Novel pyrimidine compounds as kinase inhibitors having biological activity against EGFR mutants

Abstract

The present invention relates to compounds of Formula I characterized by inhibiting protein tyrosine kinase (PTK), comprising EGFR mutants, pharmaceutical compositions comprising therapeutically effective amounts of the corresponding compounds, and methods of use thereof. # imgabs0 #

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 376,253, filed on September 19, 2022. Technical Field

[0002] The present invention relates to compounds characterized by inhibiting protein tyrosine kinases (PTK), including EGFR mutants, pharmaceutical compositions comprising a therapeutically effective amount of the corresponding compounds, and methods of use thereof. Background Art

[0003] Protein tyrosine kinase (PTK) is a large series of enzymes that catalyze phosphorylation processes, which transfer phosphate groups from nucleoside triphosphates (usually ATP) to protein amino acid residues. They span the cell membrane and play the role of "switch" in the cell signal transduction cascade from extracellular signals through the membrane to the cytoplasmic part and even the inner core. Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase (RTK) family, which includes EGFR / ERBB1, HER2 / ERBB2 / NEU, HER3 / ERBB3 and HER4 / ERBB4. Ligands, such as the binding of epidermal growth factor (EGF) induce conformational changes in EGFR, which promote the formation of receptor homodimers or heterodimers, leading to the activation of EGFR tyrosine kinase activity. EGFR overexpression or activation and acquired EGFR T790M mutations are observed in human cancers and are associated with a high rate of cancer cell proliferation and drug resistance. The EGFR T790M mutation is present in approximately 50% to 60% of drug-resistant cases and is an acquired gatekeeper mutation of threonine to methionine (T790M) in the EGFR gene.

[0004] The present invention disclosed herein is a compound having inhibitory activity against EGFR mutants, such as L858R, T790M, C797S, exon 20 insertion, HER2, etc. Examples of compounds structurally similar to the compounds of the present invention are disclosed in the following documents: WO 2009158571, WO 2013014448, WO 2015127872, WO 2015188777, WO2015195228, WO 2016023422, WO 2016029839, WO 2016054987, WO 2016070816, WO2016173438, WO 2017086830, WO 2017120429, WO 2017162510, WO 2017205459. Summary of the invention

[0005] Several embodiments disclosed herein relate to inhibitors of PTK, primarily the inhibition of EGFR mutants represented by Formula I:

[0006]

[0007] in:

[0008] Q is a bicyclic heterocyclic group selected from:

[0009]

[0010] R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic acid ester or carboxamide;

[0011] X is selected from a direct bond, -O-, -S- or -N(R')-;

[0012] R' is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, amino, hydroxyalkylamino, aryl or heterocyclyl;

[0013] R" is selected from:

[0014]

[0015] Q' is a heterocyclic group selected from pyrimidinyl and pyridinyl:

[0016] Y is selected from H or -NR'R'. R'R' may form an aliphatic heterocyclic ring;

[0017] or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION

[0018] The present invention relates to compounds that can inhibit protein tyrosine kinases, such as various EGFR mutants.

[0019] In the compound of formula (I):

[0020]

[0021] Q is a bicyclic heterocyclic group selected from:

[0022]

[0023] R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, lower alkyl carboxylate or lower alkyl carboxylate amide mono- or di-substituted by nitrogen; preferably selected from Cl, Br and carboxylic acid.

[0024] X is selected from -O- or -N(R')-; preferably -NH-;

[0025] R' is selected from H, halogen, halogenated lower alkyl, lower alkyl; preferably lower alkoxy or halogen.

[0026] R" is selected from:

[0027]

[0028] Preferably

[0029] Q' is selected from pyrimidinyl and pyridinyl:

[0030] Y is selected from H or -NR'R', and R'R' may form an aliphatic heterocyclic ring;

[0031] Preferably, the -NR'R' group is selected from substituted or unsubstituted N,N-dimethylamino (-NMe2), pyrrolidine, morpholine, piperidine and piperazine,

[0032] or a pharmaceutically acceptable salt thereof.

[0033] In the compound of formula (I):

[0034]

[0035] Q is:

[0036]

[0037] X is -NH-;

[0038] R is selected from chlorine and bromine;

[0039] R' is selected from: H, F, Cl, -CH3, -OCH3, -COOH;

[0040]

[0041] R" is Y is selected from:

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] Unless otherwise indicated, as used herein, the term "halogen" includes fluorine (-F), chlorine (-Cl), bromine (-Br) or iodine (-I), such as fluorine (-F) and chlorine (-Cl).

[0045] Unless otherwise specified, as used herein, the term "lower alkyl" includes 1 to 6 saturated monovalent hydrocarbon groups having straight or branched portions, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and the like.

[0046] Unless otherwise stated, as used herein, the term "lower alkenyl" embraces lower alkyl groups as defined above having at least one carbon-carbon double bond, such as -CH2-CH=CH2.

[0047] Unless otherwise indicated, as used herein, the term "lower alkynyl" encompasses lower alkyl groups as defined above having at least one carbon-carbon triple bond, such as

[0048] Unless otherwise stated, as used herein, the term "halogen-lower alkyl" includes alkyl groups substituted with 1 to 6 halogens, such as trifluoromethyl (-CF3).

[0049] Unless otherwise stated, as used herein, the term "carboxylic acid, carboxylic acid lower alkyl ester" includes carboxylic acid and / or carboxylic acid lower alkyl ester. Unless otherwise stated, as used herein, the term "lower alkoxy" includes -O-lower alkyl, wherein lower alkyl is as defined above, such as methoxy (-OCH3) and ethoxy (-OCH2CH3).

[0050] Unless otherwise indicated, as used herein, the term "amino" includes -NH2 groups, -NH-lower alkyl groups or -N(lower alkyl)2 groups, wherein lower alkyl groups are as defined above, such as methylamino (-NHMe), dimethylamino (-NMe2) and diethylamino (-NEt2).

[0051] Unless otherwise stated, as used herein, the term "hydroxyalkylamino" includes a HO-lower alkyl-NH2 group, a HO-lower alkyl-NH-lower alkyl or a HO-lower alkyl-N(lower alkyl)2 group, wherein lower alkyl is as defined above, such as -NH-CH2CH2OH.

[0052] As used herein, the term "aliphatic" is selected from lower alkyl, lower alkenyl, lower alkynyl or cyclic alkyl, alkenyl, alkynyl.

[0053] Unless otherwise indicated, as used herein, the term "aryl" comprises organic radicals derived from aromatic hydrocarbons by removing one hydrogen, such as phenyl or naphthyl, preferably phenyl, and is unsubstituted or substituted with one or two substituents selected from halogen, halogenated lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy, lower alkoxy, carboxyl, carboxyalkyl, amino, carbamoyl, carbamate, ureido, mercapto, sulfo, lower alkylene, lower alkylsulfonyl, sulfonamide; aryl comprises an aromatic ring fused to an aliphatic ring, such as a saturated or partially saturated ring.

[0054] Unless otherwise indicated, as used herein, the term "heterocyclyl" or "heterocycle" includes rings containing about 3 to 12 atoms, preferably 4 to 8 atoms, wherein one or more atoms are selected from O, N and S, and the remaining ring atoms are carbon. The concept of heterocyclyl can be a monocyclic, bicyclic, spirocyclic or even bridged ring system. Fused heterocyclic ring systems can include carbocyclic rings and only need to include one heterocyclic ring that can be aromatic or partially saturated or saturated. Bicyclic or tricyclic ring systems can include carbocyclic rings. Carbocyclic rings include cycloalkyl, cycloalkenyl or aryl rings. Examples of heterocyclic groups include, but are not limited to, azetidine, pyrrolidine, pyrrolidone, piperidine, piperidone, piperazine, morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine and hydantoin, pyrrole, indole, pyrazole, indazole, triazole, benzotriazole, imidazole, benzimidazole, thiophene, benzothiophene, thiazole, benzothiazole, furan, benzofuran, oxazole, benzazole, isoxazole, tetrazole, pyridine, pyrimidine, triazine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, methylenedioxyphenyl. Heterocyclic and heterocyclic rings may be optionally substituted and the substituents are selected from the groups defined above as substituents for the aryl group.

[0055] The present invention also discloses a method for treating a PTK expression-related disease or condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I. As used herein, the term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. In some embodiments, the subject is a human.

[0056] The compounds listed in the following examples can show inhibition of receptor tyrosine kinases (PTKs). The compounds can be administered to subjects in the form of free bases. The compounds can also be administered in the form of salts, hydrates and / or prodrugs (which will be converted into active forms in vivo).

[0057] The compounds in the following examples can be administered to a subject by various routes. These routes include, but are not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, by inhalation, vaginal, intraocular, by topical application, subcutaneous, intrafatty, intraarticular, intraperitoneal, or intrathecal. In the embodiments described herein, the compounds are preferably administered orally.

[0058] Pharmaceutical compositions having the characteristics of formula I or pharmaceutically acceptable salts thereof suitable for oral administration include but are not limited to tablets, capsules, powders, granules, pellets, pastes, powders and tinctures. Preferred pharmaceutical compositions are tablets and capsules.

[0059] The following examples are intended to further illustrate certain embodiments of the present invention and should not be construed as limiting the scope of the present invention. Any feature, structure, component, material, step or method described and / or shown in any embodiment in this specification sheet can be used together with any feature, structure, component, material, step or method described and / or shown in any other embodiment in this specification sheet or replace any feature, structure, component, material, step or method described and / or shown in any other embodiment in this specification sheet.

[0060] The inhibition results of the exemplary compounds on epidermal growth factor receptor (EGFR) containing L858R and T790M mutations are listed in the table below.

[0061] Table 1. Inhibition of epidermal growth factor receptor (EGFR) (L858R, T790M)

[0062] Examples The percentage of enzyme activity Examples The percentage of enzyme activity Examples The percentage of enzyme activity 1 26.43％ 29 55.34％ 57 81.33％ 2 48.79％ 30 48.23％ 58 75.83％ 3 16.99％ 31 61.74％ 59 81.92％ 4 7.46％ 32 70.64％ 60 81.02％ 5 33.93％ 33 63.43％ 61 36.04％ 6 9.22％ 34 71.20％ 62 59％ 7 11.29％ 35 62.01％ 63 82％ 8 36.13％ 36 55.70％ 64 65％ 9 84.74％ 37 60.88％ 65 77％ 10 18.97％ 38 57.23％ 66 23％ 11 63.66％ 39 49.13％ 67 22％ 12 45.98％ 40 70.66％ 68 15％ 13 87.89％ 41 75.32％ 69 52％ 14 93.12％ 42 58.99％ 70 16％ 15 43.54％ 43 53.22％ 71 28％ 16 52.33％ 44 87.38％ 72 93％ 17 82.58％ 45 78.53％ 73 25％ 18 82.78％ 46 73.97％ 74 40％ 19 64.42％ 47 84.72％ 75 43％ 20 74.48％ 48 57.18％ 76 51％ 21 74.82％ 49 77.63％ 77 90％ 22 27.71％ 50 85.61％ 78 70％ 23 19.49％ 51 37.44％ 79 31％ 24 81.22％ 52 92.90％ 80 47％ 25 67.42％ 53 90.88％ 81 23％ 26 25.48％ 54 88.32％ 82 42％ 27 47.12％ 55 22.75％ 83 37％ 28 48.87％ 56 21.02％ 84 29％

[0063] *: Inhibition percentage of enzyme activity (relative to DMSO control) of each compound at a concentration of 0.05 μM. The lower the percentage, the higher the inhibitory activity.

[0064] The following examples of formula I (but not limited to) can be prepared according to the method described in Scheme I-Scheme II, which is used to provide the possible synthetic route of this series of compounds and is by no means to be construed as being restrictive. These series of compounds can also be synthesized by other alternative methods.

[0065]

[0066]

[0067] wherein R, R', R", X, Q and Q' are as previously defined.

[0068] The following examples (but not limited to) can be prepared according to the range of chemistries described in Schemes I-II above.

[0069]

[0070]

[0071]

[0072]

[0073] For ease of reference, the abbreviations used have the following meanings:

[0074] EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature,

[0075] DIPEA: diisopropylethylamine, DCM: dichloromethane, DMF: N,N-dimethylformamide, DMAP: 4-N,N-dimethylaminopyridine, MsCl: methanesulfonyl chloride, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TEA: triethylamine, Pd / C: palladium on activated carbon, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, CDI: 1,1'-carbonyldiimidazole, DCC: N,N'-dicyclohexylcarbodiimide, HBTU: 2-(1h-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, BOC: tert-butoxycarbonyl protecting group,

[0076] eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minute, mmol: millimole, bis=di: di or double,

[0077] TLC: Thin layer chromatography,

[0078] Example 1 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0079] Method A:

[0080]

[0081] A solution of 2,4-dichloropyrimidine (4.0 g) and 1H-indole (4.0 g, 2.0 equivalents of pyrimidine) in anhydrous THF (10 mL) was cooled in an ice / salt bath, and a solution of methylmagnesium bromide (12 mL, 3N in hexane) was added dropwise. After the addition was complete, the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with ethyl acetate (50 mL) and thoroughly washed with saturated NaHCO (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na SO and concentrated to evaporate the solvent to give 3-(2-chloropyrimidine-4-yl)-1H-indole (4.4 g) as a yellow solid. Mass: (M+1), 231.

[0082] Method B:

[0083]

[0084] 3-(2-chloropyrimidin-4-yl)-1H-indole (4.0 g, 17 mmol), 4-fluoro-2-methoxy-5-nitroaniline (4.8 g, 26 mmol), methanesulfonic acid (0.9 mL) and isopropanol (15 mL) were charged into a 100 mL sealed tube. The resulting mixture was stirred at 120° C. for 10 hours, and TLC indicated that no starting material 3-(2-chloropyrimidin-4-yl)-1H-indole remained. The reaction was stopped at this time. The resulting mixture was condensed and diluted with ethyl acetate (250 mL). The organic layer was thoroughly washed with HCl (1 M, 50 mL×3), brine (50 mL), and dried over anhydrous Na2SO4. After concentration to dryness, a yellow solid was obtained as a crude product N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (about 4 g). Mass: (M+1), 380.

[0085] Method C:

[0086]

[0087] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidine-2-amine (580mg, 1.50mmol) was dissolved in a mixed solvent (20mL, 1:1 ratio) of MeOH and DCM. The solution was cooled with an ice bath and stirred thoroughly. Zinc powder (400mg, 6.25mmol, 5.0 equivalents) and ammonium formate (400mg, 6.25mmol, 5.0 equivalents) were added successively. The reaction progress was monitored by TLC, and the detection result showed that the reaction was completed within half an hour. The resulting solution was treated with saturated NaHCO3 solution (20mL) and brine (20mL). After drying with anhydrous Na2SO4, the solution was passed through diatomaceous earth to remove high polar impurities at the baseline of TLC. Thus, the solvent was removed by rotary evaporation, and a sticky brown solid (450mg) was obtained as a crude product. Additional purification can be accomplished using column chromatography (eluent: hexane to hexane:EtOAc = 2:1) to afford a tan solid as product N 1 -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine (340 mg). Mass: (M+1), 350.

[0088] In large-scale reactions, N 1Purification of -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine can be accomplished by following this protocol: Dissolve the crude product in a minimum amount of DMF (0.5 mL in this case) and add the solution to a large amount of water (10 mL in this case) to precipitate the product. Use suction filtration to isolate the product and dry it by flowing air. If the purity is not up to standard, a second purification may be required.

[0089] Method D:

[0090]

[0091] 4-bromocrotonic acid (500mg, 3.0mmol), THF (3mL) and anhydrous DMF (180 μ L) are loaded into a 50mL round-bottomed flask. The mixture is cooled in an ice bath, and oxalyl chloride (260 μ L, 1.0 equivalent of acid) is added dropwise. A large amount of bubbles are formed during the addition. The gained mixture is stirred half an hour in an ice bath, and then at room temperature stirred for another half an hour to obtain a bright yellow solution. Excessive oxalyl chloride is removed by rotary evaporation, and residual is taken away with toluene (about 1mL), yellow oil is obtained as thick acyl chloride, which is diluted with anhydrous THF and kept on one side for other reaction.

[0092] On the other hand, N 1 -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine (500 mg, 1.2 mmol) and potassium carbonate (400 mg, 3.0 mmol) were dissolved in a mixed solvent of THF:H2O (5 mL:2.5 mL). The solution was cooled in an ice bath, and the previously prepared acid chloride solution in THF was added dropwise until TLC indicated that no amine remained.

[0093] The obtained mixture is diluted with DCM (20mL).After being treated with saturated NaHCO (about 10mL) and brine (about 10mL), the organic layer is dried with anhydrous NaSO and passed through silica gel to remove the high polar impurities at the baseline of TLC. The solvent is removed by rotary evaporation to obtain 500mg of the crude product as a brown solid. Additional purification can be completed with column chromatography (eluent: hexane to hexane: EtOAc=1:2), and a tan solid (250mg) is obtained as product (E) -4- bromo-N- (5- ((4- (1H- indol-3-yl) pyrimidine-2-yl) amino) -2- fluoro- 4- methoxyphenyl) but-2-eneamide. Mass: (M+1), 497.

[0094] Method E:

[0095]

[0096] (E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)but-2-enamide (1.0 g, 2.0 mmol) was dissolved in DMF (1.0 mL). N,N-dimethylamine hydrochloride (500 mg, 6.0 mmol, 3.0 equiv) and N,N-diisopropylethylamine (1.1 mL, 6.0 mmol, 3.0 equiv) were added sequentially, and the resulting mixture was stirred at room temperature overnight. Meanwhile, TLC analysis indicated that the starting material was completely consumed. A large amount of water (mL) was added inside the reaction vessel to precipitate the product. Filtration was applied to separate the crude product as a tan solid (1.0 g). Further purification can be accomplished with column chromatography (eluent: DCM to 10% MeOH in DCM) to give a tan solid (400 mg) as the desired product (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide.

[0097] At this stage, the purity of the product varied from 95% to 99%. A second purification could be accomplished by recrystallization from EtOH (in this particular example 260 mg of pure product was obtained, >99% HPLC purity).

[0098] Mass:(M+1),461.

[0099] Due to the limitation of length and space, only the complete preparation procedure of (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide is disclosed in detail in Example 1. Other compounds can be prepared by similar methods by changing specific chemicals in specific steps, which will be shown in the following examples respectively.

[0100] About Protecting Groups

[0101] It is worth mentioning that, in some special cases, protection of reactive functional groups may be necessary to achieve some of the above reactions. Generally speaking, the need for such protecting groups and the conditions for adding and / or removing such groups are obvious to those skilled in the art of organic synthesis.

[0102] Example 2 (E)-4-(Dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

[0103] This compound was prepared analogously to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 475.

[0104] Example 3 (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0105] This compound was prepared according to Example 1 by substituting 2,4-dichloro-5-methylpyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 445.

[0106] Example 4 (E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0107] This compound was prepared analogously to Example 1 by substituting 2,4-dichloro-5-(trifluoromethyl)pyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 529.

[0108] Example 5 (E)-4-(Dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide

[0109] This compound was prepared analogously to Example 1 by substituting 2,4-dichloro-5-fluoropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 479.

[0110] Example 6 (E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0111] This compound was prepared analogously to Example 1 by substituting 2,4,5-trichloropyrimidine for 5-2,4-dichloropyrimidine in Method A. Mass: (M+1), 495.

[0112] Example 7 (E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0113] This compound was prepared analogously to Example 1 by substituting 5-bromo-2,4-dichloropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 495.

[0114] Example 8 (E)-N-(2-(Dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide

[0115] By substituting 1-methyl-1H-indole for 1H-indole in Method A, adding S with dimethylamine prior to the reduction step (Method C) N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 542.

[0116] S N Typical methods for Ar reactions

[0117]

[0118] N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidine-2-amine (300 mg, 0.75 mmol, 1.0 equiv.), dimethylamine hydrochloride (600 mg, 10 equiv.), KCO (1.0 g, 10 equiv.) and acetonitrile (20 mL) were loaded into a sealed tube. The resulting mixture was stirred at about 75-80 ° C for 12 hours. The resulting reaction mixture was filtered and the filtrate was diluted with DCM (20 mL). After being treated with brine (10 mL), the organic layer was dried over anhydrous NaSO and concentrated. Column chromatography gave a brown solid (200 mg) as the desired product 2-methoxy-N 4 ,N 4 -Dimethyl-N 1 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine.

[0119] Example 9 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide

[0120] This compound was prepared analogously to Example 1 by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 473.

[0121] Example 10 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)-4-morpholinobut-2-enamide

[0122] By substituting 1-methyl-1H-indole for 1H-indole in Method A, adding S with methylamine prior to the reduction step (Method C) N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 528.

[0123] Example 11 (E)-4-(Dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2-enamide

[0124] By substituting 1-methyl-1H-indole for 1H-indole in Method A, adding S with methylamine prior to the reduction step (Method C) N Ar step, this compound was prepared similarly to Example 1. Mass: (M+1), 486.

[0125] Example 12 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide

[0126] Addition of S using methylamine prior to the reduction step (Method C) N Ar step, this compound was prepared similarly to Example 1. Mass: (M+1), 472.

[0127] Example 13 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide

[0128] This compound was prepared analogously to Example 9 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 474.

[0129] Example 14 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide

[0130] This compound was prepared analogously to Example 13 by substituting 2-methoxy-4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 458.

[0131] Example 15 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0132] This compound was prepared analogously to Example 13 by substituting 4-chloro-2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 478.

[0133] Example 16 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0134] This compound was prepared analogously to Example 13 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 444.

[0135] Example 17 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide

[0136] This compound was prepared analogously to Example 1 by substituting 2-methoxy-4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 457.

[0137] Example 18 (E)-4-(Dimethylamino)-N-(4-methoxy-2-methyl-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

[0138] This compound was prepared analogously to Example 17 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 471.

[0139] Example 19 (E)-4-(Dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

[0140] This compound was prepared according to Example 8 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 457.

[0141] Example 20 (E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0142] This compound was prepared analogously to Example 1 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 443.

[0143] Example 21 (E)-N-(2-Chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide

[0144] This compound was prepared according to Example 19 by substituting 4-chloro-5-nitroaniline for 2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 491.

[0145] Example 22 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0146] This compound was prepared analogously to Example 1 by substituting 4-chloro-2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 477.

[0147] Example 23 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide

[0148] Before the reduction step (method C), S using dimethylamine was added. N This compound was prepared analogously to Example 1 following the Ar step and substituting piperazine for dimethylamine in Method E. Mass: (M+1), 527.

[0149] Example 24 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-morpholinobut-2-enamide

[0150] Before the reduction step (method C), S using morpholine was added. NThis compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 570.

[0151] Example 25 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-morpholinophenyl)-4-morpholinobut-2-enamide

[0152] By substituting 1-methyl-1H-indole for 1H-indole in Method A, adding S using morpholine prior to the reduction step (Method C) N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 584.

[0153] Example 26 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide

[0154] By substituting 7-azaindole for the 1H-indole in Method A, the addition of S with methylamine prior to the reduction step (Method C) N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 515.

[0155] Example 27 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide

[0156] Addition of S using methylamine prior to the reduction step (Method C) N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 514.

[0157] Example 28 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0158] Before the reduction step (method C), S using dimethylamine was added. N This compound was prepared similarly to Example 1 following the Ar step and substituting piperidine for the dimethylamine in Method E. Mass: (M+1), 526.

[0159] Example 29 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide

[0160] Before the reduction step (method C), S using dimethylamine was added. N This compound was prepared similarly to Example 1 following the Ar step and substituting 1-methylpiperazine for the dimethylamine in Method E. Mass: (M+1), 541.

[0161] Example 30 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0162] Before the reduction step (method C), S using dimethylamine was added. N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 528.

[0163] Example 31 (E)-N-(2-(Diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperidin-1-yl)but-2-enamide

[0164] By substituting 1-methyl-1H-indole for 1H-indole in Method A, S using diethylamine was added prior to the reduction step (Method C). N This compound was prepared similarly to Example 1 following the Ar step and substituting piperidine for the dimethylamine in Method E. Mass: (M+1), 568.

[0165] Example 32 (E)-N-(2-(Diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide

[0166] By substituting 1-methyl-1H-indole for 1H-indole in Method A, S using diethylamine was added prior to the reduction step (Method C). N This compound was prepared similarly to Example 1 following the Ar step and substituting 1-methylpiperazine for the dimethylamine in Method E. Mass: (M+1), 583.

[0167] Example 33 (E)-N-(2-(Diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide

[0168] By substituting 1-methyl-1H-indole for 1H-indole in Method A, S using diethylamine was added prior to the reduction step (Method C). N This compound was prepared analogously to Example 1 following the Ar step and substituting piperazine for dimethylamine in Method E. Mass: (M+1), 569.

[0169] Example 34 (E)-N-(2-(Diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide

[0170] By substituting 1-methyl-1H-indole for 1H-indole in Method A, S using diethylamine was added prior to the reduction step (Method C). N This compound was prepared analogously to Example 1 following the Ar step and substituting pyrrolidine for the dimethylamine in Method E. Mass: (M+1), 554.

[0171] Example 35 (E)-N-(2-(Diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide

[0172] By substituting 1-methyl-1H-indole for 1H-indole in Method A, S using diethylamine was added prior to the reduction step (Method C). N This compound was prepared analogously to Example 1 following the Ar step and substituting morpholine for the dimethylamine in Method E. Mass: (M+1), 570.

[0173] Example 36 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide

[0174] This compound was prepared analogously to Example 29 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 542.

[0175] Example 37 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide

[0176] This compound was prepared analogously to Example 23 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 528.

[0177] Example 38 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide

[0178] This compound was prepared analogously to Example 34 by substituting 7-azaindole for 1H-indole in Method A and dimethylamine for diethylamine in Method E. Mass: (M+1), 513.

[0179] Example 39 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0180] This compound was prepared analogously to Example 30 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1),529.

[0181] Example 40 (E)-N-(2-(Dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide

[0182] This compound was prepared analogously to Example 29 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 555.

[0183] Example 41 (E)-N-(2-(Dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide

[0184] This compound was prepared analogously to Example 23 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 541.

[0185] Example 42 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide

[0186] Before the reduction step (method C), S using 2-aminoethanol was added. N Ar step, this compound was prepared similarly to Example 35. Mass: (M+1), 558.

[0187] Example 43 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide

[0188] Before the reduction step (method C), S using 2-aminoethanol was added. N Ar step, this compound was prepared similarly to Example 34. Mass: (M+1), 542.

[0189] Example 44 (E)-4-(Dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide

[0190] By substituting 1-methyl-1H-indole for 1H-indole in Method A, adding S with dimethylamine prior to the reduction step (Method C) N Ar step, this compound was prepared similarly to Example 1. Mass: (M+1), 500.

[0191] Example 45 (E)-N-(2-(Dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide

[0192] This compound was prepared analogously to Example 44 by substituting pyrrolidine for dimethylamine in Method E. Mass: (M+1), 526.

[0193] Example 46 (E)-N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide

[0194] This compound was prepared analogously to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A and 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 487.

[0195] Example 47 (E)-N-(2-Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide

[0196] This compound was prepared analogously to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A and morpholine for dimethylamine in Method E. Mass: (M+1), 517.

[0197] Example 48 (E)-N-(2-Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide

[0198] This compound was prepared analogously to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A and pyrrolidine for dimethylamine in Method E. Mass: (M+1), 501.

[0199] Example 49 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol

[0200] This compound was prepared analogously to Example 43, substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine for 1-methyl-1H-indole and modifying Method D to substitute 2-chloropyridine for pyridine. Mass: (M+1), 483.

[0201] Method for replacing pyridine by Buchwald reaction

[0202]

[0203] Ethyl 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)amino)benzoate (100 mg, 0.22 mmol, 1.0 equiv), 2-chloropyridine (25 mg, 1.0 equiv), K3PO4 (140 mg, 3.0 equiv), Pd2(dba)3 (10 mg, ca. 10% wt) and BINAP (10 mg, ca. 10% wt) were added to toluene (2 mL). The resulting mixture was purged with nitrogen and heated in a sealed tube at about 110 °C for 12 h. The reaction was stopped at this point and the resulting mixture was treated with saturated NaHCO3 (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Purification by preparative TLC gave a yellow solid as the desired product (55 mg, 48% yield).

[0204] Example 50 N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0205] By replacing 1-methyl-1H-pyrrolo[2,3-b]pyridine in method A with 1-methyl-1H-indole, N This compound was prepared similarly to Example 8, substituting 2-(methylamino)ethan-1-ol for dimethylamine in the Ar step. To obtain the final product, the following steps were also employed. Mass: (M+1), 473.

[0206] Typical method of EDC esterification reaction:

[0207]

[0208] A round-bottom flask was charged with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethan-1-ol (450 mg, 1.0 mmol), benzoic acid (145 mg, 1.2 mmol, 1.2 equiv), EDC hydrochloride (290 mg, 1.5 mmol, 1.5 equiv), 4-dimethylaminopyridine (12 mg, 0.1 mmol, 0.1 equiv) and DCM (10 mL). The resulting mixture was stirred at room temperature overnight (about 12 hours), and TLC analysis indicated that the starting material 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethan-1-ol was completely consumed. The reaction was stopped at this point, and the resulting mixture was treated with saturated NaHCO3 (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Purification by column chromatography gave a white solid as the desired product (390 mg, 0.7 mmol, 70% yield).

[0209] *DCC, CDI or HBTU can replace EDC hydrochloride as coupling reagent in some cases.

[0210] Zinc reduction:

[0211]

[0212] Restore the program to the same level as Example 1 Method CThe reaction mixture was similarly prepared as described in . Starting from ethyl 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)benzoate (280 mg, 0.5 mmol) to give the desired product 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl benzoate (200 mg, 0.38 mmol, 76% yield).

[0213] Typical method for EDC coupling reaction to form amides:

[0214]

[0215] Starting materials acrylic acid (20 mg, about 1.1 equivalents) and HOBt hydrate (32 mg, about 1.0 equivalents) were added to DCM (2 mL). At the same time, EDC hydrochloride (70 mg, about 1.5 equivalents) was added, and then starting material benzoic acid 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl ester (130 mg, 0.25 mmol, 1.0 equivalents) was added. The resulting mixture was stirred overnight until TLC analysis showed that the starting material amine was completely consumed. The reaction was stopped at this time, and the resulting mixture was treated with saturated NaHCO (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na SO and concentrated to dryness. A white solid was obtained as the desired product (82 mg, 0.14 mmol, 56% yield) by preparative TLC.

[0216] Typical method for ester hydrolysis:

[0217]

[0218] The starting material, ethyl 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)benzoate (30 mg, 0.05 mmol) was dissolved in a mixed solvent of methanol:HO (0.9 mL:0.1 mL). Meanwhile, LiOH (2.5 mg, 2.0 eq) was added to the solution and stirred at room temperature for 2 hours. TLC analysis indicated that the reaction was complete and the resulting mixture was condensed to dryness. The residue was dissolved in DCM (5 mL) and treated with saturated NH4Cl (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. A white solid was obtained as the desired product by preparative TLC (15 mg, 0.03 mmol, 60% yield).

[0219] Example 51 N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0220] This compound was prepared analogously to Example 42 by modifying Method D to an EDC-catalyzed coupling reaction with acrylic acid. Mass: (M+1), 459.

[0221] Example 52N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N 2 -(Pyrimidin-4-yl)benzene-1,2,4-triamine

[0222] Add the use of N before the reduction step (method C) 1 ,N 1 -Dimethylethylene-1,2-diamine N This compound was prepared analogously to Example 48 by following the Ar step and changing Method D to the Buchwald approach with 4-chloropyrimidine. Mass: (M+1), 510.

[0223] Example 53 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol

[0224] This compound was prepared analogously to Example 42 by adapting Method D to the Buchwald method using 2-chloropyridine. Mass: (M+1), 482.

[0225] Example 54N1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N 2 -(Pyridin-2-yl)benzene-1,2,4-triamine

[0226] Add the use of N before the reduction step (method C) 1 ,N 1 -Dimethylethane-1,2-diamine N This compound was prepared analogously to Example 43 by following the Ar step and changing Method D to the Buchwald method using 4-chloropyrimidine. Mass: (M+1), 523.

[0227] Example 55 2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

[0228] This compound was prepared analogously to Example 49 by substituting 7-azaindole for 1-methyl-1H-indole in Method A. Mass: (M+1), 470.

[0229] Example 56 2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

[0230] This compound was prepared analogously to Example 49 by substituting 1H-indole for 1-methyl-1H-indole in Method A. Mass: (M+1), 469.

[0231] Example 57 2-((4-((4-(5-Fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

[0232] This compound was prepared analogously to Example 49 by substituting 5-fluoro-1-methyl-1H-indole for 1-methyl-1H-indole in Method A. Mass: (M+1), 501.

[0233] Example 58 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynamide

[0234] This compound was prepared analogously to Example 54 by substituting 5-fluoro-1-methyl-1H-indole for 1-methyl-1H-indole in Method A and converting Method D to an EDC-catalyzed coupling reaction with but-2-ynoic acid. Mass: (M+1), 530.

[0235] Example 59 (E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide

[0236] This compound was prepared analogously to Example 58 by modifying Method D to an EDC-catalyzed coupling reaction with crotonic acid. Mass: (M+1), 532.

[0237] Example 60 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol

[0238] This compound was prepared analogously to Example 53 by adapting Method D to the Buchwald method using 4-chloropyrimidine. Mass: (M+1), 483.

[0239] Example 61 (E)-N-(5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-hydroxyethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide

[0240] Prior to the reduction step (Method C), the N-terminal residue was replaced by 2-(methylamino)ethan-1-ol. 1 ,N 1 -Dimethylethane-1,2-diamine as S N Ar reagents, this compound was prepared similarly to Example 59. Mass: (M+1), 504.

[0241] Example 62 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0242] This compound was prepared analogously to Example 1 by substituting 7-azaindole for 1H-indole in Method A and morpholine for dimethylamine in Method E. Mass: (M+1), 504.

[0243] Example 63 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0244] This compound was prepared analogously to Example 62 by substituting 4-chloro-2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 520.

[0245] Example 64 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-morpholinobut-2-enamide

[0246] This compound was prepared analogously to Example 62 by substituting 2-methoxy-4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 500.

[0247] Example 65 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0248] This compound was prepared analogously to Example 62 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 486.

[0249] Example 66 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0250] This compound was prepared analogously to Example 62 by substituting piperidine for morpholine in Method E. Mass: (M+1), 502.

[0251] Example 67 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0252] This compound was prepared analogously to Example 63 by substituting piperidine for morpholine in Method E. Mass: (M+1),519.

[0253] Example 68 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(piperidin-1-yl)but-2-enamide

[0254] This compound was prepared analogously to Example 64 by substituting piperidine for morpholine in Method E. Mass: (M+1), 498.

[0255] Example 69 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0256] This compound was prepared analogously to Example 65 by substituting piperidine for morpholine in Method E. Mass: (M+1), 484.

[0257] Example 70 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0258] This compound was prepared analogously to Example 66 by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 514.

[0259] Example 71 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0260] This compound was prepared analogously to Example 62 by substituting dimethylamine for morpholine in Method E. Mass: (M+1), 462.

[0261] Example 72 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-morpholinobut-2-enamide

[0262] This compound was prepared analogously to Example 62 by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 517.

[0263] Example 73 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide

[0264] By adding S with methylamine before the reduction step (method C) N Ar step, this compound was prepared similarly to Example 71. Mass: (M+1), 473.

[0265] Example 74 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(piperidin-1-yl)but-2-enamide

[0266] By adding S with methylamine before the reduction step (method C) N Ar step, this compound was prepared similarly to Example 66. Mass: (M+1), 514.

[0267] Example 75 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)but-2-enamide

[0268] This compound was prepared analogously to Example 73 by substituting 5-azaspiro[2.4]heptan-7-ol for dimethylamine in Method E. Mass: (M+1), 542.

[0269] Example 76 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0270] By adding S using dimethylamine before the reduction step (method C) N Ar step, this compound was prepared similarly to Example 71. Mass: (M+1), 488.

[0271] Example 77 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide

[0272] This compound was prepared analogously to Example 76 by substituting piperidine for dimethylamine in Method E. Mass: (M+1), 528.

[0273] Example 78 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino-4-methoxyphenyl)-4-morpholinobut-2-enamide

[0274] By adding S using ammonium before the reduction step (method C) N This compound was prepared similarly to Example 62 by the Ar step and then protection of the -NH2 group by -Boc. The other steps were accomplished by conventional protocols and an additional step using TFA was used to remove the -Boc group following Method E. Mass: (M+1), 502.

[0275] Example 79 (E)-N-(5-((5-cyano-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0276] This compound was prepared analogously to Example 2 by substituting 2,4-dichloropyrimidine for 2,4-dichloropyrimidine-5-carbonitrile in Method A. Mass: (M+1), 500.

[0277] Example 80 (E)-2-((5-(4-(Dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid

[0278] This compound was prepared similarly to Example 79 using a subsequent acid hydrolysis procedure. Mass: (M+1), 519.

[0279] Example 81 (E)-2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid ethyl ester

[0280] This compound was prepared analogously to Example 80 by subsequent EDC esterification using ethanol. Mass: (M+1), 547.

[0281] Example 82 (E)-N-(5-((5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide

[0282] This compound was prepared according to Example 1 by substituting 2,4-dichloro-5-methylpyrimidine for 2,4-dichloropyrimidine-5-carbonitrile in Method A. Mass: (M+1), 486.

[0283] Example 83 (E)-2-((5-(4-(Dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid

[0284] This compound was prepared similarly to Example 82 using a subsequent acid hydrolysis procedure. Mass: (M+1), 505.

[0285] Example 84 (E)-2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid ethyl ester

[0286] This compound was prepared analogously to Example 83 by subsequent EDC esterification using ethanol. Mass: (M+1), 533.

Claims

1. A compound of formula I in: Q is a bicyclic heterocyclic group selected from: R is selected from H, halogen, halogen-lower alkyl, -CN, carboxylic acid, carboxylic acid ester or carboxamide; X is selected from a direct bond, -O-, -S- or -N(R')-; R' is selected from H, halogen, halogenated lower alkyl, lower alkyl, hydroxy, lower alkoxy, amino, hydroxyalkylamino, aryl or heterocyclyl; R" is selected from: Q' is a heterocyclic group selected from pyrimidinyl and pyridinyl: Y is selected from H or -NR'R'. R'R' may form an aliphatic heterocyclic ring; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein the compound of formula I Q is a bicyclic heterocyclic group selected from: R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, lower alkyl carboxylate or lower alkyl carboxylate amide mono- or di-substituted by nitrogen; preferably selected from Cl, Br and carboxylic acid. X is selected from -O- or -N(R')-; preferably -NH-; R' is selected from H, halogen, halogenated lower alkyl, lower alkyl; preferably lower alkoxy or halogen. R" is selected from: Preferably Q' is selected from pyrimidinyl and pyridinyl: Y is selected from H or -NR'R', and R'R' may form an aliphatic heterocyclic ring; Preferably, the -NR'R' group is selected from substituted or unsubstituted N,N-dimethylamino (-NMe2), pyrrolidine, morpholine, piperidine and piperazine, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound of formula I: Q is X is -NH-; R is selected from H, fluorine, chlorine, bromine, methyl or trifluoromethyl; R' is selected from: H, F, Cl, -CH3, -OCH3, -COOH; R" is Y is selected from: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which is selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is selected from: (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-4-(dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-4-(dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide; (E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)-4-morpholinobut-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-2-methyl-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide; (E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-morpholinobut-2-enamide; (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-morpholinophenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide; (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperazin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(4-methylpiperazin-1-yl)but-2-enamide; (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(piperazin-1-yl)but-2-enamide; (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-4-(dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide; (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide; (E)-N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(2-Fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(pyrrolidin-1-yl)but-2-enamide; 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol; N-(2-((2-hydroxyethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide; N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide; N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N 2 -(pyrimidin-4-yl)benzene-1,2,4-triamine; 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyridin-2-ylamino)phenyl)amino)ethan-1-ol; N 1 -(2-(dimethylamino)ethyl)-5-methoxy-N 1 -Methyl-N 4 -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-N 2 -(Pyridin-2-yl)benzene-1,2,4-triamine; 2-((4-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol; 2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol; 2-((4-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-ynamide; (E)-N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide; 2-((5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol; (E)-N-(5-((4-(5-fluoro-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-hydroxyethyl)(methyl)amino)-4-methoxyphenyl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-morpholinobut-2-enamide; (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(7-hydroxy-5-azaspiro[2.4]hept-5-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-(piperidin-1-yl)but-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino-4-methoxyphenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((5-cyano-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid; (E)-ethyl 2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate; (E)-N-(5-((5-cyano-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid; (E)-ethyl 2-((5-(4-(dimethylamino)but-2-enylamino)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, which is selected from: (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-4-(dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-4-(dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)but-2-enamide; (E)-N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(5-((5-bromo-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobut-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide; (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)-4-morpholinobut-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)but-2-enamide; or a pharmaceutically acceptable salt thereof.

7. A method for synthesizing the compound of formula I according to claim 1, wherein the method is carried out by the synthesis procedure in the following scheme 1 or scheme 2: Scheme I Solution II wherein R, R', R", X, Q and Q' are as previously defined.

8. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate of the compound, and a pharmaceutically acceptable carrier.

9. A compound suitable for use in a method for treating an EGFR mutant comprising L858R, T790M in a subject by administering an effective amount of the compound according to any one of claims 1 to 6.

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