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

Abstract

The present invention relates to compounds of formula I characterized by the inhibition of protein tyrosine kinases (PTKs), such as EGFR mutants, their pharmaceutical compositions containing therapeutically effective amounts of the corresponding compounds, and methods of use therefor.

Description

[Technical Field]

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

[0002] The present invention relates to compounds characterized by the inhibition of protein tyrosine kinases (PTKs), such as EGFR mutants, their pharmaceutical compositions containing therapeutically effective amounts of the corresponding compounds, and methods of use therefor. [Background technology]

[0003] Protein tyrosine kinases (PTKs) are a large family of enzymes that catalyze the phosphorylation process, transferring a phosphate group from a nucleoside triphosphate (often ATP) to an amino acid residue in a protein. They span the cell membrane and act as "switches" in cell signaling cascades, from extracellular signals through the membrane to the cytoplasm and then to the nucleus. The epidermal growth factor receptor (EGFR) belongs to a family of receptor tyrosine kinases (RTKs), including EGFR / ERBB1, HER2 / ERBB2 / NEU, HER3 / ERBB3, and HER4 / ERBB4. Binding of ligands, such as epidermal growth factor (EGF), induces conformational changes in EGFR, promoting the formation of receptor homodimers or heterodimers and activating EGFR tyrosine kinase activity. Overexpression or activation of EGFR, as well as the acquired EGFR T790M mutation, have been observed in human cancers and are associated with high rates of cancer cell proliferation and drug resistance. The EGFR T790M mutation, a gatekeeper mutation of threonine-methionine (T790M) in the EGFR gene, was present in approximately 50-60% of cases of acquired resistance.

[0004] The present invention disclosed herein relates to compounds having inhibitory activity against EGFR mutations, such as L858R, T790M, C797S, exon 20 insertion, and HER2. Examples of compounds similar in structure to those of the present invention are disclosed in the following documents: WO2009158571, WO2013014448, WO2015127872, WO2015188777, WO2015195228, WO2016023422, WO2016029839, WO2016054987, WO2016070816, WO2016173438, WO2017086830, WO2017120429, WO2017162510, WO2017205459. Summary of the Invention [Problem to be solved by the invention]

[0005] Some embodiments disclosed herein relate to inhibitors of PTKs represented by Formula I, or a pharmaceutically acceptable salt thereof, primarily directed against EGFR mutants: [Means for solving the problem]

[0006] [ka]

[0007] During the ceremony: Q is a bicyclic heterocyclyl selected from:

[0008] [ka]

[0009] R is selected from H, halogen, halogen-lower alkyl, —CN, a carboxylic acid, a carboxylic acid ester, or a carboxylic acid amide; X is selected from a direct bond, —O—, —S—, or —N(R′)—; R' is selected from H, halogen, halogen-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxylalkylamino, aryl, or heterocyclyl; R″ is selected from the following:

[0010] [ka]

[0011] Q' is heterocyclyl and is selected from pyrimidinyl and pyridinyl: Y is selected from H and -NR'R', where R'R' can form an aliphatic heterocyclic ring. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention is directed to compounds that can inhibit protein tyrosine kinases, such as various EGFR mutants.

[0013] [ka]

[0014] In the compounds of formula I, Q is a bicyclic heterocyclyl selected from:

[0015] [ka]

[0016] R is selected from H, halogen, methyl, trifluoromethyl, -CN, carboxylic acid, carboxylic acid lower alkyl ester or carboxylic acid lower alkyl amide, mono- or dual-substituted with 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, halogen-lower alkyl, lower alkyl, preferably lower alkoxy or halogen; R″ is selected from the following:

[0017] [ka]

[0018] Q' is selected from pyrimidinyl and pyridinyl: Y is selected from H or -NR'R', where R'R' can 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.

[0019] [ka]

[0020] In compounds of formula I, Q is:

[0021] [ka]

[0022] X is -NH-; R is selected from chlorine and bromine; R' is selected from the following: H, F, Cl, -CH3, -OCH3, -COOH;

[0023] [ka]

[0024] [ka]

[0025] R'' is the compound 10; Y is selected from:

[0026] [ka]

[0027] or a pharmaceutically acceptable salt thereof.

[0028] The term "halogen," as used herein, unless otherwise indicated, includes fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I), e.g., fluoro (-F) and chloro (-Cl).

[0029] The term "lower alkyl," as used herein, unless otherwise indicated, includes one to six saturated monovalent hydrocarbon radicals having straight or branched moieties, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and the like.

[0030] The term "lower alkenyl," as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon double bond, e.g., -CH2-CH=CH2.

[0031] The term "lower alkynyl," as used herein, unless otherwise indicated, includes lower alkyl groups, as defined above, having at least one carbon-carbon triple bond, e.g., -CH2-C≡CH.

[0032] The term "halogen-lower alkyl," as used herein, unless otherwise indicated, includes 1 to 6 halogen-substituted alkyl, such as trifluoromethyl (-CF3).

[0033] As used herein, the term "carboxylic acid, carboxylic acid lower alkyl ester" includes carboxylic acid and / or carboxylic acid lower alkyl ester unless otherwise specified. As used herein, the term "lower alkoxy" includes, unless otherwise specified, -O-lower alkyl groups in which lower alkyl is as defined above, such as methoxy (-OCH) and ethoxy (-OCHCH).

[0034] The term "amino," as used herein, unless otherwise indicated, includes the group -NH, -NH-lower alkyl, or -N(lower alkyl), where lower alkyl is as defined above, for example, methylamino (-NHMe), dimethylamino (-NMe), and diethylamino (-NEt).

[0035] The term "hydroxylalkylamino," as used herein, unless otherwise indicated, refers to the group HO-lower alkyl-NH, HO-lower alkyl-NH-lower alkyl, or HO-lower alkyl-N(lower alkyl) where lower alkyl is as defined above, such as -NH-CHCHOH.

[0036] The term "aliphatic" as used herein is selected from lower alkyl, lower alkenyl, lower alkynyl or cyclic alkyl, cyclic alkenyl, cyclic alkynyl.

[0037] The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, preferably phenyl, such as phenyl or naphthyl, and is unsubstituted or substituted with one or two substituents selected from halogen halogen-lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cyano, lower alkylcyano, hydroxy-lower alkoxy, carboxy, carboxyalkyl, aminocarbamoyl, carbamate, ureido, mercapto, sulfo, lower alkoxysulfinyl, lower alkanesulfonyl, sulfonamido; aryl includes one aromatic ring fused with an aliphatic ring, such as a saturated or partially saturated ring.

[0038] The term "heterocyclyl" or "heterocyclic," as used herein, unless otherwise indicated, contains about 3 to 12 atoms, preferably 4 to 8 atoms, where one or more atoms are selected from O, N, and S, while the remainder of the ring atoms are carbon. The heterocyclyl concept encompasses monocyclic, bicyclic, spirocyclic, and even bridged ring systems. A fused heterocyclic ring system need contain only one heterocyclic ring, which may contain a carbocyclic ring and may be aromatic or partially saturated or saturated. A bicyclic or tricyclic ring system may contain a carbocyclic ring. A carbocyclic ring includes a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. Examples of heterocyclyl groups include, but are not limited to, azetidine, pyrrolidine pyrrolidinone, piperidine piperidinone, piperazine morpholine, oxetane, tetrahydrofuran, tetrahydropyran, imidazolidine, pyrazolidine, and hydantoin, pyrrole indole pyrazole indazole, trizole, benzotrizole, imidazole, benzimdazole, thiophene, benzothiophene, thiozole, benzothiozole, furan, benzofuran, oxazole, benzoxazole, isoxazole, tetrazole, pyridine pyrimidine trizine, quinoline, isoquinoline, quinazoline, indoline, indolinone, benzotetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, and methylenedioxyphenyl. Heterocycles and heterocyclic rings can be optionally substituted, and the substituents may be selected from the group defined above as substituents for aryl.

[0039] The present invention also discloses a method of treating a disease or disorder associated with PTK expression in a subject in need of such treatment, 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, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0040] The compounds in the following examples can exhibit receptor tyrosine kinase (PTK) inhibition. The compounds can be administered to a subject in the form of a free base. They can also be administered in the form of a salt, hydrate, and / or prodrug (which is converted to an active form in vivo).

[0041] The compounds of the following examples can be administered to a subject via various routes, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, intravaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular, intraperitoneal or intrathecal. In this embodiment, the compounds are preferably administered orally.

[0042] Pharmaceutical compositions characterized by Formula I or a pharmaceutically acceptable salt thereof suitable for oral administration include tablets, capsules, dusts, granules, drops, pastes, powders, and tinctures, of which preferred pharmaceutical compositions are tablets and capsules.

[0043] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention. Any feature, structure, component, material, step, or method described and / or illustrated in any embodiment herein may be used in conjunction with or in place of any feature, structure, component, material, step, or method described and / or illustrated in any other embodiment herein.

[0044] For example, the inhibitory results of the compounds against epidermal growth factor receptor (EGFR) mutants including L858R and T790M are shown in the table below.

[0045] [Table 1]

[0046] *Inhibition rate of enzyme activity of each compound at 0.05 μM concentration (relative to DMSO control). The lower the inhibition rate, the higher the inhibitory activity.

[0047] The following examples of Formula I can be prepared according to the methods described in Scheme I-Scheme II, which are used to provide possible synthetic routes for this series of compounds, but are not intended to be limiting in any way. These compounds may also be synthesized by other alternative approaches.

[0048] [ka]

[0049] [ka]

[0050] [ka]

[0051] wherein R, R', R'', X, Q, and Q' are as defined above.

[0052] The following examples can be prepared according to, but are not limited to, a range of chemical processes set forth above in Schemes I-II.

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] For ease of reference, the following abbreviations are used and have the following meanings: EtOH: ethanol, MeOH: methanol, IPA: isopropanol, EtOAc: ethyl acetate, RT: room temperature, 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-butyloxycarbonyl protecting group. eq: equivalent, g: gram, mg: milligram, ml: milliliter, min: minute, mmol: millimole, bis = di: 2 or dual, TLC: thin layer chromatography;

[0058] Example 1 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide Method A:

[0059] [ka]

[0060] 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, hexanes) was added dropwise. After the addition was complete, the resulting mixture was stirred overnight at room temperature. The resulting mixture was then diluted with ethyl acetate (50 mL) and washed thoroughly with saturated NaHCO (25 mL) and brine (25 mL). The organic layer was dried over anhydrous NaSO and concentrated to dryness to give a yellow solid as 3-(2-chloropyrimidin-4-yl)-1H-indole (4.4 g). Mass: (M+1), 231. Method B:

[0061] [ka]

[0062] A 100 mL sealed tube was charged with 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). The resulting mixture was stirred at 120 °C for 10 hours, and TLC showed that no starting 3-(2-chloropyrimidin-4-yl)-1H-indole remained. The reaction was stopped at this point. The resulting mixture was concentrated 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, crude product N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (approximately 4 g) was obtained as a yellow solid. Mass: (M+1), 380. Method C:

[0063] [ka]

[0064] N-(4-Fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (580 mg, 1.50 mmol) was dissolved in a mixture of MeOH and DCM (20 mL, 1:1 ratio). The solution was cooled in an ice bath and stirred thoroughly. Zinc powder (400 mg, 6.25 mmol, 5.0 equiv.) and ammonium formate (400 mg, 6.25 mmol, 5.0 equiv.) were added sequentially. The reaction progress was monitored by TLC and was shown to be complete within 30 min. The resulting solution was treated with saturated NaHCO3 solution (20 mL) and brine (20 mL). After drying over anhydrous Na2SO4, the solution was passed through Celite to remove highly polar impurities at the TLC baseline. The solvent was then removed by rotary evaporation to give the crude product as a brown viscous solid (450 mg). Further purification can be achieved by column chromatography (eluent: hexane to hexane:EtOAc=2:1) ​​to give product N 1A tan solid was obtained as -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine (340 mg). Mass: (M+1), 350.

[0065] In large scale reactions, N 1 Purification of -(4-(1H-indol-3-yl)pyrimidin-2-yl)-4-fluoro-6-methoxybenzene-1,3-diamine can be achieved by following the protocol below: the crude product was dissolved in a minimum amount of DMF (0.5 mL in this case) and the solution was added to a large amount of water (10 mL in this case) to precipitate the product. Suction filtration was applied, and the product was isolated and dried under airflow. If the purity was not satisfactory, a second purification run may be required. Method D:

[0066] [ka]

[0067] A 50 mL round-bottom flask was charged with 4-bromocrotonic acid (500 mg, 3.0 mmol), THF (3 mL), and anhydrous DMF (180 μL). The mixture was cooled in an ice bath, and oxalyl chloride (260 μL, 1.0 equiv. of acid) was added dropwise. A large amount of gas bubbles formed during the addition. The resulting mixture was stirred in the ice bath for 30 minutes and then at room temperature for an additional 30 minutes to give a bright yellow solution. The excess oxalyl chloride was removed by rotary evaporation, and extraction with toluene (approximately 1 mL) produced a yellow oil as the crude acid chloride, which was diluted with anhydrous THF and set aside for further reaction.

[0068] 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 mixture of THF and HO (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 showed no amine remained.

[0069] The resulting mixture was diluted with DCM (20 mL). After treatment with saturated NaHCO3 (approximately 10 mL) and brine (approximately 10 mL), the organic layer was dried over anhydrous Na2SO4 and passed through a silica gel plug to remove highly polar impurities at the TLC baseline. Removal of the solvent by rotary evaporation afforded 500 mg of the crude product as a brown solid. Column chromatography (eluent: hexane to hexane: EtOAc = 1:2) afforded the product, (E)-4-bromo-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)but-2-enamide, as a tan solid (250 mg). Mass: (M+1), 497, Method E:

[0070] [ka]

[0071] (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 had been completely consumed. A large amount of water (mL) was added to the mixture to precipitate the product. The crude product was isolated by filtration as a tan solid (1.0 g). Column chromatography (eluent: DCM vs. 10% MeOH in DCM) afforded 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.

[0072] At this stage, the purity of the product is 95%-99%. A second purification can be performed by recrystallization from EtOH (in this case, 260 mg of pure product, HPLC purity greater than 99%). Mass: (M+1),461.

[0073] Due to length and space limitations, Example 1 discloses in detail the entire procedure for preparing (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide. Other compounds can be prepared by a similar approach by varying specific chemicals at specific steps, as shown in the following examples, respectively.

[0074] protecting group It is worth mentioning that in certain special circumstances, protection of reactive functionalities may be necessary to achieve some of the reactions described above. Generally, the need for such protecting groups will be apparent to those skilled in the art of organic synthesis, as will the conditions for adding and / or removing such groups.

[0075] Example 2 (E)-4-(Dimethylamino)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)buta-2-enamide This compound was prepared similarly according to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 475.

[0076] Example 3 (E)-N-(5-((4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide 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.

[0077] 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 This compound was prepared similarly according to Example 1 by substituting 2,4-dichloro-5-(trifluoromethyl)pyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 529.

[0078] Example 5 (E)-4-(dimethylamino)-N-(2-fluoro-5-((5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)buta-2-enamide This compound was prepared similarly according to Example 1 by substituting 2,4-dichloro-5-fluoropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 479.

[0079] 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 This compound was prepared similarly according to Example 1 by substituting 2,4,5-trichloropyrimidine for 5-2,4-dichloropyrimidine in Method A. Mass: (M+1), 495.

[0080] 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 This compound was prepared similarly according to Example 1 by substituting 5-bromo-2,4-dichloropyrimidine for 2,4-dichloropyrimidine in Method A. Mass: (M+1), 495.

[0081] Example 8 (E)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using dimethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 542.

[0082] S N Typical method for _Ar reaction

[0083] [ka]

[0084] A sealed tube was charged with N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine (300 mg, 0.75 mmol, 1.0 equiv.), dimethylamine hydrochloride (600 mg, 10 equiv.), K2CO3 (1.0 g, 10 equiv.), and acetonitrile (20 mL). The resulting mixture was stirred at approximately 75-80 °C for 12 h. The resulting mixture was filtered, and the filtrate was diluted with DCM (20 mL). After treatment with brine (10 mL), the organic layer was dried over anhydrous Na2SO4 and concentrated. Column chromatography afforded the desired product, 2-methoxy-N 4 ,N 4 -Dimethyl-N 1 A brown solid (200 mg) was obtained as -(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-5-nitrobenzene-1,4-diamine.

[0085] Example 9 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-(dimethylamino)but-2-enamide This compound was prepared similarly according to Example 1 by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 473.

[0086] Example 10 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, followed by S-reaction with methylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 528.

[0087] Example 11 (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)buta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, followed by S-reaction with methylamine prior to the reduction step. N Prepared similarly with the addition of the Ar step (Method C). Mass: (M+1), 486.

[0088] Example 12 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-(dimethylamino)but-2-enamide This compound was prepared similarly according to Example 1, with the addition of an SN Ar step with methylamine before the reduction step (Method C). Mass: (M+1), 472.

[0089] 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 This compound was prepared similarly according to Example 9 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 474.

[0090] 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 This compound was prepared similarly according to Example 13 by substituting 2-methoxy-4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. (M+1), 458.

[0091] 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 This compound was prepared similarly according 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.

[0092] 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 This compound was prepared similarly according to Example 13 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 444.

[0093] Example 17 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-(dimethylamino)but-2-enamide This compound was prepared similarly according to Example 1 by substituting 2-methoxy-4-methyl-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. (M+1), 457.

[0094] Example 18 (E)-4-(Dimethylamino)-N-(4-methoxy-2-methyl-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)buta-2-enamide This compound was prepared similarly according to Example 17 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 471.

[0095] Example 19 (E)-4-(Dimethylamino)-N-(4-methoxy-3-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)buta-2-enamide 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.

[0096] Example 20 (E)-N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide This compound was prepared similarly according to Example 1 by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 443.

[0097] Example 21 (E)-N-(2-chloro-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-(dimethylamino)but-2-enamide 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.

[0098] Example 22 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-(dimethylamino)but-2-enamide This compound was prepared similarly according 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.

[0099] 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 This compound was prepared according to Example 1 using dimethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M+1), 527.

[0100] Example 24 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1 using morpholine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 570.

[0101] Example 25 (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-morpholinophenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, followed by S-reaction with morpholine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 584.

[0102] Example 26 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1, Method A, substituting 7-azaindole for 1H-indole, followed by S-reaction with methylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 515.

[0103] Example 27 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1 using methylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 514.

[0104] 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 This compound was prepared according to Example 1 using dimethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M+1), 526.

[0105] 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 This compound was prepared according to Example 1 using dimethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting 1-methylpiperazine for dimethylamine in Method E. Mass: (M+1), 541.

[0106] Example 30 (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1 by adding dimethylamine before the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 528.

[0107] 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 This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using diethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting piperidine for dimethylamine in Method E. Mass: (M+1), 568.

[0108] 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 This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using diethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting 1-methylpiperazine for dimethylamine in Method E. Mass: (M+1), 583.

[0109] 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 This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using diethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting piperazine for dimethylamine in Method E. Mass: (M+1), 569.

[0110] 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 This compound was prepared according to Example 1 by substituting 1-methyl-1H-indole for 1H-indole in Method A and then reacting with diethylamine prior to the reduction step (Method C). N Prepared by adding the Ar step and substituting pyrrolidine for dimethylamine in Method E. Mass: (M+1), 554.

[0111] Example 35 (E)-N-(2-(diethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using diethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C) and substituting morpholine for dimethylamine in Method E. Mass: (M+1), 570.

[0112] 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 This compound was prepared similarly according to Example 29 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 542.

[0113] 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 This compound was prepared similarly according to Example 23 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 528.

[0114] 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 This compound was prepared similarly according to Example 34 by substituting 7-azaindole for 1H-indole in Method A and dimethylamine for diethylamine in Method E. Mass: (M+1), 513.

[0115] Example 39 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-(dimethylamino)-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according to Example 30 by substituting 7-azaindole for 1H-indole in Method A. Mass: (M+1), 529.

[0116] 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 This compound was prepared similarly according to Example 29 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 555.

[0117] 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 This compound was prepared similarly according to Example 23 by substituting 1-methyl-1H-indole for 1H-indole in Method A. Mass: (M+1), 541.

[0118] Example 42 (E)-N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 35 using 2-aminoethanol prior to the reduction step. N Prepared similarly with the addition of the Ar step (Method C). Mass: (M+1), 558.

[0119] 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 This compound was prepared according to Example 34 using 2-aminoethanol prior to the reduction step. N Prepared similarly with the addition of the Ar step (Method C). Mass: (M+1), 542.

[0120] Example 44(E)-4-(dimethylamino)-N-(2-(dimethylamino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)buta-2-enamide This compound was prepared according to Example 1, substituting 1-methyl-1H-indole for 1H-indole in Method A, using dimethylamine prior to the reduction step. N Prepared similarly by adding an Ar step (Method C). Mass: (M+1), 500.

[0121] 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 This compound was prepared similarly according to Example 44 by substituting pyrrolidine for dimethylamine in Method E. Mass: (M+1), 526.

[0122] 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 This compound was prepared similarly according 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.

[0123] Example 47 (E)-N-(2-fluoro-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according 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.

[0124] 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 This compound was prepared similarly according 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.

[0125] 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 This compound was prepared similarly to Example 43, substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine for 1-methyl-1H-indole and modifying Method D to replace the pyridine with 2-chloropyridine. Mass: (M+1), 483.

[0126] Pyridine substitution by the Buchwald reaction

[0127] [ka]

[0128] 2-((2-Amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)amino)ethylbenzoate (100 mg, 0.22 mmol, 1.0 equiv), 2-chloropyridine (25 mg, 1.0 equiv), KPO (140 mg, 3.0 equiv), Pd(dba) (10 mg, −10% wt), and BINAP (10 mg, −10% wt) were added to toluene (2 mL). The resulting mixture was flushed with nitrogen and heated in a sealed tube at approximately 110 °C for 12 h. At this point, the reaction was stopped, and the resulting mixture was rehydrated with saturated NaHCO (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous NaSO and concentrated to dryness. Prep-TLC gave a yellow solid as the desired product (55 mg, 48% yield).

[0129] 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 This compound can be prepared according to Example 8, by substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine for 1-methyl-1H-indole in Method A. N Prepared similarly by replacing dimethylamine with 2-(methylamino)ethan-1-ol in step Ar. The following steps were also applied to obtain the final product. Mass: (M+1), 473.

[0130] Typical procedure for EDC esterification:

[0131] [ka]

[0132] 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 (approximately 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. At this point, the reaction was stopped, and the resulting mixture was diluted with saturated NaHCO3 (5 mL) solution and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Column chromatography afforded a white solid as the desired product (390 mg, 0.7 mmol, 70% yield).

[0133] *In some circumstances, DCC, CDI, or HBTU may be used as coupling reagents instead of EDC hydrochloride.

[0134] Zinc reduction:

[0135] [ka]

[0136] The reduction procedure was the same as in Method C of Example 1.

[0137] Starting with 2-((5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)-2-nitrophenyl)(methyl)amino)ethyl benzoate (280 mg, 0.5 mmol), 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) was obtained.

[0138] Typical procedure for EDC coupling reaction for amide formation:

[0139] [ka]

[0140] The starting acrylic acid (20 mg, approximately 1.1 equiv.) and HOBt hydrate (32 mg, approximately 1.0 equiv.) were added to DCM (2 mL). Meanwhile, EDC hydrochloride (70 mg, approximately 1.5 equiv.) was added, followed by the starting 2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethylbenzoate (130 mg, 0.25 mmol, 1.0 equiv.). The resulting mixture was stirred overnight until the starting amine was completely consumed based on TLC analysis. At this point, the reaction was stopped, and the resulting mixture was diluted with saturated NaHCO3 (5 mL) and brine (5 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness. Preparative TLC gave a white solid as the desired product (82 mg, 0.14 mmol, 56% yield).

[0141] Typical methods for ester hydrolysis

[0142] [ka]

[0143] The starting material, 2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethylbenzoate (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 equiv.) was added to the solution and stirred at room temperature for 2 h. TLC analysis indicated that the reaction was complete and the resulting mixture was concentrated 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. Preparative TLC gave a white solid as the desired product (15 mg, 0.03 mmol, 60% yield).

[0144] Example 51 N-(2-((2-hydroxyethyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide This compound was prepared similarly according to Example 42 by modifying Method D to an EDC-catalyzed coupling reaction with acrylic acid. Mass: (M+1), 459.

[0145] 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 This compound was prepared according to Example 48 using N 1 ,N 1 -dimethylethane-1,2-diamine N Prepared similarly, with the addition of the Ar step (Method C) and modification of Method D to the Buchwald approach using 4-chloropyrimidine. Mass: (M+1), 510.

[0146] 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 This compound was prepared similarly according to Example 42 by modifying Method D to the Buchwald approach using 2-chloropyridine. Mass: (M+1), 482.

[0147] Example 54N 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 This compound was prepared according to Example 43 using N 1 ,N 1 -dimethylethane-1,2-diamine N Prepared similarly, with the addition of the Ar step (Method C) and modification of Method D to the Buchwald approach using 4-chloropyrimidine. Mass: (M+1), 523.

[0148] 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 This compound was prepared similarly according to Example 49 by substituting 7-azaindole for 1-methyl-1H-indole in Method A. Mass: (M+1), 470.

[0149] Example 56 2-((4-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-5-methoxy-2-(pyrimidin-4-ylamino)phenyl)amino)ethan-1-ol This compound was prepared similarly according to Example 49 by substituting 1H-indole for 1-methyl-1H-indole in Method A. (M+1), 469.

[0150] 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 This compound was prepared similarly according to Example 49, by substituting 5-fluoro-1-methyl-1H-indole for 1-methyl-1H-indole in Method A. Mass: (M+1), 501.

[0151] 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)buta-2-ynamide This compound was prepared similarly according to Example 54 by substituting 5-fluoro-1-methyl-1H-indole for 1-methyl-1H-indole in Method A and modifying Method D to an EDC-catalyzed coupling reaction with but-2-ynoic acid. Mass: (M+1), 530.

[0152] 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)buta-2-enamide This compound was similarly prepared in a similar manner according to Example 58 by modifying Method D to an EDC-catalyzed coupling reaction with crotonic acid. Mass: (M+1), 532.

[0153] 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 This compound was prepared similarly according to Example 53 by modifying Method D to the Buchwald approach using 4-chloropyrimidine. Mass: (M+1), 483.

[0154] 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)buta-2-enamide This compound was prepared according to Example 59 using S N As an Ar reaction reagent, N 1 ,N 1 Prepared similarly (Method C) by substituting 2-(methylamino)ethan-1-ol for -dimethylethane-1,2-diamine. Mass: (M+1), 504.

[0155] Example 62 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-fluoro-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according to Example 1 by substituting 7-azaindole for 1H-indole in Method A and morpholine for dimethylamine in Method E. (M+1), 504.

[0156] Example 63(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according 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.

[0157] Example 64(E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according 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.

[0158] Example 65 (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according to Example 62, by substituting 2-methoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 486.

[0159] 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 This compound was prepared similarly according to Example 62 by substituting piperidine for morpholine in Method E. Mass: (M+1), 502.

[0160] 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 This compound was prepared similarly according to Example 63 by substituting piperidine for morpholine in Method E. (M+1), 519.

[0161] 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 This compound was prepared similarly according to Example 64 by substituting piperidine for morpholine in Method E. (M+1), 498.

[0162] 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 This compound was prepared similarly according to Example 65 by substituting piperidine for morpholine in Method E. (M+1), 484.

[0163] 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 This compound was prepared similarly according to Example 66 by substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. (M+1), 514.

[0164] 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 This compound was prepared similarly according to Example 62 by substituting dimethylamine for morpholine in Method E. Mass: (M+1), 462.

[0165] Example 72 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2,4-dimethoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared similarly according to Example 62, substituting 2,4-dimethoxy-5-nitroaniline for 4-fluoro-2-methoxy-5-nitroaniline in Method B. Mass: (M+1), 517.

[0166] 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 This compound was prepared according to Example 71 using methylamine prior to the reduction step. N Prepared similarly with the addition of the Ar step (Method C). Mass: (M+1), 473.

[0167] 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 This compound was prepared according to Example 66 using methylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C). Mass: (M+1), 514.

[0168] 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]heptan-5-yl)but-2-enamide. This compound was prepared similarly according to Example 73, by substituting 5-azaspiro[2.4]heptan-7-ol for dimethylamine in Method E. (M+1), 542.

[0169] 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 This compound was prepared according to Example 71 using dimethylamine prior to the reduction step. N Prepared similarly by adding the Ar step (Method C). Mass: (M+1), 488.

[0170] 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 This compound was prepared similarly according to Example 76, Method E, by substituting piperidine for dimethylamine. (M+1), 528.

[0171] Example 78 (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-amino-4-methoxyphenyl)-4-morpholinobuta-2-enamide This compound was prepared according to Example 62 using ammonium sulfate prior to the reduction step. N Prepared similarly by adding an Ar step (Method C), followed by another step of protecting the -NH group via -Boc, which was achieved by routine protocol, and the -Boc group was removed in an additional step with TFA after Method E. Mass: (M+1), 502.

[0172] 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 This compound was prepared similarly according to Example 2, substituting 2,4-dichloropyrimidine-5-carbonitrile for 2,4-dichloropyrimidine. Mass: (M+l), 500.

[0173] Example 80 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid This compound was similarly prepared according to Example 79, followed by an acid hydrolysis process. Mass: (M+l), 519.

[0174] Example 81 Ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate This compound was similarly prepared by a subsequent EDC esterification process with ethanol according to Example 80. Mass: (M+l), 547.

[0175] 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 This compound was prepared according to Example 1 by substituting 2,4-dichloro-5-methylpyrimidine for 2,4-dichloropyrimidine-5-carbonitrile in Method A. (M+1), 486.

[0176] Example 83 (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid This compound was similarly prepared according to Example 82 with a subsequent acid hydrolysis process. Mass: (M+l), 505.

[0177] Example 84 Ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate This compound was similarly prepared by a subsequent EDC esterification process with ethanol according to Example 83. Mass: (M+l), 533.

Claims

1. Compounds of formula (I): 【Chemical 1】 Formula I wherein Q is a bicyclic heterocyclyl and is selected from: 【Chemistry 2】 R is selected from H, halogen, halogen-lower alkyl, —CN, carboxylic acid, carboxylic acid ester, or carboxylic acid amide; X is selected from a direct bond, —O—, —S—, or —N(R′)—; R' is selected from H, halogen, halogen-lower alkyl, lower alkyl, hydroxyl, lower alkoxy, amino, hydroxylalkylamino, aryl, or heterocyclyl; R″ is selected from: 【Chemistry 3】 or 【change】 Q' is heterocyclyl and is selected from pyrimidinyl and pyridinyl: Y is selected from H and -NR'R', where R'R' can form an aliphatic heterocyclic ring; or a pharmaceutically acceptable salt thereof.

2. 2. The compound of claim 1 , The compound of formula I is 【Chemistry 4】 Formula I Q is a bicyclic heterocyclyl selected from: 【Chemistry 5】 R is selected from H, halogen, methyl, trifluoromethyl, —CN, carboxylic acid, carboxylic acid lower alkyl ester or carboxylic acid lower alkyl amide with nitrogen mono or dual substitution; preferably selected from Cl, Br and carboxylic acid; X is selected from —O— or —N(R′)—; preferably —NH—; R' is selected from H, halogen, halogen-lower alkyl, lower alkyl, preferably lower alkoxy or halogen; R″ is selected from: 【Chemistry 6】 or 【change】 and Preferably, 【Chemistry 7】 and Q' is selected from pyrimidinyl and pyridinyl: Y is selected from H or -NR'R', where R'R' can form an aliphatic heterocyclic ring; preferably, the -NR'R' group is substituted or unsubstituted N,N-dimethylamino (-NMe ２ ), pyrrolidine, morpholine, piperidine and piperazine; The compound, or a pharmaceutically acceptable salt thereof.

3. 10. The compound of claim 1, wherein the compound of formula I is 【Chemistry 8】 Formula I Q is, 【Chemistry 9】 and X is —NH—; R is selected from H, fluorine, chlorine, bromine, methyl or trifluoromethyl; R' is selected from the following: H, F, Cl, -CH ３ , -OCH ３ , -COOH; 【Chemistry 10】 R'' is 【Chemistry 11】 and Y is selected from the following: 【Chemistry 12】 The compound, or a pharmaceutically acceptable salt thereof.

4. 2. The compound of claim 1, selected from the following: or a pharmaceutically acceptable salt thereof: 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

5. 2. The compound of claim 1, selected from the following: or a pharmaceutically acceptable salt thereof: (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-morpholinobuta-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-morpholinobuta-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-morpholinobuta-2-enamide; (E)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-morpholinophenyl)-4-morpholinobuta-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobuta-2-enamide; (E)-N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methylamino)phenyl)-4-morpholinobuta-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-morpholinobuta-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-morpholinobuta-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-morpholinobuta-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-morpholinobuta-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-morpholinobuta-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-morpholinobuta-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-chloro-4-methoxyphenyl)-4-morpholinobuta-2-enamide; (E)-N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-methylphenyl)-4-morpholinobuta-2-enamide; (E)-N-(3-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)-4-morpholinobuta-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-((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-morpholinobuta-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]heptan-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-morpholinobuta-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-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylic acid; Ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-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-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylic acid Ethyl (E)-2-((5-(4-(dimethylamino)but-2-enamido)-4-fluoro-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate.

6. 2. The compound of claim 1, selected from the following: or a pharmaceutically acceptable salt thereof: (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-morpholinobuta-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-morpholinobuta-2-enamide; (E)-4-(dimethylamino)-N-(4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(methylamino)phenyl)buta-2-enamide.

7. A process for synthesizing a compound of formula I according to claim 1 according to the synthetic procedures of Scheme 1 or Scheme 2: 【Chemistry 17】 Formula I Scheme I 【Chemistry 18】 Scheme II 【Chemistry 19】 wherein R, R', R'', X, Q, and Q' are as defined above.

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

9. A compound adapted for use in a method for treating EGFR mutants such as L858R, T790M in a subject by administering an effective amount of a compound according to any one of claims 1 to 6.

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