ac instead of Pd(OAc)₂ and CS2CO3, yield was 10 mg (17%).

Example 9.26 Method of preparation of candidate EGFR_859

Candidate EGFR_859 was prepared in a similar manner to Example 9, from 7d_l, la and 4e (Table 2), yield was 44 mg (44%).

Example 9.27 Method of preparation of candidate EGFR_860

Candidate EGFR_860 was prepared in a similar manner to Example 9, from 7o_l, la and 4e (Table 2), yield was 20 mg (13%).

Example 9.28 Method of preparation of candidate EGFR_862

Candidate EGFR_862 was prepared in a similar manner to Example 9, from 7b_l, la and 4e (Table 2), yield was 40 mg (28%).

Example 9.29 Method of preparation of candidate EGFR_870

Candidate EGFR_870 was prepared in a similar manner to Example 9, from 7p_l, la and 4e (Table 2), yield was 23 mg (23%).

Example 9.30 Method of preparation of candidate EGFR_871 Candidate EGFR_871 was prepared in a similar manner to Example 9, from 7a_l, lb ande (Table 2), yield was 17 mg (42%).

Example 9.31 Method of preparation of candidate EGFR_887

Candidate EGFR_887 was prepared in a similar manner to Example 9, from 7a_l, la andm (Table 2), yield was 8 mg (11%).

Example 9.32 Method of preparation of candidate EGFR_896

Candidate EGFR_896 was prepared in a similar manner to Example 9, from 7q_l, la ande (Table 2), using at the first step K2CO3 instead of CS2CO3, yield was 60 mg (55%).

Example 9.33 Method of preparation of candidate EGFR_910

Candidate EGFR_910 was prepared in a similar manner to Example 9, from 7a_l, lb andh (Table 2), yield was 10 mg (16%).

Example 9.34 Method of preparation of candidate EGFR_912

Candidate EGFR_912 was prepared in a similar manner to Example 9, from 7a_l, lb andf (Table 2), yield was 50 mg (36%).

Example 9.35 Method of preparation of candidate EGFR_918

Candidate EGFR_918 was prepared in a similar manner to Example 9, from 7q_l, la andf (Table 2), yield was 50 mg (34%).

Example 9.36 Method of preparation of candidate EGFR_919

Candidate EGFR_919 was prepared in a similar manner to Example 9, from 7b_l, la andf (Table 2), yield was 40 mg (31%).

Example 9.37 Method of preparation of candidate EGFR_655

Candidate EGFR_655 was prepared in a similar manner to Example 9, from 7a_l, la andu (Table 2), yield was 10 mg (10%).

Example 9.38 Method of preparation of candidate EGFR_865

Candidate EGFR_865 was prepared in a similar manner to Example 9, from 7a_l, la andv (Table 2), yield was 10 mg (25%).

Example 9.39 Method of preparation of candidate EGFR_982

Candidate EGFR_982 was prepared in a similar manner to Example 9, from 7q_l, Id andf (Table 2), yield was 13 mg (18%).

Example 9.39 Method of preparation of candidate EGFR_985

Candidate EGFR_985 was prepared in a similar manner to Example 9, from 7q_l, la andn (Table 2), using at the second step a mixture of tert-butanol/ 1,4-di oxane as solvent, yield was mg (4%).

Example 9.39 Method of preparation of candidate EGFR_989 Candidate EGFR_989 was prepared in a similar manner to Example 9, from 7q_l, la ando (Table 2), yield was 28 mg (20%).

Example 9.39 Method of preparation of candidate EGFR_990

Candidate EGFR_990 was prepared in a similar manner to Example 9, from 7q_l, la andp (Table 2), yield was 13 mg (9%).

Example 9.40 Method of preparation of candidate EGFR_993

Candidate EGFR_993 was prepared in a similar manner to Example 9, from 7q_l, la andq (Table 2), yield was 17 mg (20%).

Example 9.41 Method of preparation of candidate EGFR_994

Candidate EGFR_994 was prepared in a similar manner to Example 9, from 7q_l, la andr (Table 2), yield was 9 mg (16%).

Table 2.

Example 10 Method of preparation of candidate EGFR 70

IM LiHMDS in THF (0.51 ml, 0.51 mmol) was added to a suspension of 6a (69 mg, 0.17 mmol) and 7a_2 (91 mg, 0.51 mol) in DMF (2 ml). Pd2(dba)3 (74 mg, 0.08 mmol) and XPhos (75 mg, 0.15 mmol) were added in an argon atmosphere. RM was stirred at 100 °C for 40 h and concentrated. Product was isolated by column chromatography on silica gel using DCM/MeOH/NHs as eluent. The isolated product was further purified by preparative chromatography. Yield of EGFR 70 was 3 mg (4%).

Example 10.1 Method of preparation of candidate EGFR_348

Candidate EGFR_348 was prepared in a similar manner to Example 10, from 7d_2 and 4b yield was 30 mg (21%).

Example 10.2 Method of preparation of candidate EGFR_437

Candidate EGFR_437 was prepared in a similar manner to Example 10, from 7d_2 and 5a yield was 10 mg (9%). Example 10.3 Method of preparation of candidate EGFR_485

Candidate EGFR_485 was prepared in a similar manner to Example 10, from 7a_2 andb, yield was 15 mg (16%).

Example 10.4 Method of preparation of candidate EGFR_669

Candidate EGFR_669 was prepared in a similar manner to Example 10, from 7a_2 andd, yield was 21 mg (38%).

Example 10.5 Method of preparation of candidate EGFR_795

Candidate EGFR_795 was prepared in a similar manner to Example 10, from 7a_2 andg, yield was 95 mg (71%).

Example 10.6 Method of preparation of candidate EGFR_801

Candidate EGFR_801 was prepared in a similar manner to Example 10, from 7a_2 andk, yield was 40 mg (67%).

Example 10.7 Method of preparation of candidate EGFR_802

Candidate EGFR_802 was prepared in a similar manner to Example 10, from 7a_2 and1, yield was 30 mg (48%).

Example 10.8 Method of preparation of candidate EGFR_914

Candidate EGFR_914 was prepared in a similar manner to Example 10, from 7a_2 andw, yield was 10 mg (18%).

Example 11. Method of preparation of compound EGFR_60.

Step 1. Preparation of compound 9a_2. Pd2(dba)3 (0.11 g, 0.11 mmol) and XPhos (0.16 g, 0.33 mmol) were added in an argon atmosphere to a suspension of 9a_l (0.70 g, 3.67 mmol), A A A²-trimethylethane-l,2-diamine (0.57 g, 5.51 mmol), sodium /c/7-butylate (0.90 g, 9.18 mmol) in toluene (14 ml). RM was stirred at 110 °C for 3 h, filtered off, and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/TEA as eluent. Yield of 9a_2 was 0.31 g (41%).

Step 2. Preparation of compound 9a_3.

Solution of NBS (0.28 g, 1.57 mmol) in MeCN (3 ml) was added at 0 ° C to a solution of 9a_2 (0.31 g, 1.43 mmol) in MeCN (12 ml). RM was stirred at r.t. for 2 h, concentrated, redissolved in DCM, washed with water and concentrated. The product was isolated by column chromatography on silica gel using EtOAc/TEA as eluent. Yield of 9a_3 was 0.30 g (73%).

Step 3. Preparation of compound 9a_4.

Pd(dppf)C12 (48.0 mg, 0.06 mmol) was added in an argon atmosphere to a suspension of 9a_3 (0.23 g, 0.77 mmol), 4b_3 (0.31 g, 0.64 mmol), fhpi (0.30 g, 1.15 mmol), KOAc (0.19 g, 1.92 mmol) and K2CO3 (0.22 g, 2.05 mmol) in a mixture of 1,4-dioxane/water (7:2, 9 ml). Reaction mass was stirred at 100 °C for 3 h. Product was isolated by column chromatography on silica gel using hexane/acetone/TEA as eluent. Yield of 9a_4 was 0.30 g (90%).

Step 4. Preparation of compound 9a_5.

Compound 9a_5 was prepared in a similar manner to Example 7, step 4, from 9a_4, yield was 0.14 g (77%).

Step 5. Preparation of candidate EGFR_60.

Candidate EGFR_60 was prepared in a similar manner to Example 9, step 2, from 9a_4 and 7a_2, yield was 0.04 g (22%).

Example 11.1 Method of preparation of candidate EGFR_884.

EGFR 884

Step 1. Preparation of compound 9b_2.

Compound 9b_2 was prepared in a similar manner to Example 11, step 1, from 9b_l and 7V,7V-dimethylpiperidin-4-amine, yield was 0.56 g (48%).

Step 2. Preparation of compound 9b_3.

Compound 9b_3 was prepared in a similar manner to Example 11, step 2, from 9b_2, yield was 0.50 g (90%).

Step 3. Preparation of compound 9b_4.

Compound 9b_4 was prepared in a similar manner to Example 11, step 3, from 9b_3 and 4b_3, yield was 0.06 g (84%).

Step 4. Preparation of compound 9b_5.

Compound 9b_5 was prepared in a similar manner to Example 11, step 4, from 9b_4, yield was 0.06 g (72%).

Step 5. Preparation of candidate EGFR_884.

Candidate EGFR_884 was prepared in a similar manner to Example 11, step 5, from 9b_5, yield was 0.04 g (52%).

Example 11.2 Method of preparation of candidate EGFR_886.

EGFR 886

Step 1. Preparation of compound 9c_2.

Compound 9c_2 was prepared in a similar manner to Example 11, step 1, from 9c_l and 7V,7V-dimethylpiperidin-4-amine, yield was 0.57 g (47%).

Step 2. Preparation of compound 9c_3.

Compound 9c_3 was prepared in a similar manner to Example 11, step 2, from 9c_2 yield was 0.61 g (82%).

Step 3. Preparation of compound 9c_4.

Compound 9c_4 was prepared in a similar manner to Example 11, step 3, from 9c_3 and 4b_3, yield was 0.14 g (24%).

Step 4. Preparation of compound 9c_5.

Compound 9c_5 was prepared in a similar manner to Example 11, step 4, from 9c_4, yield was 0.08 g (91%).

Step 5. Preparation of candidate EGFR_886.

Candidate EGFR 886 was prepared in a similar manner to Example 11, step 5, from 9c_5, yield was 0.06 g (58%).

Example 12. Method of preparation of compound EGFR_59.

Step 1 Preparation of compound 10_2.

Compound 10_2 was prepared in a similar manner to Example 11, step 1, from 10_l, yield was 2.47 g (91%).

Step 2. Preparation of compound 10_3.

Solution of NIS (0.28 g, 1.2 mmol) in DMF (2.5 ml) was slowly added at 0 °C in an argon atmosphere to a solution of 10_2 (0.25 g, 1.14 mmol) in DMF (2.5 ml). The mixture was stirred at r.t. for 30 min. Reaction mixture was poured into water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using hexane/acetone/TEA as eluent. Yield of 10 3 was 0.26 g (67%).

Step 3. Preparation of compound 10_4.

Compound 10_4 was prepared in a similar manner to Example 7, step 3, except at 70°C, from 4b_3 and 10_3, yield was 0.17 g (55%).

Step 4. Preparation of compound 10_5.

Compound 10_5 was prepared in a similar manner to Example 7, step 4, from 10_4, yield was 0.06 g (76%).

Step 5. Preparation of candidate EGFR_59.

Candidate EGFR_59 was prepared in a similar manner to Example 11, step 5, from 7a_2 and 10_5, yield was 40 mg (63%).

Example 13. Method of preparation of candidate EGFR_338.

Step 1. Preparation of compound 11_2.

Solution of LiHMDS in THF (IM, 5.7 ml, 5.7 mmol) was added in an argon atmosphere to a solution of 11 1 (0.46 g, 2.85 mmol) in THF (10 ml), the mixture was mixed at r.t. for 15 min.

Solution of di-te/7-butyldicarbonate (0.7 g, 3.14 mmol) in THF (2 ml) was added. The mixture was stirred at r.t. for 2 h, Saturated aqueous solution of NH 4CI, saturated aqueous solution of NaCl and EtOAc were added. The organic phase was dried over Na2SO4, filtered off and concentrated on a rotary evaporator. Product was isolated by column chromatography on silica gel using hexane/DCM/EtOAc as eluent. Yield of 11_2 was 0.68 g (93%).

Step 2. Preparation of compound 11_3.

Solution of 2.5 M n-Buli in hexane (3.21 ml, 8.03 mmol) was slowly added at -78 °C in an argon atmosphere to a solution of 11_2 (0.91 g, 3.21 mmol) and TMEDA (0.94 g, 8.03 mmol) in THF (22 ml). The mixture was stirred at -78 °C for 1 h, and a solution of b (4.11 g, 0.02 mol) in THF (5 ml) was added. RM was brought to r.t.; saturated aqueous solution of NaCl, saturated aqueous solution of NaHSCh were added, the mixture was mixed at r.t. for 30 min. Product was extracted using EtOAc. Combined organic phases were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using EtOAc/hexane/DCM as eluent. Yield of 11 3 was 0.63 g (52%).

Step 3. Preparation of compound 11_4

Solution of 7N HC1 in 1,4-dioxane (3 ml), MeOH (1 ml) and water (0.1 ml) was added to a solution of 11_3 (0.44 g, 11.0 mmol) in 1,4-dioxane (4 ml). The resulting solution was mixed at 60 °C for 1 h. RM was concentrated and neutralized with a saturated aqueous solution of Na2CO 3. Product was extracted using EtOAc. Combined organic phases were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered and concentrated on a rotary evaporator.

Yield of 11_4 was 0.30 g (98%).

Step 4. Preparation of compound 11_5

Compound 11_5 was prepared in a similar manner to Example 6, step 2, from 11_4, yield was 0.21 g (93%)

Step 5. Preparation of compound 11_6.

Compound 11_6 was prepared in a similar manner to Example 6, step 3, from 11_5. The product was additionally purified by column chromatography on silica gel using EtOAc/hexane as eluent. Yield of 11_6 was 0.16 g (83%).

Step 6. Preparation of compound 11 7.

Compound 11 7 n was prepared in a similar manner to Example 6, step 4, from 11_6. The product was additionally purified by column chromatography on silica gel using EtOAc/MeOH/TEA as eluent. Yield of 11 7 was 0.18 g (64%).

Step 7. Preparation of compound 11_8.

Solution of 11_7 (0.13 g, 0.36 mmol) and potassium Zc/V-butylate (0.17 g, 1.4 mmol) in NMP (5 ml) was mixed at 80 °C for 5 h, water was added, and the product was extracted by EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated on a rotary evaporator. The product was isolated by column chromatography on silica gel using DCM/MeOH as eluent. Yield of 11_8 was 60 mg (47%).

Step 8. Preparation of candidate EGFR_338.

Candidate EGFR_338 was prepared in a similar manner to Example 10, from 11_8 and 7a_2, yield was 20 mg (32%).

Example 14. Method of preparation of candidate EGFR 1006.

Step 1. Preparation of compound 7s_2.

Solution of methoxymethyl chloride (294 mg, 3.47 mmol) in DCM (2 ml) was added at 0 °C to a solution of 7s_l (645 mg, 2.31 mmol), DIPEA (550 mg, 4.16 mmol) in DCM (15 ml). After 45 minutes, RM was concentrated. The product was isolated by column chromatography on silica gel using EtOAc/hexane as eluent. Yield of 7s_2 was 710 mg (99%).

Step 2. Preparation of compound 7s_3. Suspension of 7s_2 (680 mg, 2.09 mmol), Fe (354 mg, 6.27 mmol), CaCl 2 (234 mg, 2.09 mmol) in a mixture of EtOH/water (4: 1, 15 ml) was stirred at 80 °C for 3 h, filtered off and concentrated. The product was isolated by column chromatography on silica gel using EtOAc/hexane as gradient eluent. Yield of 7s_3 was 548 mg (94%).

Step 3. Preparation of compound 7s_4.

Compound 7s_4 was prepared in a similar manner to Example 9, Step 1, from 7s_3 and la, yield was 220 mg (53%).

Step 4. Preparation of candidate EGFR 1006.

Candidate EGFR_1006 was prepared in a similar manner to Example 9, Step 2, from 7s_4 and 4f, yield was 20 mg (13%).

Example 15. Analysis of prepared compounds.

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

Equipment data:

Table 6. Chromatography/mass spectrometry

Table 7. NMR spectrometer

Table 8. Analytical data for exemplary compounds

Example 16. Determination of turbidimetric solubility of compounds in buffer.

Solubility of the compounds was determined in 0.01 M sodium-phosphate buffer pH = 7.4.

Initial solution of the candidate (10 mM in DMSO) was diluted with 0.01 M sodium phosphate buffer pH = 7.4 to a concentration of 100 pM (test solution 1), 80 pM (test solution 2), 60 pM (test solution 3), 50 pM (test solution 4), 40 pM (test solution 5), 30 pM (test solution 6), 20 pM (test solution 7), 10 pM (test solution 8). Test solutions were introduced into wells of a 96- plate (Coming 3635, UV Plate). The plate containing test solutions was incubated for 2 h in a thermo-shaker (Biosan PST-60HL-4, Latvia).

The absorption at a wavelength of 620 nm was determined using the Sunrise microplate spectrophotometer (Tecan, Australia). A graph of solutions' optical density as a function of concentration was plotted for samples with optical density values different from those of the blank, linear dependence equation was determined, and solubility values were calculated.

Table 9. Results of determination of turbidimetric solubility of compounds in buffer.

* A - solubility value is in the range of >100 pM

** B - solubility value is in the range of 50-100 pM

Example 17. In vitro inhibitory activity against EGFR.

IC50 values of the compounds disclosed in the present invention were determined using a biochemical assay of inhibition of kinase activity in a non-cellular system.

Inhibition of EGFR wild type and EGFR L858R/T790M/C797S kinase activity was determined using SignalChem kinase system and ADP-Glo™ Kinase Assay (#V9102, Promega) detection kit.

Necessary buffers were prepared using:

1. H2O (LC-MS).

2. 5X Reaction Buffer A (ThermoFisher, #PV6135).

3. 2mM DTT (Sigma, #646563-10X.5ML).

4. Poly 4: 1 Glu,Tyr Peptide (SignalChem, #P61-58-lMG). 5. ATP (V915B, Promega).

Kinase buffers:

1. 4X kinase buffer (5X reaction buffer A, 200 pM DTT, 4% DMSO, H2O).

2. IX kinase buffer (4X kinase buffer, H2O).

3. Mix (2 parts of Poly 4: 1 Glu, Tyr peptide, 1 part of 4X kinase buffer, 1 part of 100 pM ATP).

Kinase was dissolved in IX kinase buffer. Inhibitors were titrated from 50 pM in increments of 5 in IX kinase buffer with 12 concentration points.

Measurements were carried out in a 384-well format (Corning, #4513) in a reaction volume of 5 pl. Kinase (2 pl) and inhibitor (1 pl) were preincubated for 10 minutes. IX kinase buffer was used as a negative control. 2 ml of the mix was added to each of the mixture of kinase and inhibitor (the final concentration of the peptide was 0.2 mg/ml, that of ATP was 10 pM), thereafter the plate was centrifuged at 400 ref for a minute, then incubated for 1 hour at 25 °C, the amount of ADP obtained during the kinase reaction was detected using ADP-Glo™ detection system (Promega, #V9102). Luminescence signal was measured using Spark 20M tablet multifunction reader (Tecan, Switzerland). IC 50 value was calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt:

where A is the upper asymptote; D is the lower asymptote; C is IC50, the half maximal inhibitory concentration, B is the parameter of curvature (slope).

Table 10. Results of inhibition of kinase activity

* A - IC50 value is in the range of <10 nM

** B - IC50 value is in the range of 10-50 nM

*** C - IC50 value is in the range of >50 nM The compounds of the present invention demonstrated effective inhibition of kinase activity with a target EGFR mutation L858R/T790M/C797S, and also demonstrated low activity against wild-type EGFR.

Example 18. Antiproliferation activity against Ba/F3 EGFR L858R/T790M/C797S cell line.

Antiproliferation activity of EGFR inhibitors was measured in a cellular assay on continuous cultures of Ba/F3 EGFR L858R/T790M/C797S cells (murine pro-B cell line, KYinno, KC-0122) using AlamarBlue intravital dye (ThermoFisher, #DAL1100). Cells were cultured in a growth medium (DMEM high glucose (Gibco, #12800-082) supplemented with 10% FBS (Gibco, #16140-071)), then transferred to 96-well culture plates (Corning, #3599) at 1.5x103 cells in 100 ml of medium per well. Test compounds were dissolved in DMSO and diluted with a growth medium to a final concentration ranging from 0 to 10 pM. Next, 100 pl of diluted compounds was added to each well (the final concentration of DMSO was no more than 1%) and incubated at 37 °C in an incubator with 5% CO₂ for 72 hours. Following incubation, 20 ml of AlamarBlue reagent (ThermoFisher, #DAL1100) was added to each well, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) for 1 minute at 550 rpm, then additionally incubated for 6 hours at 37 °C in an incubator with 5% CO₂. The number of living cells was detected on a Spark 20M multimode plate reader (Tecan, Switzerland) by way of measuring the fluorescent signal at an excitation wavelength (lEx) of 540 nm and an emission wavelength (lEm) of 590 nm. IC50 value was calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg- Marquardt:

Table 11. Results of determination of antiproliferation activity against Ba/F3 EGFR L858R/T790M/C797S cell line.

* A - IC50 value is in the range of <400 nM

** B - IC50 value is in the range of 400-800 nM

The compounds according to the present invention showed antiproliferation activity against Ba/F3 EGFR L858R/T790M/C797S cell line.

Example 19. Antiproliferation activity against Ba/F3 EGFR Dell9/T790M/C797S cell line.

Antiproliferation activity of EGFR inhibitors was measured in a cellular assay on continuous cultures of Ba/F3 EGFR Dell9/T790M/C797S cells (murine pro-B cell line, KYinno, KC-0116) using AlamarBlue intravital dye (ThermoFisher, #DAL1100). Cells were cultured in a growth medium (DMEM high glucose (Gibco, #12800-082) supplemented with 10% FBS (Gibco, #16140-071)), then transferred to 96-well culture plates (Corning, #3599) at 1.5x103 cells in 100 ml of medium per well. Test compounds were dissolved in DMSO and diluted with a growth medium to a final concentration ranging from 0 to 10 pM. Next, 100 pl of diluted compounds was added to each well (the final concentration of DMSO was no more than 1%) and incubated at 37 °C in an incubator with 5% CO₂ for 72 hours. Following incubation, 20 ml of AlamarBlue reagent (ThermoFisher, #DAL1100) was added to each well, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) for 1 minute at 550 rpm, then additionally incubated for 6 hours at 37 °C in an incubator with 5% CO₂. The number of living cells was detected on a Spark 20M multimode plate reader (Tecan, Switzerland) by way of measuring the fluorescent signal at an excitation wavelength (lEx) of 540 nm and an emission wavelength (lEm) of 590 nm. IC50 value was calculated using SparkControl Magellan V 3.0 software (Tecan, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg- Marquardt:

Table 12. Results of determination of antiproliferation activity against Ba/F3 EGFR Dell9/T790M/C797S cell line.

* A - IC50 value is in the range of <200 nM

** B - IC50 value is in the range of 200-400 nM

The compounds according to the present invention showed antiproliferation activity against Ba/F3 EGFR Del 19/T790M/C797S cell line.

Claims

Claims:

1. A compound of Formula I:

Xi is -CH-, -N- or -C(R₆)-; each n, m is independently 0, 1, 2, 3 or 4; each Ri is independently -H; -Hal; - C(Hal)₃; -CN; -NR₇R₈; -C(0)NR₉Rio; -C(O)ORu; -C(O)RI₂; -ORB; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals RH; -(C₃- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Ri4_a;

R₂ is -P(O)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; -P(O)((C₃- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R_15a; -P(O)((Ci- C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; - P(O)(O(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15c; -P(O)(O(C₃- Ce)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)(O(Ci- C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R_15e; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅f; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g;

R₃ is -H; -Hal; -CN; -C(Hal)₃; -NR_7aR_8a; -C(0)NR_9aRio_a; -C(O)ORu_a; -C(O)Ri_2a; -ORi_3a; -(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6t>; -(Ce-Ci₂)aryl, unsubstituted or substituted by one or several radicals Ri6_C; 4-10-membered heteroaryl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals Riea; each R4 is independently -H; -Hal; -CN; -NR?bRsb; -C(Hal)3; -C(0)NR9bRiob; -C(O)ORub; - C(0)Ri2b; -ORob; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a; -(C3- Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Rnb; 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals RI_7C; or -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals Riva;

Rs is:

-NR_7CRIS; -NR₇dRi9; -Wi; -OW₂; -NR_aW₃; -C(0)W₄; or -(CH₂)W₅; wherein each Wi, W2, W3, W₄ or W5 is independently -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20; 4-7-membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R20,

Reis -Hal, -CN, -C(Hal)3, CH(Hal)₂, OHhHal, -NR_7eRsc; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R7, R_7a, R₇b, R₇e, Rs, Rs_a, Rsb, Rsc, R9, Rg_a, R9b, Rio, Rioa, Riob is independently -H, -(Ci- Ce)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from - Hal, -NH₂, -OH, (=0); each R?_c, R₇d, RB is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cw)alkyl, unsubstituted or substituted by one or several substituents selected from - Hal, -OH, -NO₂, -NR23R₂₄, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0); each Rn, R12, R13, Ru_a, Ri2a, Ri3a, Rub, Rub, Ri3b is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2i_a, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each RI₄, Ri_4a, R₁₅, Ru_a, R₁₅, R₁₅a, R₁₅b, R₁₅e, Rua, R₁₅e, R₁₅f, R₁₅g, Rie, Ri6a, Ri6b, Ri6c, Ried, RI₇, Ri_7a, Ri-zb, R17C, Ri7d is independently -Hal, -H, -OH, -NO₂, -NR2₃R2₄, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R20 is independently (=0), -NR₇fRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -2-8 membered heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22_a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, 4-10 membered heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsd is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R21, R2ia, R2 , R21C, R22, R22a, R22b, R22C is independently -Hal, -H, -OH, -NO₂, -NR23R24, - (C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, - O(C₁-C₆)alkyl, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

2. The compound according to claim 1, wherein

Li is a chemical bond, R2 is -P(0)((C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R₁₅; -P(O)((C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; -P(O)((C₁-C₆)alkyl))((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅b; -P(0)(0(C₁-C₆)alkyl)₂, unsubstituted or substituted by one or several radicals R_15C; -P(O)(O(C₃-C₆)cycloalkyl)₂, unsubstituted or substituted by one or several radicals R₁₅a; - P(O)(O(C₁-C₆)alkyl)(O(C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅e; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(0)(0(C₁-C₆)alkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), unsubstituted or substituted by one or several radicals R₁₅; -P(O)(O(C₃-C₆)cycloalkyl)((C₃-C₆)cycloalkyl), unsubstituted or substituted by one or several radicals R₁₅; or Li is -NH-, R2 is -SO₂(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R₁₅r; or -SO₂(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R_15g, wherein each R₁₅, R₁₅a, R₁₅, R₁₅a, R₁₅b, R₁₅e, R₁₅d, R₁₅e, R₁₅f, R₁₅g is independently -Hal, -H, -OH, -NO₂, - NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH₂, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl,

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

3. The compound according to claim 1, wherein Re is -Hal, -CN, -C(Hal)₃, CH(Hal)₂, CTLHal.

4. The compound according to claim 1, wherein Ri each independently represents by Hal; - C(Hal)₃; -O(CHah); -CN; -O(C₁-C₆)alkyl, -O(CH₂)₂O-(C₁-C₆)alkyl.

5. The compound as claimed in claim 1, wherein Ri each independently represents by -F, - Cl, -Br, -CF₃, -CC1₃, -O(CF₃), -O(CC1₃), -OCH₃, -OCH₂CH₃, -O(CH₂)₂O-CH₃, -O(CH₂)₂O-CH₂- CH₃.

6. The compound according to claim 1, wherein R2 is -P(O)((C₁-C₆)alkyl)₂, -P(O)((C₃- C₆)cycloalkyl)₂, -P(O)((C₁-C₆)alkyl))((C₃-C₆)cycloalkyl)), -P(O)(O(C₁-C₆)alkyl)₂, -P(O)(O(C₃- C₆)cycloalkyl)₂, -P(O)(O(C₁-C₆)alkyl)((C₃-C₆)cycloalkyl), P(O)(O(C₁-C₆)alkyl)((C₁-C₆)alkyl), P(O)(O(C₃-C₆)cycloalkyl)((C₁-C₆)alkyl), P(O)(O(C₃-C₆)cycloalkyl)((C₃-Ce)cycloalkyl), SO₂(C₁-C₆)alkyl.

7. The compound according to claim 6, wherein R2 is -P(O)(CH₃)₂, P(O)(CH2CH₃)₂, -

P(O)(CH₃)(CH2CH₃), -P(O)(cyclopropyl)₂, -P(O)(CH₃)(cyclopropyl),

P(O)(CH₂CH₃)(cyclopropyl), -P(O)(OCH₃)₂, -P(O)(OCH₂CH₃)₂, -P(O)(OCH₃)(OCH₂CH₃), - P(O)(OCH₃)(CH₃), -P(O)(OCH₃)(CH₂CH₃), -P(O)(OCH₂CH₃)(CH₃),

P(O)(OCH₂CH₃)(CH₂CH₃), -P(O)(OCH₃)(cyclopropyl), -P(O)(OCH₂CH₃)(cyclopropyl), - SO₂CH₃, SO₂CH₂CH₃.

8. The compound according to claim 1, wherein R₃ is -H; -Hal; -C(Hal)₃, -CN; -NRvaRsa; - C(0)NR₉aRio_a; -CO(O)Ru_a; -C(O)Ri2a; -ORi_3a; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Rie_a; -(C₃-Ce)cycloalkyl, unsubstituted or substituted by one or several radicals Ri6b; phenyl, unsubstituted or substituted by one or several radicals Ri6c, wherein each R?_a, Rsa, R9a, Rioa is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rua, Ri2a, Ri3a, is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each R^a, Ri6b, Ri6c, R21, Riia, R2ib, R21C is independently -H, -OH, - NO₂, -NR2₃R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0), -O(Ci- Ce)alkyl; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

9. The compound according to claim 1, wherein R3 is -CN; phenyl, unsubstituted or substituted by one radical Ri6c, selected from prop-2-enamidyl, 3-hydroxypropanamidyl, 3- (dimethylamino)propanamidyl, wherein Ri6_C is -Hal, -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0).

10. The compound according to claim 1, wherein each R4 is independently -H; -Hal; -C(Hal)3; -CN; -NR₇bRsb; -C(0)NR9bRiob; -C(O)Rub; -C(O)ORi2b; -0Ri3t>; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals Ri_7a, wherein each R?b, Rsb, R%, Riob is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each Rub, Ri2b, Ri3b is independently -H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R21, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R2ia, -(Ce-Ci2)aryl, unsubstituted or substituted by one or several radicals R2ib, -(C4- Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R2i_c; each Ri7a, R21, Riia, R2ib, R21C is independently -H, -OH, -NO₂, -Hal, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0), -O(Ci- Ce)alkyl; each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

11. The compound according to claim 10, wherein each R4 is independently -H; -(C₁-C₆)alkyl, -O(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -OH, - NO₂, -NH₂

12. The compound according to claim 1, wherein R5 is:

-NR_7cRi8; -NR_7dRi9; -Wi; -0W₂; -NRaW₃; -C(0)W₄; or -(CH₂)W₅; wherein each Wi, W2, W3, W4 or W5 is independently -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R20, selected from

wherein p is 0, 1, 2 or 3; each Yi, Y2 is independently CH2, CHR20, C(R2o)₂, NH, NR20, S or O; each R?_c, R?d Ra is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from - Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rsd is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R22, R22a, R22b, R22C is independently -H, -OH, - NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

13. The compound according to claim 12, wherein R5 is:

-NR_7CRIS; -NR₇dRi9; -Wi; -0W₂; -NRaW₃; -C(0)W₄; or -(CH₂)W₅ R; wherein each Wi, W2, W3, W4 or W5 is independently

wherein p is 0, 1, 2 or 3; each R?_c, R?d is independently -H, -(C₁-C₆)alkyl; R₁₅ is -(Ci-Cio)alkyl, unsubstituted or substituted by one or several substituents selected from - Hal, -OH, -NO₂, -NR23R24, (=0);

R19 is 2-10 membered heteroalkyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several substituents selected from -Hal, -OH, -NO₂, -NR23R24, (=0); each R20 is independently (=0), -NRvfRsd, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals R22, -(C2-Ce)heteroalkyl with 1 or 2 heteroatoms selected from N, O or S, unsubstituted or substituted by one or several radicals R22a, -(C₃-C₆)cycloalkyl, unsubstituted or substituted by one or several radicals R22b, -(C4-Cs)heterocyclyl with 1 or 2 heteroatoms selected from N, S or O, unsubstituted or substituted by one or several radicals R22_C; each R?f, Rxd, Ra is independently H, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R22, R22a, R22b, R22C is independently -H, -OH, -NO₂, -NR23R24, -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from -Hal, -NH2, -OH, (=0); each R23, R24 is independently -H; -(C₁-C₆)alkyl, unsubstituted or substituted by one or several radicals selected from (=0), -OH, -NR25R26; -(C2-Ce)alkenyl, unsubstituted or substituted by one or several radicals selected from (=0), -NR25aR26_a; each R25, R26, R25a, R26a is independently -H, -(C₁-C₆)alkyl;

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

14. The compound according to claim 12, wherein R5 is:

[2-(dimethylamino)ethyl](methyl)amino, 4-(4-m ethylpiperazine- 1 -yl)piperidine- 1 -yl, 4- methylpiperazine-l-yl, 4-(dimethylamino)piperidine-l-yl, 4-morpholine-l-yl, 4-m ethyl- 1,4- diazepan-l-yl, l-isopropylpiperidine-4-yl, (l-methylpiperidine-4-yl)oxy, (l-methylpiperidine-3- yl)amino, (l-methylpiperidine-4-yl)amino, methyl(l-methylpiperidine-4-yl)amino, (4- methylpiperazine- 1 -yl)methanone, (4-m ethylpiperazine- 1 -yl)m ethyl, (2-methyl-2- azabicyclo[2.2.1]heptane-5-yl)oxy, (l-methylpyrrolidine-3-yl)oxy, (l-methylpipiridine-4-yl)oxy, 1 -acetylpiperidine- 1-yl, piperidine- 1-yl, l-(2-(dimethylamino)-2-oxoethyl)piperidine.

15. The compound according to any of claims 1-14, which are: (2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-lJ7-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_48);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)-4-fluorophenyl)dimethylphosphine oxide formate (EGFR_58);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)-l_JH-pyrrolo[2,3-

Z>]pyridine-4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_59);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-methoxyphenyl)-l_JH-pyrrolo[2,3-

Z>]pyridine-4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_60);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)-5-fluorophenyl)dimethylphosphine oxide acetate (EGFR_65);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)-6-fluorophenyl)dimethylphosphine oxide formate (EGFR_66);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)-4-(trifluoromethyl)phenyl)dimethylphosphine oxide (EGFR_68);

(2-((6-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-7J7-pyrrolo[2,3-J]pyrimidine-4- yl)amino)phenyl)dimethylphosphine oxide (EGFR_69);

2-((5-chloro-2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-l//-pyrrolo[2,3-Z>]pyridine- 4-yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_70);

(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-177-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)diethylphosphine oxide (EGFR_74); dimethyl(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine- 4-yl)amino)phenyl)phosphonate (EGFR_76);

N-(2-((2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-177-pyrrolo[2,3-Z>]pyrimidine-4- yl)amino)phenyl)methanesulfonamide formate (EGFR_79);

2-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl-4-((2-dimethylphosphoryl)phenyl)amino)- 177-pyrrolo[2,3-Z>]pyridine-5-carbonitrile (EGFR_338);

(4-fluoro-2-((2-(4-(4-(4-methylpiperazine-l-yl)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-

Z>]pyridine-4-yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_348);

(2-((6-(4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)-7J7-pyrrolo[2,3-J]pyrimidine-4- fluorophenyl)dimethylphosphine oxide acetate (EGFR_437); dimethyl(2-((6-(4-(4-(4-methylpiperazine- 1 -yl)piperidine- 1 -yl)phenyl)-7J7-pyrrolo[2,3 - d]pyrimidine-4-yl)amino)phenyl)phosphine oxide (EGFR_440);

(4-fluoro-6-((6-(4-(4-(4-methylpiperazine-l-yl)piperidine-l-yl)phenyl)-7_JH-pyrrolo[2,3- d]pyrimidine-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_441); (2-fluoro-6-((6-(4-(4-(4-methylpiperazine-l-yl)piperidine-l-yl)phenyl)-7Z/-pyrrolo[2,3- d]pyrimidine-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_483);

(2-((5-chloro-2-(4-(4-(4-methylpiperazine-l-yl)piperidine-l-yl)phenyl)-177-pyrrolo[2,3-

Z>]pyridine-4-yl)phenyl)dimethylphosphine oxide (EGFR_485); dimethyl(2-((2-(3-(4-m ethylpiperazine- l-yl)phenyl)-l/7-pyrrolo[2, 3 -Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_655); dimethyl(2-((2-(4-morpholinophenyl)-l7/-pyrrolo[2,3-/)]pyridine-4-yl)amino)phenyl)phosphine oxide formate (EGFR_656); dimethyl(2-((2-(4-(4-m ethylpiperazine- l-yl)phenyl)-l/7-pyrrolo[2, 3 -Z>]pyridine-4- yl)amino)phenyl)phosphine oxide formate (EGFR_667); dimethyl(2-((2-(4-(4-methyl-l,4-diazepan-l-yl)phenyl)-lZ7-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide formate (EGFR_668);

(2-((2-(4-((l-isopropylpiperidine-4-yl)amino)phenyl)-l_JH-pyrrolo[2,3-b]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_669);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_743); dimethyl(2-((2-(4-(l-methylpiperidine-4-yl)oxy)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide formate (EGFR_752);

(2-((2-(4-(2-(dimethylamino)ethyl(methyl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)diethylphosphine oxide formate (EGFR_774); dimethyl(2-((2-(4-(l-methylpiperidine-4-yl)amino)phenyl)-lJ7-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_795); dimethyl(2-((2-(4-(methyl(l-methylpiperidine-4-yl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide formate (EGFR_796);

(4-(4-((2-(dimethylphosphoryl)phenyl)amino)-17/-pyrrolo[2,3-Z>]pyridine-2-yl)phenyl)(4- methylpiperazine-l-yl)methanone formate (EGFR_797); dimethyl(2-((2-(4-((4-methylpiperazine-l-yl)methyl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide formate (EGFR_798);

(S)-dimethyl(2-((2-(4-((l-methylpiperidine-3-yl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_801);

(R)-dimethyl(2-((2-(4-((l-methylpiperidine-3-yl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_802);

(2-chloro-6-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-lJ7-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_853);

120 (2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-6- (trifluoromethyl)phenyl)dimethylphosphine oxide formate (EGFR_854);

(6-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)- 2,3-difluorophenyl)dimethylphosphine oxide (EGFR_855);

(2-((2-(4-(4-(dimethylamino)piperidine-lyl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-4- methoxyphenyl)dimethylphosphine oxide acetate (EGFR_856);

(2-((2-(4-(4-(dimethylamino)piperidine-lyl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-4-

(trifluoromethoxy)phenyl)dimethylphosphine oxide acetate (EGFR_857);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)- 4,6-difluorophenyl)dimethylphosphine oxide acetate (EGFR_858);

2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-4- fluorophenyl)dimethylphosphine oxide (EGFR_859);

4-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-3-

(dimethylphosphoryl)benzonitrile formate (EGFR_860);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-6- fluorophenyl)dimethylphosphine oxide (EGFR_862);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-5-fluoro-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_865);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-5- methoxyphenyl)dimethylphosphine oxide formate (EGFR_870);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)di ethylphosphine oxide acetate (EGFR_871);

(2-((2-(4-(4-(dimethylamino)piperi dine- 1 -yl)-2-(tri fluoromethoxy )phenyl)-l/7-pyrrolo[2, 3- Z>]pyridine-4-yl)amino)phenyl)dimethylphosphinoxide acetate (EGFR_884);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)-2-methylphenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_886);

2-((2-(4-(4-(dimethylamino)piperidine-l-yl)-3 -methylphenyl)- l/7-pyrrolo[2, 3 -Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_887);

(2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4-yl)amino)-6- methoxyphenyl)dimethylphosphine oxide acetate (EGFR_896); diethyl(2-((2-(4-((methyl(l-methylpiperidine-4-yl)amino)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_910); diethyl(2-((2-(4-((l-methylpiperidine-4-yl)oxy)phenyl)-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)phosphine oxide acetate (EGFR_912); (2-((2-(4-(4-(dimethylamino)piperidine-l-yl)phenyl)-5-methyl-l_JH-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide (EGFR_914);

(2-metoxy-6-((2-(4-((l-methylpiperidine-4-yl)oxy)phenyl)-lJ/-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide (EGFR_918);

(2-fluoro-6-((2-(4-((l-methylpiperidine-4-yl)oxy)phenyl)-lJ/-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide formate (EGFR_919);

(R)-(2-methoxy-6-((2-(4-((l-methylpyrrolidine-3-yl)oxy)phenyl)-l//-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide (EGFR_989);

(S)-(2-methoxy-6-((2-(4-((l-methylpyrrolidine-3-yl)oxy)phenyl)-17/-pyrrolo[2,3-Z>]pyridine-4- yl)amino)phenyl)dimethylphosphine oxide (EGFR_990); dicyclopropyl(2-metoxy-6-((2-(4-((l-methylpiperidine-4-yl)oxy)phenyl)-17/-pyrrolo[2,3-

Z>]pyridine-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_982);

(2-methoxy-6-((2-(4-((2-methyl-2-azabicyclo[2.2.1]heptane-5-yl)oxy)phenyl)-17/-pyrrolo[2,3- Z>]pyridine-4-yl)amino)phenyl)dimethylphosphine oxide (EGFR_985);

1-(4-(4-(4-((2-(dimethylphosphoryl)-3-methoxyphenyl)amino)-l//-pyrrolo[2,3-Z>]pyridine-2- yl)phenoxy)piperidine- 1 -yl)ethane- 1 -one (EGFR_993);

2-(4-(4-(4-((2-(dimethylphosphoryl)-3-methoxyphenyl)amino)-lZ/-pyrrolo[2,3-Z>]pyridine-2- yl)phenoxy)piperidine- 1 -yl)-A,A-dimethylacetamide (EGFR_994);

(2-methoxymethoxy-6-((2-(4-((l-methylpiperidine-4-yl)oxy)phenyl)-17/-pyrrolo[2,3-Z>]pyridine- 4-yl)amino)phenyl)dimethylphosphine oxide acetate (EGFR_1006).

16. A method of inhibiting the biological activity of the epidermal growth factor receptor (EGFR) in a subject, consisting in contacting the kinase domain of EGFR with a compound according to any of claims 1-15 or its pharmacologically acceptable salt, solvate, or stereoisomer.

17. A pharmaceutical composition containing a compound according to any of claims 1-15 or its pharmaceutically acceptable salt, solvate or stereoisomer, and one or more pharmaceutically acceptable excipients.

18. The pharmaceutical composition according to claim 17 intended for the prevention or treatment of a disease or disorder mediated by EGFR activity.

19. The pharmaceutical composition according to claim 18, wherein the specified disease or disorder is a disease or disorder mediated by EGFR activity with mutation L858R and/or mutation T790M and /or deletion in exon 19 and/ or mutation C797S.

20. The pharmaceutical composition according to claim 19, wherein a disease or disorder mediated by EGFR activity is an oncological disease.

21. The pharmaceutical composition according to claim 20, 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 cancer, esophageal cancer, stomach 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.

22. The pharmaceutical composition according to claim 20, wherein the oncological disease is a non-small cell lung cancer.

23. A method of treating a disease or disorder mediated by EGFR activity, including the administration in a therapeutically effective amount of a compound according to any ofclaims 1- 15 or its pharmacologically acceptable salt, solvate or stereoisomer, or pharmaceutical composition according to claim 17 to a subject in need of such treatment.

24. The method according to claim 23, wherein the specified disease or disorder is a disease or disorder mediated by EGFR activity with mutation L858R and/ or mutation T790M and / or deletion in exon 19 and/ or mutation C797S.

25. The method according to claim 24, wherein the disease or disorder mediated by EGFR activity is an oncological disease.

26. The method according to claim 25, 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 cancer, esophageal cancer, stomach 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.

27. The method according to claim 26, wherein the oncological disease is a non-small cell lung cancer.

28. A use of a compound according to any of claims 1-15 or its pharmacologically acceptable salt, solvate or stereoisomer, or pharmaceutical composition according to claim 17 for the treatment of a disease or disorder mediated by EGFR activity in a subject in need of such treatment.

29. The use of a compound according to claim 28, wherein the specified disease or disorder is a disease or disorder mediated by EGFR activity with mutation L858R and/or mutation T790M and/or deletion in exon 19 and/or mutation C797S.

30. The use of a compound according to claim 29, wherein the disease or disorder mediated by EGFR activity is an oncological disease.

31. The use of a compound according to claim 30, wherein the disease or disorder is bladder cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, head

123 and neck cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, nonHodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocellular cancer, esophageal cancer, stomach 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.

32. The use of a compound according to claim 30, wherein the oncological disease is a nonsmall cell lung cancer.

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