Heteroaryl derivatives and uses thereof

Abstract

The present invention relates to a heteroaryl derivative and its use. The heteroaryl derivative represented by formula (I) and the pharmaceutical composition containing the same can effectively suppress HER2 activity, and are therefore useful for treating or preventing HER2-related diseases.

Description

[Technical field]

[0001] The present invention relates to a heteroaryl derivative and its medical use. In particular, the present invention relates to a heteroaryl derivative having HER2 inhibitory activity.

[0002] This research was funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare, and was supported by the National Drug Development Project of the National Drug Development Corporation (Project ID: HN21C0826). [Background technology]

[0003] Human epidermal growth factor receptor 2 (HER2) is a human EGFR family member, and abnormal expression or activity of HER2 is known to be a major cause of various cancers, such as breast cancer, lung cancer, gastric cancer and ovarian cancer (J Control Release, 2010, 146(3), 264-275). In particular, amplification of the HER2 gene or overexpression of the HER2 protein is observed in about 15-25% of breast cancer patients, which are classified as HER2 positive. Cancer is caused by wild-type HER2 and various mutations of HER2, such as L755S, V777L, D769H / Y, T862A and L755_T759del in the kinase domain.

[0004] Trastuzumab (Herceptin), a representative HER2 monoclonal antibody TM ) and pertuzumab (Perjeta TM ) inhibits the HER2 signaling mechanism and is therefore used as a treatment for breast cancer, reported to improve clinical outcomes compared with chemotherapy alone (Journal of Clinical Oncology, 2002, 20(3), 719-726). Antibody-drug conjugates (ADCs), produced by linking cytotoxic drugs to HER2-selective antibodies, are also under development as related therapeutic agents, and the small molecule compound lapatinib (Tykerb) has been used as a treatment for breast cancer. TM ) and tucatinib (Tukysa TM) have been developed and are being used as therapeutic agents for breast cancer.

[0005] Data from Phase 1 and 2 clinical trials showed that patients with HER2 mutations were treated with the HER2 inhibitor afatinib (Giotrifol). TM ), neratinib (Nerlynx TM ) or dacomitinib (Vidinpro TM ) has been reported to have a partial response to HER2 mutations (Annals of Oncology, 2015, 26(7), 1421-1427). In particular, the SUMMIT clinical trial reported that patients with HER2 mutant breast cancer treated with neratinib had an objective response rate (ORR) of 24%, patients with HER2 mutant lung cancer had an ORR of 3.8%, and all other cancers with HER2 mutations had an ORR of 0% (Nature, 2018, 554 (7691), 189-194). However, the finding that ORR results differed depending on the disease suggested that HER2 inhibitory efficacy was cancer specific and that there were variant-specific differences in a single cancer (Nature, 2018, 554 (7691), 189-194). Similar results were seen in studies of HER2 monoclonal antibodies and antibody-drug conjugates (ADCs), indicating that ORR differs depending on the type of mutation. This indicates that there remains a need for methods to prevent or treat various HER2 mutations. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] J Control Release, 2010, 146(3), 264-275 [Non-Patent Document 2] Journal of Clinical Oncology, 2002, 20(3), 719-726 [Non-Patent Document 3] Annals of Oncology, 2015, 26(7), 1421-1427 [Non-Patent Document 4] Nature, 2018, 554 (7691), 189-194 Summary of the Invention [Problem to be solved by the invention]

[0007] As a result of intensive efforts to develop new drugs, the inventors have discovered that the compounds of the present invention can efficiently inhibit HER2 and therefore have therapeutic and preventive effects on HER2-related diseases, thereby completing the present invention.

[0008] Accordingly, an object of the present invention is to provide a novel heteroaryl derivative or a pharma- ceutically acceptable salt or stereoisomer thereof, and a process for preparing the same.

[0009] Another object of the present invention is to provide a pharmaceutical use of a heteroaryl derivative or a pharma- ceutically acceptable salt or stereoisomer thereof. [Means for solving the problem]

[0010] In accordance with the above object, the present invention provides a compound represented by the following formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof: [ka] wherein ring A, X1, X2, Y1, Y2, Y3, L and Z are as defined herein. Effect of the Invention

[0011] The compound of formula (I), its stereoisomer or its pharma- ceutically acceptable salt can exhibit excellent inhibitory activity against HER2. Therefore, the compound of the present invention can be used as a HER2 inhibitor, and a pharmaceutical composition containing the compound can be useful as a therapeutic agent for HER2-related diseases, particularly cancer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Below the invention is described in further detail.

[0013] The embodiments of the present invention may be modified in various forms, and the scope of the present invention is not limited to the following embodiments. The embodiments of the present invention are also provided to more completely explain the present invention to those skilled in the art. Furthermore, throughout this specification, a part that "comprises" a certain element does not exclude other elements, but may further include other elements, unless otherwise specified.

[0014] As used herein, the term "halo" or "halogen," unless otherwise specified, refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0015] The term "alkyl", unless otherwise specified, refers to a straight or branched chain saturated hydrocarbon radical with one hydrogen removed. For example, "C 1-10 "Alkyl" refers to an alkyl having a backbone formed from 1 to 10 carbon atoms. 1-10 Alkyl can include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, i-pentyl, tert-pentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.

[0016] The term "alkoxy" refers to an alkyl group linked through -O-, such as, for example, C 1-4 Alkoxy can include, but is not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, and the like.

[0017] The term "alkylamino" refers to an amino substituted with one or two alkyl groups. For example, C 1-6 Alkylamino is a group having one or two C 1-6 Amino substituted with an alkyl group, i.e., -NH(C 1-6 alkyl) or -N(C 1-6alkyl)2, which may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, and ethylpropylamino.

[0018] The term "hydroxyalkyl" refers to a straight or branched chain alkyl having a carbon atom substituted with hydroxy (-OH), including, but not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, and n-butyl substituted with hydroxy. Similarly, "hydroxyalkoxy" refers to a straight or branched chain alkoxy having a carbon atom substituted with hydroxy (-OH).

[0019] The term "haloalkyl" refers to a straight or branched chain alkyl having a carbon atom substituted with one or more halo (F, Cl, Br, and I). Examples of haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, and n-butyl substituted with one or more halo.

[0020] The term "deuterated" means that at least one hydrogen atom (H) present in a hydrocarbon group is replaced with a deuterium atom (D), for example, deuterated C 1-6 Alkyl is C 1-6 It means that at least one hydrogen atom bonded to a carbon atom of an alkyl group is replaced with a deuterium atom.

[0021] The term "carbocycle" refers to an aromatic or non-aromatic hydrocarbon ring, which may be saturated or unsaturated and may include monocyclic or polycyclic rings. For example, the term "C 3-10 "Carbocycle" refers to a carbocycle having a skeleton formed from 3 to 10 carbon atoms and which may have one or more substituents. A carbocycle is classified into C 3-15 carbocycle, C 3-10 carbocycle, C 3-7 carbocycle, C 6-12 In particular embodiments, aromatic C 6-10 Carbocycles include benzene and naphthalene.

[0022] The term "cycloalkyl" refers to a non-aromatic hydrocarbon ring radical that may include monocyclic or polycyclic rings. Cycloalkyl may include saturated rings, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like. Additionally, cycloalkyl may include unsaturated rings having one or more carbon-carbon double bonds in the ring, so long as the ring is not rendered aromatic by the presence of the double bonds, for example, cyclopentenyl, and the like may also fall into this category. Cycloalkyl is classified as C, C , or C 2 , depending on the number of carbon atoms that compose the ring. 3-14 Cycloalkyl, C 3-12 Cycloalkyl, C 3-10 Cycloalkyl, C 3-6 Cycloalkyl, C 6-12 cycloalkyl, and the like.

[0023] The term "aryl" refers to an aromatic hydrocarbon ring radical that may contain a monocyclic or polycyclic ring. Specific examples of aryl may include, but are not limited to, phenyl, naphthalenyl, fluorenyl, anthracenyl, phenanthrenyl, biphenyl, terphenyl, and the like. Furthermore, for aryl, any hydrocarbon ring radical having at least one ring in which electrons are delocalized by alternating single and double bonds, i.e., conjugated pi bonds, may be included in this category. Aryl is classified according to the number of carbon atoms that constitute the ring, as follows: C 6-12 Aryl, C 6-10 This includes, but is not limited to, aryl and the like.

[0024] The term "polycyclic ring" refers to at least bicyclic rings, including spiro rings, fused or fused rings, or bridged rings.

[0025] The term "heterocycle" refers to an aromatic or non-aromatic ring having one or more heteroatoms, which may be saturated or unsaturated and may include a monocyclic or polycyclic ring. For example, a "5- to 12-membered heterocycle" refers to a heterocycle having a skeleton formed from a total of 5 to 12 atoms including heteroatoms and carbon atoms, and which may have one or more substituents. Depending on the number of atoms constituting the ring, the heterocycle may include, but is not limited to, a 5- to 12-membered heterocycle, a 5- to 10-membered heterocycle, a 5- to 7-membered heterocycle, etc.

[0026] The term "heteroaryl" refers to an aromatic heterocyclyl having one or more heteroatoms in the ring, which may include monocyclic or polycyclic rings. Heteroaryl refers to a radical obtained by removing one hydrogen atom from an aromatic heterocycle, such as thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine. The heteroaryl may be, but is not limited to, aryl, imidazopyrazine, pyrazolopyridine, triazolopyridine, triazolopyrimidine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, dibenzofuran, pyrazolopyridine, etc. Furthermore, for heteroaryl, any heterocyclic radical having at least one ring in which electrons are delocalized by alternating single and double bonds, i.e., conjugated π bonds, may be included in this category. Furthermore, heteroaryl may include, but is not limited to, 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 6-12 membered heteroaryl, 6-10 membered heteroaryl, etc., depending on the number of atoms constituting the ring.

[0027] The term "heterocycloalkyl" refers to a non-aromatic heterocyclyl having one or more heteroatoms in the ring, which may be a monocyclic or polycyclic ring. Heterocycloalkyl may include saturated rings. In addition, heterocycloalkyl may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, so long as the ring is not aromatic due to the presence of the double bonds. Heterocycloalkyl may include, but is not limited to, 3-15 membered heterocycloalkyl, 3-12 membered heterocycloalkyl, 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 5-14 membered heterocycloalkyl, 5-12 membered heterocycloalkyl, etc., depending on the number of atoms that constitute the ring. Heterocycloalkyl is a radical obtained by removing one hydrogen atom from a non-aromatic heterocycle, e.g., aziridine, azetidine, pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, isoxazolidine. , benzo[d]isoxazolidine, oxazine, azabicyclo[2,2,1]heptane, 2-azaspiro[3.3]heptane, 5-oxa-6-azaspiro[2.4]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, diazaspiro[5.5]undecane, diazabicyclo[2.2.1]heptane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, and the like.

[0028] The term "heteroatom" refers to an atom other than carbon (C) and can be, for example, an O, N, P, Si, or S atom, more specifically, an N, O, or S atom. The heterocycles, heteroaryls, and heterocycloalkyls described herein can contain one or more heteroatoms, for example, 1, 1-2, 1-3, or 1-4 heteroatoms.

[0029] The term "substitution" refers to replacing hydrogen atoms in a molecular structure with a substituent so that the valence of the specified atom is not excessive and the substitution results in a chemically stable compound. For example, "group A substituted with substituent B" or "group A has substituent B" means that a hydrogen atom bonded to an atom such as carbon constituting the skeleton of group A is replaced with substituent B, so that group A and substituent B form a covalent bond. Thus, it is practically difficult or impossible for a group that does not have a removable hydrogen atom to have a substituent. In this respect, when a range of combinations of various groups and substituents, including groups that are difficult to have a substituent, are exemplified in this specification, combinations of groups and substituents that are clearly impossible to replace should be interpreted as being excluded from the scope. Non-limiting examples of such substituents include halo (F, Cl, Br, or I), C, aryl ... 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, Hydroxy, C 1-10Alkoxy, amino, nitro, thiol, thioether, imine, cyano, phosphine, carboxy, carbamoyl, acetal, thiocarbonyl, sulfonyl, sulfonamide, ketone, aldehyde, ester, acetyl, amide, oxo (=O), haloalkyl (e.g., trifluoromethyl), substituted aminoacyls and aminoalkyls, monocyclic rings or fused or non-fused polycyclic rings as carbocyclic cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or monocyclic rings or fused or non-fused polycyclic rings as heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclohex ... linyl or thiazinyl), carbocycle, heterocyclic ring, monocyclic ring, fused polycyclic ring, non-fused polycyclic ring, fused polycyclic aryl or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothienyl or benzofuranyl), amino (primary, secondary or tertiary), aryl, aryloxy and aryl-alkyl. Furthermore, each of the above exemplified substituents may be unsubstituted or substituted with a substituent selected from the group of these substituents.

[0030] The above same or different types of one or more substituents may be substituted at the same or different positions, and may be substituted successively.The term "successively" means that a certain substituent is substituted in the formula, and then another substituent is substituted successively on the substituent, for example, when an alkyl group is substituted, then a cycloalkyl group is substituted on the alkyl group, and a carbonyl group is substituted on the cycloalkyl group successively, and the name as carbonylcycloalkylalkyl can indicate that the group is formed by successive substitution.

[0031] In the chemical structural formulae shown in this specification, the symbol for carbon atom (C) and the symbol for hydrogen atom (H) may be omitted according to typical methods for expressing chemical structural formulae, and for example, even if a hydrogen atom symbol is not assigned, it should be interpreted that the number of hydrogen atoms that satisfy the valence of the carbon forming the backbone are actually bonded to the carbon atom. However, when a deuterium (D) is shown in a chemical structural formula, it should be interpreted that the deuterium (D) is bonded to carbon (C).

[0032] In this specification, the symbol "-" connecting atoms and / or groups may mean a single bond, and the symbol "=" may mean a double bond. The symbol may be omitted or may be shown when necessary, such as when specifying the bond atom or bond position.

[0033] The bond orientation of the linking radicals described herein is arbitrary unless otherwise specified. For example, [ka] The radical L linked by is -MW-, where -MW- is linked to ring A and ring B in the same direction as reading from left to right. [ka] and ring A and ring B can be linked in the reverse left-to-right reading order to form [ka] can be formed.

[0034] The term "stereoisomers" as used herein refers to compounds that have the same chemical or molecular formula but are sterically different. In this specification, stereoisomers include enantiomers and diastereomers, and diastereomers also include conformational isomers such as rotational isomers and cis / trans isomers, where each isomer and mixtures thereof are included within the scope of the present invention. For example, formula (I) of the present invention may include stereoisomers of formula (I) since the stereochemical structure is not specified. In particular, solid line bonds attached to asymmetric carbon atoms in chemical structural formulas may be used as stereoisomers. [ka] is a solid wedge bond indicating the absolute configuration of a stereocenter [ka] and dashed wedge bonds [ka] It is to be understood that stereoisomers of the example compounds described herein are also included within the scope of the present invention.

[0035] Heteroaryl Derivatives One embodiment of the present invention is a compound of formula (I): [ka] [During the ceremony: Ring A is aromatic or non-aromatic C 6-12 A carbocyclic ring or a 5- to 12-membered heterocyclic ring, where ring A is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR A1 R A2 , -NO2, -OR A3 , -C(=O)-NR A1 R A2 , -C(=O)-OR A3 , -NH-C(=O)-(C 1-6 alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 substituted with alkoxy or halo; R A1 ~R A3 are each independently H or C 1-6 is alkyl; X1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6Haloalkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C 1-6 Alkyl or C 1-6 substituted with haloalkyl; X2 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR B1 R B2 , -NO2, -OR B3 Or halo; R B1 ~R B3 are each independently H or C 1-6 is alkyl; Y1 is CR1 or N; Y2 is CR2, C(-LZ) or N; Y3 is CR3 or N; R1 is H, C 1-6 Alkyl, C 1-6 alkylamino or -CN; R2 is H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 haloalkyl, -CN, -NH2 or halo; R3 is H, halo, -OR4, or -NR5R6, or R3 combined with L to form a 5-6 membered heterocycle; R4 is H, C 1-6 Alkyl, -(CH2)nO-(C 1-6 Alkyl), C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -(CH2)n-(C 3-6 -(cycloalkyl), 3- to 6-membered heterocycloalkyl, or -(CH2)n-(3- to 6-membered heterocycloalkyl), where cycloalkyl and heterocycloalkyl are C 1-6 Alkyl, C 1-6Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR C1 R C2 , -NO2, -OR C3 with or without one or more substituents selected from the group consisting of: Each n is independently an integer of 1 to 4; R C1 ~R C3 are each independently H or C 1-6 is alkyl; R5 and R6 are each independently H or C 1-6 alkyl, or R5 and R6 are joined together to form a 3- to 12-membered heterocycle, where the heterocycle is unsubstituted or 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR D1 R D2 , -NO2, -OR D3 , substituted with halo or 3-6 membered heterocycloalkyl; R D1 ~R D3 are each independently H or C 1-6 is alkyl; L is -NH-, [ka] or L is combined with R3 to form a 5- to 6-membered heterocycle, where ring B is a 3- to 8-membered heterocycle containing a N atom in the ring, and ring B is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 with or without one or more substituents selected from the group consisting of haloalkyl, -OH and halo; Z is [ka] and; Z1 is H, C 1-6 Alkyl, C 1-6haloalkyl, -CN, halo, or 5-6 membered heteroaryl; Z2 and Z3 each independently represent H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkylamino, C 1-6 Haloalkyl, Halo, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -(CH2)m-(C 1-6 alkylamino), -(CH2)m-(C 3-12 -(CH2)m-(3- to 12-membered heterocycloalkyl), -(CH2)m-(3- to 12-membered heterocycloalkyl), or -(CH2)m-NH-(3- to 12-membered heterocycloalkyl), where -CH2-, cycloalkyl, and heterocycloalkyl are each independently selected from the group consisting of C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Haloalkyl, -OH, =O, -C(=O)-(C 1-6 with or without one or more substituents selected from the group consisting of alkoxy and 3- to 6-membered heterocycloalkyl; m is independently an integer from 1 to 4; and The heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O. or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0036] In certain embodiments of formula (I) above, Ring A is aromatic C 6-12 A carbocycle or an aromatic or non-aromatic 5- to 12-membered heterocycle, where ring A is C 1-6 Alkyl, -NR A1 R A2 , -OR A3 , -C(=O)-NR A1 R A2 , -C(=O)-OR A3 , -NH-C(=O)-(C 1-6alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C 1-6 Alkyl, C 1-6 substituted with alkoxy or halo; R A1 ~R A3 are each independently H or C 1-6 is alkyl; The heterocycle and heteroaryl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; and X1, X2, Y1, Y2, Y3, L and Z are as defined above.

[0037] In another embodiment of formula (I) above, Ring A is [ka] and; A1 to A9 each independently represent CH or N; B1 to B3 each independently represent CH2, NH, O, or S; Here, ring A is C 1-6 Alkyl, -NR A1 R A2 , -OR A3 , -C(=O)-NR A1 R A2 , -C(=O)-OR A3 , -NH-C(=O)-(C 1-6 alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C 1-6 Alkyl, C 1-6 substituted with alkoxy or halo; R A1 ~R A3 are each independently H or C 1-6 is alkyl; Heteroaryl contains at least one heteroatom selected from the group consisting of N, S, and O; and X1, X2, Y1, Y2, Y3, L and Z are as defined above.

[0038] In another embodiment of formula (I) above, X1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C 1-6 Alkyl or C 1-6 substituted with haloalkyl; X2 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -NR B1 R B2 Or halo; R B1 and R B2 are each independently C 1-6 is alkyl; Each heterocycloalkyl contains at least one heteroatom independently selected from the group consisting of N, S, and O; and Rings A, Y1, Y2, Y3, L and Z are as defined above.

[0039] In another embodiment of formula (I) above, Ring A is aromatic C 6-12 A carbocycle or an aromatic or non-aromatic 5- to 12-membered heterocycle, where ring A is C 1-6 Alkyl, -NR A1 R A2 , -OR A3 , -C(=O)-NR A1 R A2 , -C(=O)-OR A3 , -NH-C(=O)-(C 1-6 alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C 1-6 Alkyl, C 1-6substituted with alkoxy or halo; R A1 ~R A3 are each independently H or C 1-6 is alkyl; X1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C 1-6 Alkyl or C 1-6 substituted with haloalkyl; X2 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -NR B1 R B2 Or halo; R B1 and R B2 are each independently C 1-6 is alkyl; heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; and Y1, Y2, Y3, L and Z are as defined above.

[0040] In another embodiment of formula (I) above, Y1 is CR1 or N; Y2 is CR2, C(-LZ) or N; Y3 is CR3 or N; R1 is H or -CN; R2 is H or halo; R3 is H, halo, -OR4, or -NR5R6, or R3 combined with L to form a 5-6 membered heterocycle; R4 is C 1-6 Alkyl, -(CH2)nO-(C 1-6 Alkyl), C 1-6haloalkyl, 3- to 6-membered heterocycloalkyl, or -(CH2)n-(3- to 6-membered heterocycloalkyl), where cycloalkyl and heterocycloalkyl are C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR C1 R C2 , -NO2, -OR C3 with or without one or more substituents selected from the group consisting of: Each n is independently an integer of 1 to 4; R C1 ~R C3 are each independently H or C 1-6 is alkyl; R5 and R6 are each independently H or C 1-6 alkyl, or R5 and R6 are joined together to form a 3-12 membered heterocycle, where the heterocycle is a 4-6 membered monocyclic ring or a 5-12 membered spirocycle, and the heterocycle is unsubstituted or substituted with halo or a 3-6 membered heterocycloalkyl; The heterocycle and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; and Rings A, X1, X2, L and Z are as defined above.

[0041] In another embodiment of formula (I) above, L is -NH-, [ka] or L is combined with R3 to form a 5- to 6-membered heterocycle, where ring B is a 3- to 8-membered heterocycle containing a N atom in the ring, and ring B is C 1-6 Alkyl, C 1-6 with or without one or more substituents selected from the group consisting of haloalkyl and halo; Z is [ka] and; Z1 is H, -CN, halo, or 5-6 membered heteroaryl; Z2 and Z3 each independently represent H, C 1-6 Alkyl, C 1-6 Alkylamino, Halo, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -(CH2)m-(C 1-6 alkylamino), -(CH2)m-(C 3-12 -(CH2)m-(3- to 12-membered heterocycloalkyl), -(CH2)m-(3- to 12-membered heterocycloalkyl), or -(CH2)m-NH-(3- to 12-membered heterocycloalkyl), where -CH2-, cycloalkyl, and heterocycloalkyl are each independently selected from the group consisting of C 1-6 Alkyl, deuterated C 1-6 Alkyl, -OH, =O, -C(=O)-(C 1-6 with or without one or more substituents selected from the group consisting of alkoxy and 3- to 6-membered heterocycloalkyl; Each m is independently an integer of 1 to 4; heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; and Ring A, X1, X2, Y1, Y2 and Y3 are as defined above.

[0042] In another embodiment of formula (I) above, Ring A is [ka] and; A1 to A9 each independently represent CH or N; B1 to B3 each independently represent CH2, NH, O, or S; Here, ring A is C 1-6 Alkyl, -NR A1 R A2 , -OR A3 , -C(=O)-NR A1 R A2 , -C(=O)-OR A3 , -NH-C(=O)-(C 1-6alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C 1-6 Alkyl, C 1-6 substituted with alkoxy or halo; X1 is C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-12 cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C 1-6 Alkyl or C 1-6 substituted with haloalkyl; X2 is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -NR B1 R B2 Or halo; R B1 and R B2 are each independently C 1-6 is alkyl; Y1 is CR1 or N; Y2 is CR2, C(-LZ) or N; Y3 is CR3 or N; R1 is H or -CN; R2 is H or halo; R3 is H, halo, -OR4, or -NR5R6, or R3 combined with L to form a 5-6 membered heterocycle; R4 is C 1-6 Alkyl, -(CH2)nO-(C 1-6 Alkyl), C 1-6 haloalkyl, 3- to 6-membered heterocycloalkyl, or -(CH2)n-(3- to 6-membered heterocycloalkyl), where cycloalkyl and heterocycloalkyl are C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -CN, -NR C1 R C2, -NO2, -OR C3 with or without one or more substituents selected from the group consisting of: Each n is independently an integer of 1 to 4; R C1 ~R C3 are each independently H or C 1-6 is alkyl; R5 and R6 are each independently H or C 1-6 alkyl, or R5 and R6 are joined together to form a 3-12 membered heterocycle, where the heterocycle is a 4-6 membered monocyclic ring or a 5-12 membered spirocycle, and the heterocycle is unsubstituted or substituted with halo or a 3-6 membered heterocycloalkyl; L is -NH-, [ka] or L is combined with R3 to form a 5- to 6-membered heterocycle, where ring B is a 3- to 8-membered heterocycle containing a N atom in the ring, and ring B is C 1-6 Alkyl, C 1-6 with or without one or more substituents selected from the group consisting of haloalkyl and halo; Z is [ka] and; Z1 is H, -CN, halo, or 5-6 membered heteroaryl; Z2 and Z3 each independently represent H, C 1-6 Alkyl, C 1-6 Alkylamino, Halo, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -(CH2)m-(C 1-6 alkylamino), -(CH2)m-(C 3-12 -(CH2)m-(3- to 12-membered heterocycloalkyl), -(CH2)m-(3- to 12-membered heterocycloalkyl), or -(CH2)m-NH-(3- to 12-membered heterocycloalkyl), where -CH2-, cycloalkyl, and heterocycloalkyl are each independently selected from the group consisting of C 1-6 Alkyl, deuterated C 1-6Alkyl, -OH, =O, -C(=O)-(C 1-6 with or without one or more substituents selected from the group consisting of alkoxy and 3- to 6-membered heterocycloalkyl; m is independently an integer from 1 to 4; and The heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O.

[0043] In another embodiment of formula (I) above, L is -NH-, [ka] and; Here, the heterocycle containing N is C 1-6 Alkyl, C 1-6 with or without one or more substituents selected from the group consisting of haloalkyl and halo, L is bonded to R3 to form a 5- to 6-membered heterocycle containing N; N-containing heterocycles may or may not contain, in addition to N, at least one further heteroatom selected from S and O; and Ring A, X1, X2, Y1, Y2, Y3 and Z are as defined above.

[0044] In certain embodiments, the scope of the present invention includes a compound selected from the following group, or a pharma- ceutically acceptable salt or stereoisomer thereof:

[0045] 1> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 2> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 3> 1-(4-((4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 4> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-((1-methylazetidin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 5> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 6> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one; 7> 1-(4-((4-((4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 8> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 9> 1-(4-((4-((4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 10> 1-(4-((7-methoxy-4-((2-methoxy-4-((1-(2-methoxypyrimidin-5-yl)-1H-pyrazol-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 11> 1-(4-((4-((5-chloro-2-methoxy-4-(3-methoxyphenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 12> 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinoline-3-carbonitrile; 13> Methyl 4-(4-((6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)benzoate; 14> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-chloro-2-fluoroethan-1-one; 15> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one; 16> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; 17> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 18> 1-(5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one; 19> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 20> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one; 21> 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)prop-2-en-1-one; 22> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)acrylamide; 23> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-morpholinoquinazolin-6-yl)acrylamide; 24> N-(4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)acrylamide; 25> (E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide; 26> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)but-2-enamide; 27> 1-(4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one; 28> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)but-2-ynamide; 29> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 30> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 31> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(pyrrolidin-2-yl)acrylamide; 32> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 33> (R,E)-N-(4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 34> (R,E)-N-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 35> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(2-methyl-2-azabicyclo[3.1.0]hexan-3-yl)acrylamide; 36> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpiperidin-2-yl)acrylamide; 37> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 38> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)but-2-enamide; 39> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)but-2-enamide; 40> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)but-2-enamide; 41> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 42> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 43> (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 44> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 45> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methyl-5-oxopyrrolidin-2-yl)acrylamide; 46> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 47> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 48> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 49> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 50> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 51> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 52> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)-2-fluoroacrylamide; 53> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 54> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 55> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 56> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 57> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 58> (R,Z)-N-(4-((5-chloro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 59> (R,E)-N-(4-((5-chloro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 60> (R,E)-2-fluoro-N-(4-((5-fluoro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 61> (R,Z)-2-fluoro-N-(4-((5-fluoro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 62> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinoxalin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 63> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinoxalin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 64> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(naphthalen-2-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 65> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(naphthalen-2-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 66> (R,E)-N-(4-((4-(benzo[d]oxazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 67> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((2-methylbenzo[d]oxazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 68> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((2-methylbenzo[d]oxazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 69> (E)-2-fluoro-N-(4-((4-((2-hydroxy-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 70> (Z)-2-fluoro-N-(4-((4-((2-hydroxy-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 71> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 72> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 73> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 74> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-phenoxyphenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 75> (R,E)-2-fluoro-N-(4-((4-(imidazo[1,2-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 76> (R,Z)-2-fluoro-N-(4-((4-(imidazo[1,2-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 77> (R,E)-2-fluoro-N-(4-((4-(imidazo[1,2-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 78> (R,E)-N-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 79> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 80> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 81> (R,E)-N-(4-((4-(benzo[d]thiazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 82> (R,Z)-N-(4-((4-(benzo[d]thiazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 83> (R,Z)-N-(4-((4-(benzo[d]thiazol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 84> (R,E)-N-(4-((4-(benzo[d]thiazol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 85> (R,E)-N-(4-((4-(benzo[d][1,3]dioxol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 86> (R,Z)-N-(4-((4-(benzo[d][1,3]dioxol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 87> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinolin-7-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 88> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinolin-7-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 89> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-indazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 90> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-indazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 91> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 92> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 93> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 94> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 95> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 96> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 97> (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 98> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 99> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 100> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 101> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 102> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-fluoroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 103> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-fluoroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 104> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-ethoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 105> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-(trifluoromethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 106> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-cyclopropoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 107> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-cyclopropoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 108> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-(oxetan-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 109> tert-Butyl (R,E)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(oxetan-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate; 110> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-((3R)-hexahydro-1H-pyrrolidin-3-yl)acrylamide; 111> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 112> (S,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 113> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 114> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(3,3-difluoroazetidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 115> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 116> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 117> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinazolin-6-yl)acrylamide; 118> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(methylamino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 119> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-6-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 120> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 121> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 122> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 123> (R,E)-N-(4-((4-(4-(dimethylamino)phenoxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 124> Methyl (R,E)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamido)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)benzoate; 125> (R,Z)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamido)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)-N,N-dimethylbenzamide; 126> (R,E)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamido)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)-N,N-dimethylbenzamide; 127> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-(dimethylamino)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 128> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 129> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 130> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-morpholinoquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 131> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpiperidin-2-yl)acrylamide; 132> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 133> (R,Z)-N-(4-((4-(3-acetamidophenoxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 134> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 135> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 136> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-chloro-3-(1-methylpyrrolidin-2-yl)acrylamide; 137> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-cyclopropyl-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 138> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-cyclopropyl-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 139> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 140> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 141> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 142> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 143> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 144> (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide; 145> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide; 146> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4,4-dimethylpent-2-enamide; 147> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-(1H-pyrazol-1-yl)acrylamide; 148> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 149> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 150> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 151> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-(methoxy-d3)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 152> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-(methoxy-d3)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 153> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide; 154> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide; 155> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide; 156> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide; and 157> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide.

[0046] The compound of the present invention of formula (I) can exist in the form of pharmaceutically acceptable salt.Therefore, the scope of the compound of the present invention includes the pharmaceutically acceptable salt of the compound of formula (I) above.As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic acid addition salt of a compound, which has an effective concentration, is relatively non-toxic and harmless to patients, and the harmful effects caused by the salt do not reduce the beneficial effectiveness of the compound of formula (I).

[0047] In particular, pharma- ceutically acceptable salts may be acid addition salts formed with free acids, where the acid addition salts may be derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphoric acid, non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids, and organic acids such as trifluoroacetic acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid.

[0048] Such pharma- ceutically acceptable salt types may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0049] The acid addition salts can be prepared in a conventional manner, for example by dissolving the derivative of formula (I) in an organic solvent such as methanol, ethanol, acetone, methylene chloride or acetonitrile, and adding an organic or inorganic acid to form a precipitate which is then filtered and dried, or by distilling off the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

[0050] Furthermore, the pharma-ceutically acceptable salt may be a salt obtained by using a base or a metal salt.As an example of a metal salt, an alkali metal or alkaline earth metal salt may be obtained by dissolving a compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate.As an alkali metal salt, a sodium salt, a potassium salt or a calcium salt may be pharma-ceutically suitable.Furthermore, the corresponding salt may be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0051] Furthermore, compounds of the present invention may have chiral carbon centers and therefore may exist in the form of R or S isomers or mixtures, individual enantiomers or mixtures or individual diastereomers or mixtures, and all such stereoisomers and mixtures thereof (e.g., racemic mixtures) are intended to fall within the scope of the present invention.

[0052] Furthermore, the compounds of the present invention may include hydrates and solvates of the compounds of formula (I). The hydrates and solvates can be prepared using known methods and are preferably non-toxic and water-soluble. In particular, the hydrates and solvates are preferably obtained by combining the compounds with 1-5 molecules of water and alcoholic solvents (especially ethanol, etc.), respectively.

[0053] Additionally, administration of a compound of the invention may result in the formation of metabolites in vivo; in particular, such metabolites may be produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, etc. of the administered compound. For example, compounds produced by a process comprising contacting a mammal with a compound of the invention for a period of time sufficient to yield a metabolite of the compound are also included within the scope of the invention.

[0054] Furthermore, the compounds of the present invention may be produced in the form of prodrugs, which may have little or no pharmacological activity themselves, but may be converted into compounds with desired activity when administered to the body, for example, by hydrolysis. Such prodrugs may be derivatives of compounds that contain biologically reactive functional groups, which may be cleaved from the compounds or otherwise reacted under biological conditions (in vivo or in vitro) to provide the compounds. Typically, prodrugs are inactive or at least less active than the compounds, thereby allowing the compounds to exert their activity after cleavage from the biologically reactive functional groups. The biologically reactive functional groups are hydrolyzed or oxidized under biological conditions to form the compounds. For example, prodrugs may contain biologically hydrolyzable groups. Examples of biologically hydrolyzable groups include, but are not limited to, biologically hydrolyzable phosphates, biologically hydrolyzable esters, biologically hydrolyzable amides, biologically hydrolyzable carboxylic esters, biologically hydrolyzable carbamates, and biologically hydrolyzable ureidos.

[0055] Use of Heteroaryl Derivatives Another aspect of the present invention provides the pharmaceutical use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0056] The compound of formula (I) of the present invention or a pharma- ceutically acceptable salt or stereoisomer thereof can inhibit the activity of human epidermal growth factor receptor 2 (HER2). In particular, the compound of formula (I) of the present invention or a pharma- ceutically acceptable salt or stereoisomer thereof can inhibit the binding between HER2 and a ligand.

[0057] Thus, the present invention provides a HER2 inhibitor comprising as an active ingredient a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0058] The present invention further provides a method of inhibiting the activity of HER2, comprising contacting a sample or cell with a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0059] As such, the compounds of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof may be used in the treatment or prevention of HER2-associated diseases, in particular cancer.

[0060] In particular, the compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof exhibits excellent inhibitory activity against HER2 mutations (e.g., HER2 T798I, HER2 L755S, HER2 T862A, etc.) and is useful for treating or preventing cancers induced by HER2 or HER2 mutations.

[0061] Here, "prevention" refers to any action for inhibiting or delaying the onset, spread and recurrence of the disease, and "treatment" refers to any action that ameliorates or beneficially alters the symptoms of the disease, such as by administration of a compound.

[0062] Thus, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof for the treatment or prevention of a HER2-associated disease.

[0063] The present invention also provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the treatment or prevention of a HER2-associated disease.

[0064] The present invention also provides a method of treating or preventing a HER2-associated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0065] In particular, the present invention relates to the treatment of pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cavity cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia. , retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumors, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, The present invention provides a method for treating or preventing at least one disease selected from the group consisting of ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal region cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmacologic acceptable salt or stereoisomer thereof.

[0066] Here, the term "subject in need thereof" can be any animal, including human (patient), that has or may develop a disease, particularly mammals such as monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits and guinea pigs, particularly mammals including humans. Furthermore, the subject in need thereof can be a biological sample.

[0067] Furthermore, "administration" means providing the intended substance to a subject in need thereof in any suitable manner, and administration of the compounds of the present invention can be achieved via any common route, such as oral or parenteral, so long as the route allows the substance to reach the target tissue.

[0068] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof as an active ingredient.

[0069] The present invention also provides a pharmaceutical composition for the treatment or prevention of a HER2-related disease, said composition comprising as an active ingredient a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0070] The HER2-related disease may be, for example, cancer. The cancer may be a solid cancer or a blood cancer, including all cancers for which the pharmaceutical composition of the present invention can exert therapeutic and preventive efficacy by inhibiting HER2 activity. The cancer may be not only a primary cancer but also a metastatic cancer. Specific examples of the HER2-related disease include pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, Colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer , malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal region cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer.

[0071] The pharmaceutical composition may contain conventional and non-toxic pharmaceutically acceptable additives, which are mixed into the formulation by conventional methods. Thus, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer as an active ingredient, and comprising a pharmaceutically acceptable additive. For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or stereoisomer and a pharmaceutically acceptable carrier. As the pharmaceutically acceptable carrier, at least one of saline solution, sterilized water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, etc. may be used, and other conventional additives such as antioxidants, buffers and bacteriostatic agents may be added as necessary.

[0072] In addition, the pharmaceutical composition may be formulated into an injection preparation such as an aqueous solution, suspension or emulsion, a pill, a capsule, a granule or a tablet by further adding a diluent, a dispersant, a surfactant, a binder and a lubricant. Thus, the composition of the present invention may be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, etc.

[0073] These preparations can be produced by conventional methods used in the field of formulations or by the methods disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton PA, and can be formulated into various preparations depending on the disease or ingredient.

[0074] Furthermore, the pharmaceutical compositions of the present invention may further comprise one or more active ingredients that exhibit the same or a similar medical effect in addition to the compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0075] The pharmaceutical compositions can be prepared into various formulations for oral administration (eg, tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (eg, intramuscular, intravenous or subcutaneous injections).

[0076] For example, pharmaceutical compositions can be prepared into oral preparations, and additives used here can include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, etc. In particular, oral solid preparations include tablets, pills, powders, granules, capsules, etc. Such solid preparations can be formulated by mixing at least one additive, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple additives, lubricants such as magnesium stearate and talc can also be used. In addition, oral liquid preparations can include suspensions, emulsions, syrups, etc., and liquid preparations can include various additives such as wetting agents, sweeteners, flavoring agents, and preservatives in addition to water and liquid paraffin that are generally used as simple diluents.

[0077] In addition, examples of parenteral administration preparations may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. For non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. may be used. As a suppository base, witepsol TM , Macrogol, Tween TM 61, cocoa butter, laurin fat, glycerogelatin, etc. may be used. The injection may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0078] The compounds or compositions of the invention may be administered to a patient in a therapeutically or pharma- ceutical effective amount.

[0079] The term "therapeutically effective amount" as used herein refers to an amount of a compound of formula (I) that is effective in treating or preventing a HER2-related disease. In particular, a "therapeutically effective amount" is an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment, and the effective dose level of a compound or composition can be determined by factors including the type, age and sex of the individual, severity, type of disease, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, drugs used in combination with the composition, and other factors well known in the medical field.

[0080] The compounds or compositions of the present invention can be administered as individual therapeutic agents or in combination with other therapeutic agents, can be administered sequentially or simultaneously with marketed therapeutic agents, and can be administered in single or multiple doses. Taking into account all of the above factors, it is important to administer the smallest amount that provides maximum efficacy without side effects, and such amounts can be easily determined by those skilled in the art.

[0081] The dosage of the pharmaceutical composition of the present invention can be determined by a specialist depending on various factors such as the patient's condition, age, sex, and complications, etc. The active ingredient of the pharmaceutical composition of the present invention has excellent safety and therefore can be used in an amount equal to or greater than the determined dosage.

[0082] Furthermore, for the manufacture of medicaments using the compounds of formula (I), adjuvants, diluents, carriers, etc. may be mixed, and the compounds may be prepared as combination preparations together with other active agents so as to exert a synergistic effect of the active ingredients.

[0083] The descriptions of applications, compositions and methods of treatment in the present invention apply in the same manner unless they contradict each other. EXAMPLES

[0084] Mode of the invention The present invention will be described in detail below through examples and experimental examples. However, the following examples and experimental examples are merely for explaining the present invention, and the scope of the present invention is not limited thereto.

[0085] Analytical and purification conditions 1. HPLC analysis conditions Instrument name: Waters Corporation e2695 Column: YMC-Pack ODS-AM, 150×4.6 mm, 3 μm, 12 nm, 40° C. Mobile phase: 10% → 90% acetonitrile / H2O + 0.1% TFA Analysis time: 20 minutes, flow rate: 1mL / min UV detector: 254nm

[0086] 2. LC-MS analysis conditions Instrument name: Waters Corporation AQUITY UPLC Column: AQUITY UPLC (登録商標) BEH C18, 50×2.1mm, 5μm, 40℃ Mobile phase: Acetonitrile / H2O+0.1% TFA Flow rate: 0.6mL / min UV detector: 254nm

[0087] 3. MPLC purification conditions Device name: CombiFlash by Teledyne ISCO, Inc. (登録商標) Rf+ UV detector: 254nm

[0088] 4. Preparative HPLC purification conditions (A) Device name: ACCQPrep by Teledyne ISCO, Inc. (登録商標) HP125 Column: XBridge (登録商標) Prep Shield RP18, 250×19mm, 10μm Mobile phase: Acetonitrile / 0.1% TFA H2O Flow rate: 25mL / min UV detector: 254nm

[0089] 5. Preparative HPLC purification conditions (B) Device name: ACCQPrep by Teledyne ISCO, Inc. (登録商標) ACCQPrep HP125 Column: XBridge (登録商標) Prep Shield RP18, 250×19mm, 10μm Mobile phase: Acetonitrile / 0.1% FA H2O Flow rate: 25mL / min UV detector: 254nm

[0090] 6. 1 H NMR Device name: Bruker Ascend TM 400 (400MHz)

[0091] Commercially available reagents were used without further purification. In this specification, room temperature (rt) or ambient temperature refers to 5°C to 40°C, for example 10°C to 30°C and for other examples 20°C to 27°C, and is not strictly limited to the above ranges. A rotary evaporator was used for concentration under reduced pressure or solvent distillation removal.

[0092] Preparation Example 1: Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one (Example 1) [Reaction Scheme 1] [ka] [Step 1] Preparation of 7-(5-methoxy-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 1-Fluoro-5-methoxy-2-methyl-4-nitrobenzene (1.0 equiv.), [1,2,4]triazolo[1,5-a]pyridin-7-ol (1.2 equiv.) and Cs2CO3 (2.4 equiv.) were dissolved in DMSO (0.2 M) and then stirred at 80° C. for 2 h. The reaction mixture was poured with ice water to form a solid, which was then filtered to obtain the desired compound as a yellow solid (yield: 99%, MS (ESI): m / z 301 [M+H]+ ) was obtained.

[0093] [Step 2] Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline 7-(5-Methoxy-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.0 equiv.), ammonium chloride (0.45 equiv.) and iron (4.5 equiv.) prepared in step 1 were dissolved in ethanol-water solution (3:1), followed by stirring at 80° C. for 1 h. The mixture was filtered through a Celite filter and then concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a brown solid (yield: 98%, MS (ESI): m / z 271 [M+H] + ) was obtained.

[0094] [Step 3] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxy-6-nitroquinazolin-4-amine 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.0 eq.) obtained in step 2 and 4-chloro-7-methoxy-6-nitroquinazoline (1.0 eq.) were dissolved in sec-BuOH (0.05 M) and then 4M HCl (0.2 eq.) dissolved in 1,4-dioxane was added thereto, followed by stirring at 100° C. for 1 h. Ether was added to the reaction mixture and then the desired compound was obtained after filtration as a yellow solid (yield: 95%, MS (ESI): m / z 474 [M+H] + ) was obtained.

[0095] [Step 4]N 4 Preparation of -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxy-6-nitroquinazolin-4-amine (1.0 equiv.) obtained in step 3 and SnCl2.2H2O (5.0 equiv.) were dissolved in ethyl acetate (0.1 M) and the mixture was stirred at 60° C. for 2 h. Aqueous ammonia was added to the reaction mixture, which was then concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a pale yellow solid (yield: 65%, MS (ESI): m / z 444 [M+H] + ) was obtained.

[0096] [Step 5] Preparation of tert-butyl 4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidine-1-carboxylate N produced in step 4 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equiv.) and tert-butyl 4-oxopiperidine-1-carboxylate (3.0 equiv.) were dissolved in acetic acid (0.1M) followed by stirring at room temperature for 1 h. Sodium triacetoxyborohydride (4.0 equiv.) was added to the mixture followed by stirring at room temperature for 1 h. The organic material was extracted with saturated aqueous NaHCO3 and dichloromethane, then the remaining water in the combined organic layers was removed using MgSO4 and the combined organic layers were concentrated. The desired compound obtained as a yellow solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 627 [M+H] + ).

[0097] [Step 6]N 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxy-N 6 Preparation of -(piperidin-4-yl)quinazoline-4,6-diamine The compound obtained in step 5, tert-butyl 4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidine-1-carboxylate (1.0 eq.) was dissolved in dichloromethane (0.1 M), then trifluoroacetic acid (TFA, 60.0 eq.) was added thereto, followed by stirring at room temperature for 1 hour and then concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 59%, MS (ESI): m / z 527 [M+H] + ) was obtained.

[0098] [Step 7] Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one N obtained in step 6 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxy-N 6 -(Piperidin-4-yl)quinazoline-4,6-diamine (1.0 equiv.) was dissolved in tetrahydrofuran (THF, 0.1 M), 1M NaHCO3 aqueous solution (5.0 equiv.) was added thereto at 0° C., and acryloyl chloride (1.0 equiv.) was added thereto, followed by stirring at 0° C. for 30 min. The reaction mixture was concentrated and then purified by preparative HPLC to obtain the desired compound as an ivory solid (yield: 34%, MS (ESI): m / z 581 [M+H] + ) was obtained.

[0099] Preparation of the compounds of Examples 2 to 4 The compounds of Examples 2 to 4 of the present invention were produced by a method similar to that of Production Example 1.

[0100] Chemical structures and names of the compounds of Examples 1 to 4 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 1 below.

[0101] [Table 1-1] [Table 1-2]

[0102] Preparation Example 2: Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (Example 5) [Reaction Scheme 2] [ka] [Step A1] Preparation of 7-(2-chloro-5-methoxy-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 1-Chloro-2-fluoro-4-methoxy-5-nitrobenzene (1.0 equiv.), [1,2,4]triazolo[1,5-a]pyridin-7-ol (1.0 equiv.) were dissolved in DMF (0.1 M), Cs2CO3 (1.2 equiv.) was added thereto, followed by stirring at 120° C. for 1 h. The reaction mixture was poured into ice water and stirred to form a solid, which was filtered using a filter, and the desired compound obtained as a yellow solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 321 [M+H] + ).

[0103] [Step A2] Preparation of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyaniline 7-(2-chloro-5-methoxy-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.0 eq.) obtained in step A1 and iron (4.5 eq.) were dissolved in ethanol-water solution (3:1, 0.566 M) and ammonium chloride (0.45 eq.) was added thereto, followed by stirring at 80° C. for 1 h. The reaction mixture was filtered and the organic material was extracted with water and dichloromethane, then the remaining water in the collected organic layer was removed using MgSO4 and the collected organic layer was concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 36%, MS (ESI): m / z 291 [M+H] + ) was obtained.

[0104] [Reaction Scheme 3] [ka] [Step B1] Production of 4-chloro-7-methoxyquinazolin-6-ol 4-Chloro-7-methoxyquinazolin-6-yl acetate (1.0 equiv.) was dissolved in methanol (0.7M), then aqueous ammonia (20.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 2 hours. Ether was added to the reaction mixture to form a solid, which was then filtered to obtain the desired compound as a yellow solid (yield: 100%, MS (ESI): m / z 211 [M+H] + ) was obtained.

[0105] [Step B2] Preparation of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate 4-Chloro-7-methoxyquinazolin-6-ol (1.0 eq.) obtained in step B1, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.4 eq.) and triphenylphosphine (1.3 eq.) were dissolved in dichloromethane, then di-tert-butyl azodicarboxylate (DTBAD; 1.5 eq.) was added thereto slowly at 0° C. and stirred at room temperature for 2 h. The reaction mixture was concentrated and purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a white solid (yield: 52%, MS (ESI): m / z 394 [M+H] + ) was obtained.

[0106] [Step B3] Preparation of 4-chloro-7-methoxy-6-(piperidin-4-yloxy)quinazoline tert-Butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (1.0 eq.) obtained in step B2 was added with 4.0 M HCl (20.0 eq.) dissolved in 1,4-dioxane, followed by stirring at room temperature for 4 hours. Ether was added to the reaction mixture to form a solid, which was then filtered to obtain the desired compound as a light yellow solid (yield: 100%, MS (ESI): m / z 294 [M+H] + ) was obtained.

[0107] [Step B4] Preparation of 1-(4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one 4-Chloro-7-methoxy-6-(piperidin-4-yloxy)quinazoline (1.0 eq.) obtained in step B3 was dissolved in dichloromethane (0.2 M), then triethylamine (3.5 eq.) and acryloyl chloride (1.05 eq.) were added thereto at 0° C. and stirred for 1 h. The organic material was extracted by adding aqueous NaHCO3 and dichloromethane to the reaction mixture, the water remaining in the collected organic layer was removed using MgSO4, and the collected organic layer was concentrated. The concentrated reaction mixture was purified using MPLC to obtain the desired compound as a white solid (yield: 100%, MS (ESI): m / z 348 [M+H]). + ) was obtained.

[0108] [Step B5] Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one 1-(4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one (1.0 eq.) obtained in step B4 and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyaniline (1.0 eq.) obtained in step A2 of reaction scheme 2 were dissolved in sec-BuOH (0.1 M), then 4.0 M HCl (0.3 eq.) in 1,4-dioxane was added thereto and stirred at 110° C. for 1 h. The reaction mixture was concentrated and then purified using preparative HPLC to give the desired compound as a brown oil (yield: 10%, MS (ESI): m / z 603 [M+H] + ) was obtained.

[0109] Preparation of the compounds of Examples 6 to 14 The compounds of Examples 6 to 14 of the present invention were produced by a method similar to that of Production Example 2.

[0110] Chemical structures and names of the compounds of Examples 5 to 14 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 2 below.

[0111] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0112] Preparation 3: Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one (Example 15) [Reaction Scheme 4] [ka] [Step 1] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-fluoro-7-methoxyquinazolin-4-amine (E)-N'-(2-cyano-3-fluoro-5-methoxyphenyl)-N,N-dimethylformimidamide (1.0 equivalent) and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.5 equivalent) obtained in step 2 of Preparation 1 were dissolved in acetic acid (52.0 equivalents), followed by stirring at 50°C for 16 hours. After the reaction, the organic material was extracted with saturated aqueous NaHCO3 and ethyl acetate, the organic layer was washed with brine, and the remaining water was removed with Na2SO4, followed by filtration and concentration. The reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 72%, MS (ESI): m / z 447 [M+H] + ) was obtained.

[0113] [Step 2] Preparation of tert-butyl 4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidine-1-carboxylate N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-fluoro-7-methoxyquinazolin-4-amine (1.0 equivalent) obtained in step 1, tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (2.0 equivalents) and KOtBu (3.0 equivalents) were dissolved in THF:DMF=1:1 (0.02M) and stirred at 100° C. for 16 hours under nitrogen. The reaction mixture was concentrated and purified by MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid (yield: 51%, MS (ESI): m / z 664 [M+H] + ) was obtained.

[0114] [Step 3] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-((3,3-difluoropiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine tert-Butyl 4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidine-1-carboxylate (1.0 equiv.) from step 2 and TFA (10.0 equiv.) were dissolved in dichloromethane (0.1 M) and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by MPLC (dichloromethane:methanol) to give the desired compound as an orange solid (yield: 84%, MS (ESI): m / z 564 [M+H]). + ) was obtained.

[0115] [Step 4] Preparation of 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-((3,3-difluoropiperidin-4-yl)oxy)-7-methoxyquinazolin-4-amine (1.0 eq.) obtained in step 3 and 1M aqueous NaHCO3 solution (5.0 eq.) were dissolved in tetrahydrofuran (0.1M), and then acryloyl chloride (1.0 eq.) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, the reaction mixture was concentrated and purified by preparative HPLC to obtain the desired compound as a light yellow solid (yield: 34%, MS (ESI): m / z 618 [M+H]). + ) was obtained.

[0116] Preparation of the compounds of Examples 16 and 17 The compounds of Examples 16 to 17 of the present invention were produced by a method similar to that of Production Example 3.

[0117] Chemical structures and names of the compounds of Examples 15 to 17 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 3 below.

[0118] [Table 3]

[0119] Preparation Example 4: Preparation of 1-(5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one (Example 18) [Reaction Scheme 5] [ka] [Step 1] Preparation of 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-ol 4-Chloro-7-methoxyquinazolin-6-ol (1.0 eq.) obtained in step 2 of Preparation 1, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.0 eq.) and 4M HCl (0.2 eq.) in 1,4-dioxane were dissolved in sec-BuOH (0.1M) followed by stirring at 80° C. for 2 hours. The reaction mixture was concentrated and purified by MPLC (dichloromethane:methanol) to give the desired compound as a white solid (yield: 75%, MS (ESI): m / z 445 [M+H] + ) was obtained.

[0120] [Step 2] Preparation of tert-butyl 5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-ol (1.0 eq.) obtained in step 1, tert-butyl 5-(tosyloxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.2 eq.) and K2CO3 (2.0 eq.) were dissolved in DMF (0.1 M) and stirred at 110°C for 16 h. After the reaction, the organic material was extracted with distilled water and ethyl acetate, the organic layer was washed with brine, and then the remaining water was removed with Na2SO4, followed by filtration and concentration. The reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 79%, MS (ESI): m / z 640 [M+H] + ) was obtained.

[0121] [Step 3] Preparation of 6-((2-azabicyclo[2.2.1]heptan-5-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazolin-4-amine tert-Butyl 5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in step 2 (1.0 equiv.) and TFA (20.0 equiv.) were dissolved in DCM (0.5 M) and then stirred at room temperature for 1 h. The reaction mixture was concentrated and then purified by MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid (yield: 89%, MS (ESI): m / z 540 [M+H] + ) was obtained.

[0122] [Step 4] Preparation of 1-(5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one 6-((2-azabicyclo[2.2.1]heptan-5-yl)oxy)-N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazolin-4-amine (1.0 eq.) obtained in step 3 and 1M aqueous NaHCO3 solution (5.0 eq.) were dissolved in tetrahydrofuran (0.1M), and then acryloyl chloride (1.0 eq.) was added thereto at 0°C. The mixture was stirred at room temperature for 30 min, then the reaction mixture was concentrated and purified by preparative HPLC to obtain the desired compound as a white solid (yield: 22%, MS (ESI): m / z 594 [M+H] + ) was obtained.

[0123] Preparation of the compounds of Examples 19 and 20 The compounds of Examples 19 to 20 of the present invention were prepared by a method similar to that of Preparation Example 4.

[0124] Chemical structures and names of the compounds of Examples 18 to 20 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 4 below.

[0125] [Table 4]

[0126] Preparation Example 5: Preparation of 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)prop-2-en-1-one (Example 21) [Reaction Scheme 6] [ka] [Step 1] Preparation of 7-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one Ethylene glycol (1.0 equiv.) was dissolved in anhydrous tetrahydrofuran (1.5M), NaH (0.7 equiv.) was slowly added to the solution at 0°C, and after the addition was complete, the temperature was raised to room temperature, followed by stirring for 1 h. Then, 7-fluoro-6-nitroquinazolin-4(3H)-one (0.3 equiv.) was added to the reaction mixture, and stirred at 75°C for 16 h. Acetic acid was slowly added to the reaction mixture at 0°C to adjust the pH to 7, after which the organic material was extracted with water and chloroform:isopropanol=4:1 (v / v), and then the remaining water in the collected organic layer was removed using Na2SO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The concentrated mixture was purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a light yellow solid (yield: 12%, MS (ESI): m / z 252 [M+H] + ) was obtained.

[0127] [Step 2] Preparation of 4-chloro-7-(2-chloroethoxy)-6-nitroquinazoline 7-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (1.0 equivalent) obtained in step 1 and SOCl2 (0.1M) were added thereto, DMF (0.1 equivalent) was added thereto, and then the mixture was stirred at 110°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the desired compound as a white solid, which was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 287 [M+H] + ).

[0128] [Step 3] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine 4-Chloro-7-(2-chloroethoxy)-6-nitroquinazoline (1.0 equivalent) obtained in step 2 was dissolved in isopropanol (0.1 M), and then 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.1 equivalent) prepared in step 2 of Preparation 1 was added thereto, followed by stirring at 60° C. for 1 hour. The reaction mixture was cooled and filtered to obtain a solid, which was washed with isopropanol. The obtained solid was dried under reduced pressure to obtain the desired compound as a yellow solid (yield: 65%, MS (ESI): m / z 522 [M+H] + ) was obtained.

[0129] [Step 4]N 4 Preparation of -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(2-chloroethoxy)quinazoline-4,6-diamine The N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(2-chloroethoxy)-6-nitroquinazolin-4-amine (1.0 equivalent) obtained in step 3 was dissolved in ethyl acetate (0.05 M) and then diluted with SnCl 2. 2H2O (5.0 equiv.) was added thereto, followed by stirring at 60°C for 2 hours. The reaction mixture was cooled to 0°C, and then aqueous ammonia was slowly added thereto. The organic material was extracted by adding saturated aqueous NaHCO3 and ethyl acetate to the reaction mixture, and then the remaining water in the collected organic layer was removed using Na2SO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The reaction mixture was purified by MPLC (dichloromethane:methanol) to obtain the desired compound as a white solid (yield: 83%, MS (ESI): m / z 492 [M+H] + ) was obtained.

[0130] [Step 5] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine N obtained in step 4 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(2-chloroethoxy)quinazoline-4,6-diamine (1.0 equiv.) was dissolved in DMF (0.1M), then K2CO3 (1.02 equiv.) and KI (1.0 equiv.) were added to it, and the mixture was stirred at 130°C for 16 hours. From the reaction mixture, the organic material was extracted by adding ethyl acetate and brine, then the remaining water in the collected organic layer was removed using Na2SO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The concentrated reaction mixture was purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 60%, MS (ESI): m / z 456 [M+H] + ) was obtained.

[0131] [Step 6] Preparation of 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)prop-2-en-1-one N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-4-amine (1.0 eq.) obtained in step 5 was dissolved in dichloromethane (0.05 M) and then acrylic acid (3.5 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 3.5 eq.) and N,N-diisopropylethylamine (DIPEA, 2.5 eq.) were added thereto, followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated and then purified using MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid (yield: 5%, MS (ESI): m / z 510 [M+H] + ) was obtained.

[0132] [Table 5]

[0133] Preparation Example 6: Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)acrylamide (Example 22) [Reaction Scheme 7] [ka] [Step 1] Preparation of 4-chloro-7-fluoro-6-nitroquinazoline 7-Fluoro-6-nitroquinazolin-4(3H)-one (1.0 eq.) and DMF (0.1 eq.) were dissolved in SOCl2 (20.0 eq.) followed by stirring at 80°C for 4 h. The reaction mixture was concentrated, dissolved in dichloromethane and ether was added to it. The resulting solid was filtered and then dried under reduced pressure to obtain a yellow solid. The resulting yellow solid was used in the next reaction without further purification (yield: 36%, MS (ESI): m / z 228 [M+H] + ).

[0134] [Step 2] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-fluoro-6-nitroquinazolin-4-amine 4-Chloro-7-fluoro-6-nitroquinazoline (1.0 equivalent) obtained in step 1 and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.0 equivalent) prepared in step 2 of Preparation Example 1 were dissolved in isopropanol (0.2 M) and then stirred at 50° C. for 30 minutes. The reaction mixture was filtered to obtain a solid, which was washed with ether to obtain the desired compound as an ivory solid (yield: 72%, MS (ESI): m / z 462 [M+H] + ) was obtained.

[0135] [Step 3] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(4-morpholinopiperidin-1-yl)-6-nitroquinazolin-4-amine N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (1.0 eq.) obtained in step 2, 4-(piperidin-4-yl)morpholine (2.2 eq.) and DIPEA (4.0 eq.) were dissolved in 1,4-dioxane (0.3 M) and then stirred at 110° C. for 16 h. The reaction mixture was concentrated and then purified by MPLC to give the desired compound as a yellow solid (yield: 79%, MS (ESI): m / z 612 [M+H]). + ) was obtained.

[0136] [Step 4]N 4 Preparation of -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(4-morpholinopiperidin-1-yl)quinazoline-4,6-diamine N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(4-morpholinopiperidin-1-yl)-6-nitroquinazolin-4-amine (1.0 equiv.) from step 3 and SnCl2.2H2O (5.0 equiv.) were dissolved in ethyl acetate (0.1 M) and the mixture was stirred at 60° C. for 16 h. Aqueous ammonia was added to the reaction mixture, which was then concentrated. The reaction mixture was purified using MPLC to give the desired compound as a light yellow solid (yield: 33%, MS (ESI): m / z 582 [M+H] + ) was obtained.

[0137] [Step 5] Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)acrylamide N obtained in step 44 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-(4-morpholinopiperidin-1-yl)quinazoline-4,6-diamine (1.0 equiv.) was dissolved in dichloromethane (0.1 M) and then DIPEA (3.0 equiv.) was added to it followed by stirring at 0° C. Then acryloyl chloride (1.05 equiv.) was added to it and stirred at 0° C. for 1 h. The reaction mixture was concentrated and purified using preparative HPLC to give the desired compound as a yellow solid (yield: 3%, MS (ESI): m / z 636 [M+H] + ) was obtained.

[0138] Preparation of compounds of Examples 23 to 25 The compounds of Examples 23 to 25 of the present invention were prepared by a method similar to that of Preparation 6.

[0139] Chemical structures and names of the compounds of Examples 22 to 25 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 6 below.

[0140] [Table 6]

[0141] Preparation 7: (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Example 26) [Reaction Scheme 8] [ka] [Step 1] Preparation of 4-(1H-benzo[d][1,2,3]triazol-1-yl)-5-chloroquinazolin-6-amine 6-Amino-5-chloroquinazolin-4-ol (1.0 equiv.) was dissolved in acetonitrile (0.1M), then benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 3.0 equiv.), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 4.0 equiv.) were added thereto, followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give the desired compound as a brown oil, which was used in the next reaction without further purification (yield: 15%, MS (ESI): m / z 297 [M+H] + ).

[0142] [Step 2]N 4 Preparation of -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-chloroquinazoline-4,6-diamine 4-(1H-benzo[d][1,2,3]triazol-1-yl)-5-chloroquinazolin-6-amine (1.0 equivalent) obtained in step 1 and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.0 equivalent) obtained in step 2 of Preparation 1 were dissolved in isopropanol (0.1 M) and refluxed at 90° C. for 10 minutes, then p-TsOH (0.1 equivalent) was added to the reaction mixture and refluxed at 90° C. for 30 minutes. Dichloromethane (0.05 M), brine and saturated aqueous NaHCO3 were added to the reaction mixture to extract the organic material, and the remaining water was removed using Na2SO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The concentrated mixture was purified using MPLC (dichloromethane:methanol) and then purified using preparative HPLC. The compound obtained through preparative HPLC was collected, concentrated, and brine was added to it and stirred at room temperature for 1 hour. After the reaction, the obtained solid was filtered and then dried to obtain the desired compound as a yellow solid (yield: 15%, MS (ESI): m / z 448 [M+H] + ) was obtained.

[0143] [Step 3] Preparation of (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)but-2-enamide N obtained in step 2 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-5-chloroquinazoline-4,6-diamine (1.0 equiv.) was dissolved in acetonitrile (0.1M) and then cooled to 0°C, (E)-4-(dimethylamino)but-2-enoyl chloride (1.0 equiv.) was added thereto, followed by stirring at 0°C for 1 h. Dichloromethane (0.05M) and saturated aqueous NaHCO3 were added to the reaction mixture to extract the organic material, and then the remaining water in the collected organic layer was removed using Na2SO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The concentrated mixture was purified using preparative HPLC to obtain the desired compound as a light yellow solid (yield: 26%, MS (ESI): m / z 559 [M+H] + ) was obtained.

[0144] [Table 7]

[0145] Preparation 8: Preparation of 1-(4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one (Example 27) [Reaction Scheme 9] [ka] [Step 1] Preparation of 8-chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine 6-(Methylthio)pyrimido[5,4-d]pyrimidin-4-ol (1.0 equiv.) and DMF (1.6 equiv.) were dissolved in dichloromethane (0.5M), and then oxalyl chloride (2.0 equiv.) was added thereto slowly at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the desired compound as a white solid, which was then used in the next reaction without further purification (Yield: 100%, MS (ESI): m / z 213 [M+H] + ).

[0146] [Step 2] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidin-4-amine 8-Chloro-2-(methylthio)pyrimido[5,4-d]pyrimidine (1.0 eq.) from step 1 and 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylaniline (1.0 eq.) from step 2 of Preparation 1 were dissolved in isopropyl alcohol (0.5 M), and the reaction mixture was then stirred at 45° C. for 4 hours. The reaction mixture was concentrated and purified using MPLC to give the desired compound as a yellow solid (yield: 16%, MS (ESI): m / z 447 [M+H] + ) was obtained.

[0147] [Step 3] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-amine N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(methylthio)pyrimido[5,4-d]pyrimidin-4-amine (1.0 eq.) obtained in step 2 was dissolved in dichloromethane (0.06 M), and then meta-chloroperoxybenzoic acid (m-CPBA, 2.3 eq.) was added thereto slowly at 0° C. The reaction mixture was stirred at room temperature for 2 h. Aqueous saturated NaHCO3 was added to the reaction mixture, and the organic material was extracted with DCM, and then the remaining water in the collected organic layer was removed using MgSO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The desired compound obtained as a white solid was used in the next reaction without further purification (yield: 83%, MS (ESI): m / z 479 [M+H] + ).

[0148] [Step 4] Preparation of tert-butyl 4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazine-1-carboxylate N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-amine (1.0 eq.) obtained in step 3 was dissolved in 1,4-dioxane (0.1 M), and then tert-butyl piperazine-1-carboxylate (1.7 eq.) and DIPEA (1.3 eq.) were added thereto. The reaction mixture was stirred at 70° C. for 2 h. Aqueous saturated NaHCO3 solution was added to the reaction mixture, and the organic material was extracted with DCM, and then the remaining water in the collected organic layer was removed using MgSO4, after which the collected organic layer was filtered and concentrated under reduced pressure. The desired compound obtained as a brown liquid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 585 [M+H] + ).

[0149] [Step 5] Preparation of N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4-amine tert-Butyl 4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazine-1-carboxylate (1.0 equiv.) obtained in step 4 was dissolved in dichloromethane (0.06 M), trifluoroacetic acid (40.0 equiv.) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified using MPLC to obtain the desired compound as an orange solid (yield: 82%, MS (ESI): m / z 485 [M+H]). + ) was obtained.

[0150] [Step 6] Preparation of 1-(4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-6-(piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4-amine (1.0 eq.) obtained in step 5 was dissolved in DCM (0.04 M) and triethylamine (8.0 eq.) was added thereto, followed by acryloyl chloride (1.5 eq.) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and then purified using preparative HPLC to obtain the desired compound as a yellow solid (yield: 29%, MS (ESI): m / z 539 [M+H]). + ) was obtained.

[0151] [Table 8]

[0152] Preparation 9: Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)but-2-ynamide (Example 28) [Reaction Scheme 10] [ka] [Step 1] Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)but-2-ynamide Tetronic acid (3.0 equivalents) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 3.0 equivalents) were dissolved in DMF (0.5 M) and stirred at 50° C. for 30 minutes. 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equiv.) and DIPEA (3.0 equiv.) were added to the reaction mixture, which was then stirred at 50° C. for 1 h. The reaction mixture was purified using preparative HPLC to give the desired compound (yield: 7%, MS (ESI): m / z 510 [M+H] + ) was obtained.

[0153] [Table 9]

[0154] Preparation 10: (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide (Example 29) [Reaction Scheme 11] [ka] [Step 1] Preparation of diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphonate 2-(diethoxyphosphoryl)acetic acid (3.0 equivalents) and 1,1'-carbonyldiimidazole (CDI, 3.0 equivalents) were dissolved in tetrahydrofuran (0.5 M), followed by stirring at 40°C for 30 minutes. 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equivalent) was added to the mixture, which was then stirred at 40° C. for 1 h. Water was added and the organic material was extracted with dichloromethane, and the remaining water in the combined organic layers was then removed using MgSO4, after which the combined organic layers were concentrated. The resulting yellow desired compound was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 622 [M+H] + ).

[0155] [Step 2] Preparation of tert-butyl (R,E)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate Diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphonate (1.0 equivalent) obtained in step 1 was dissolved in tetrahydrofuran (0.05M), and then lithium bis(trimethylsilyl)amide (LiHMDS, 1.0 equivalent) was added thereto at -78°C. The mixture was stirred at -78°C for 1 hour, and then tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (3.3 equivalents) was added thereto and stirred at room temperature for 1 hour. Water was added, and the organic material was extracted with dichloromethane, and then the water remaining in the collected organic layer was removed using MgSO4, and then the collected organic layer was concentrated. The desired compound obtained as a yellow solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 667 [M+H] + ).

[0156] [Step 3] Preparation of (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(pyrrolidin-2-yl)acrylamide The compound obtained in step 2, tert-butyl (R,E)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (1.0 equiv.) was dissolved in dichloromethane (0.1 M), then TFA (60.0 equiv.) was added thereto and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 59%, MS (ESI): m / z 567 [M+H] + ) was obtained.

[0157] [Step 4] Preparation of (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(pyrrolidin-2-yl)acrylamide (1.0 eq.) obtained in step 3 and 37% formaldehyde (5.0 eq.) were dissolved in 1,2-dichloroethane (DCE, 0.1 M) and then stirred at room temperature for 1 h. Sodium triacetoxyborohydride (4.0 eq.) was added to the mixture, which was then stirred at 80° C. for 1 h. Saturated aqueous NaHCO3 and dichloromethane were added to extract the organic material, and then the remaining water in the collected organic layer was removed using MgSO4, and the collected organic layer was concentrated. The reaction mixture was purified by MPLC (dichloromethane:methanol) to give the desired compound as a white solid (yield: 33%, MS (ESI): m / z 581 [M+H] + ) was obtained.

[0158] Preparation of compounds of Examples 30 to 37 The compounds of Examples 30 to 37 of the present invention were produced by a method similar to that of Production Example 10.

[0159] Chemical structures and names of the compounds of Examples 29 to 37 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 10 below.

[0160] [Table 10-1] [Table 10-2] [Table 10-3]

[0161] Preparation 11: (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)but-2-enamide (Example 38) [Reaction Scheme 12] [ka] [Step 1] Preparation of (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-bromobut-2-enamide N produced in step 4 of Production Example 1 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 eq.) was dissolved in acetonitrile (0.2M), then (E)-3-bromoacryloyl chloride (3.0 eq.) and DIPEA (4.0 eq.) were added to it at 0°C. The reaction mixture was reacted at 0°C for 1 min, then water was added to it and the organic material was extracted with ethyl acetate (EA). The water remaining in the collected organic layer was removed using Na2SO4 and the collected organic layer was concentrated. The desired compound obtained as a brown oil was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 590 [M+H] + ).

[0162] [Step 2] Preparation of (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)but-2-enamide (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-bromobut-2-enamide (1.0 equiv.) obtained in step 1, KI (1.8 equiv.) and K2CO3 (2.3 equiv.) were dissolved in DMF (0.2 M) and then reacted at 40° C. for 1 h. The reaction mixture was purified using preparative HPLC to obtain the desired compound as a white solid (yield: 8%, MS (ESI): m / z 659 [M+H] + ) was obtained.

[0163] Preparation of the compounds of Examples 39-40 The compounds of Examples 39 to 40 of the present invention were prepared by a method similar to that of Preparation Example 11.

[0164] Chemical structures and names of the compounds of Examples 38 to 40 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 11 below.

[0165] [Table 11]

[0166] Preparation Example 12: (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (Example 41) and (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (Example 111) [Reaction Scheme 13] [ka] [Step 1] Preparation of diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate 2-(diethoxyphosphoryl)-2-fluoroacetic acid (2.0 equivalents) and HATU (3.0 equivalents) were dissolved in DMF (0.5 M), followed by stirring at 50° C. for 30 minutes. 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 eq.) and DIPEA (3.0 eq.) were added to the mixture, which was then stirred at 50° C. for 1 h. Ice water was poured into the reaction mixture to form a solid, which was then filtered to obtain the desired compound as a yellow solid (yield: 95%, MS (ESI): m / z 640 [M+H] + ) was obtained.

[0167] [Step 2] Preparation of tert-butyl (R,E / Z)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate Diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate (1.0 eq.) obtained in step 1 was dissolved in DMF (0.5 M), and then NaH (1.5 eq.) was added at 0° C. The mixture was stirred at 0° C. for 30 min, and then tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (2.0 eq.) was added thereto and stirred at room temperature for 1 h. Ice water was poured into the reaction mixture to form a solid, which was then filtered to obtain the desired compound as a yellow solid (yield: 85%, MS (ESI): m / z 685 [M+H] + ) was obtained.

[0168] [Step 3] Preparation of (R,E / Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide tert-Butyl (R,E / Z)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (1.0 equiv.) obtained in step 2 was dissolved in dichloromethane (0.1 M), then TFA (60.0 equiv.) was added thereto and stirred at room temperature for 1 h, followed by concentration. The concentrated mixture was purified using MPLC (dichloromethane:methanol) to obtain the desired compound as a yellow solid (yield: 57%, MS (ESI): m / z 585 [M+H] + ) was obtained.

[0169] [Step 4] Preparation of (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide and (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (R,E / Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide (1.0 eq.) obtained in step 3 and 37% formaldehyde (5.0 eq.) were dissolved in DCE (0.1M) and stirred at room temperature for 1 h. Sodium triacetoxyborohydride (4.0 eq.) was added to the mixture, which was then stirred at 80° C. for 1 h. Saturated aqueous NaHCO3 and dichloromethane were added to the reaction mixture to extract the organic material, the remaining water was removed using MgSO4, and the organic layer was concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid.

[0170] ((R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide: Yield: 39%, MS (ESI): m / z 599 [M+H] + , ((R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide: Yield: 9%, MS (ESI): m / z 599 [M+H] + ).

[0171] Preparation of compounds of Examples 42 to 110 and 112 to 143 The compounds of Examples 42 to 110 and 112 to 143 of the present invention were produced by a method similar to that of Production Example 12.

[0172] Chemical structures and names of the compounds of Examples 41 to 143 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 12 below.

[0173]

Table 12-1

Table 12-2

Table 12-3

Table 12-4

Table 12-5

Table 12-6

Table 12-7

Table 12-8

Table 12-9

Table 12-10

Table 12-11

Table 12-12

Table 12-13

Table 12-14

Table 12-15

Table 12-16

Table 12-17

Table 12-18

Table 12-19

Table 12-20

Table 12-21

Table 12-22

Table 12-23

Table 12-24

Table 12-25

Table 12-26

Table 12-27

Table 12-28

Table 12-29

Table 12-30

Table 12-31

Table 12-32

Table 12-33

[0174] Preparation 13: Preparation of (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide (Example 144) [Reaction Scheme 14] [ka] [Step A1] Production of 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanal 2-Bromo-2-methylpropanal (2.0 equiv.) was dissolved in dichloromethane (0.15M), and then 1-(oxetan-3-yl)piperazine (1.0 equiv.) was added to it slowly at 0° C. DIPEA (1.0 equiv.) was added to the reaction mixture and stirred at room temperature for 16 h. The organic material was extracted by adding water and dichloromethane to the reaction mixture, then the remaining water in the collected organic layer was removed using Na2SO4, and the collected organic layer was concentrated to obtain the desired compound yellow liquid (yield: 100%, MS (ESI): m / z 213 [M+H] + ) was obtained.

[0175] [Reaction Scheme 15] [ka] [Step B1] Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyanoacetamide Cyanoacetic acid (2.0 equivalents), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 2.0 equivalents) and DIPEA (3.0 equivalents) were dissolved in DMF (0.1 M), followed by addition of the N 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equivalent) was added thereto and stirred at room temperature for 2 hours. The reaction mixture was added to cold water to produce a solid, which was filtered and then dried under reduced pressure to obtain the desired compound as a yellow solid. The desired compound was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 511 [M+H] + ).

[0176] [Step B2] Preparation of (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyanoacetamide (1.0 equivalent) obtained in step B1 and 2-methyl-2-(4-(oxetan-3-yl)piperazin-1-yl)propanal (2.0 equivalents) obtained in step A1 of reaction scheme 14 were dissolved in dichloromethane (0.1 M), and then pyrrolidine (6.0 equivalents) and chlorotrimethylsilane (4.0 equivalents) were added thereto at 0° C., followed by stirring for 3 hours. Water and brine were added to the reaction mixture, and the organic material was extracted with dichloromethane, then the water remaining in the collected organic layer was removed using Na2SO4, and the collected organic layer was concentrated. The reaction mixture was purified by preparative HPLC to give the desired compound as a yellow solid (yield: 68%, MS (ESI): m / z 705 [M+H] + ) was obtained.

[0177] Preparation of the compounds of Examples 145 and 146 The compounds of Examples 145 and 146 of the present invention were prepared in a manner similar to Preparation 13.

[0178] Chemical structures and names of the compounds of Examples 144 to 146 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 13 below.

[0179] [Table 13]

[0180] Preparation Example 14: Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-(1H-pyrazol-1-yl)acrylamide (Example 147) [Reaction Scheme 16] [ka] [Step 1] Preparation of 2-(1H-pyrazol-1-yl)acrylic acid 2-Bromoacrylic acid (1.0 equiv.), 1H-pyrazole (1.5 equiv.), CuI (0.2 equiv.), Cs2CO3 (2.5 equiv.) and N 1 ,N 2 -Bis(furan-2-ylmethyl)oxalamide (BFMO, 0.2 equiv.) was dissolved in DMSO (0.5 M) followed by stirring at 80 °C for 1 h. Water and brine were added to the reaction mixture and the organic material was extracted with ethyl acetate, then the water remaining in the combined organic layers was removed using Na2SO4 and the combined organic layers were concentrated. The reaction mixture was purified by MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid (yield: 6%, MS (ESI): m / z 139 [M+H] + ) was obtained.

[0181] [Step 2] Preparation of N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-(1H-pyrazol-1-yl)acrylamide 2-(1H-pyrazol-1-yl)acrylic acid (2.0 equivalents) prepared in Step 1 of Production Example 14 and propylphosphonic acid (5.0 equivalents) were dissolved in DMF (0.01 M), and then DIPEA (1.0 equivalents) and N 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equiv.) was added. The mixture was stirred at room temperature for 2 h. The reaction mixture was added to cold water and the resulting solid was filtered and then purified by preparative HPLC to give the desired compound as a yellow solid (yield: 4%, MS (ESI): m / z 564 [M+H] + ) was obtained.

[0182] [Table 14]

[0183] Preparation Example 15: Preparation of (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (Example 149) and (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (Example 150) [Reaction Scheme 17] [ka] [Step 1] Production of 5-fluoro-4-methyl-2-nitrophenol 3-Fluoro-4-methylphenol (1.0 equiv.) was dissolved in dichloromethane (0.4M), then 70% nitric acid (1.5 equiv.) was added at 0° C. and stirred at 0° C. for 30 min. After adding water to the reaction mixture, the organic material was extracted with dichloromethane, the remaining water in the combined organic layers was removed using Na2SO4, and the combined organic layers were concentrated. The reaction mixture was purified by MPLC (hexane:ethyl acetate) to give the desired compound as a yellow solid (yield: 63%).

[0184] [Step 2] 1-Fluoro-5-(methoxy-d 3 )-2-Methyl-4-nitrobenzene 5-Fluoro-4-methyl-2-nitrophenol (1.0 equiv.) prepared in step 1 was dissolved in DMF (0.5M), then iodomethane-d3 (3.0 equiv.) and K2CO3 (3.0 equiv.) were added to it, and the mixture was stirred at room temperature for 8 hours. Saturated aqueous NaHCO3 was added to the reaction mixture, and the organic material was extracted with ethyl acetate. The water remaining in the collected organic layer was then removed using Na2SO4, and the collected organic layer was concentrated. The reaction mixture was purified by MPLC (hexane:ethyl acetate) to give the desired compound as a yellow solid (yield: 80%).

[0185] [Step 3] 7-(5-(methoxy-d 3 Preparation of )-2-Methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 1-Fluoro-5-(methoxy-d3)-2-methyl-4-nitrobenzene (1.0 equivalent) prepared in step 2 was dissolved in DMSO (0.25M), then [1,2,4]triazolo[1,5-a]pyridin-7-ol (1.2 equivalent) and Cs2CO3 (2.4 equivalent) were added thereto, and the mixture was stirred at 80°C for 1 hour. Ice water was added to the reaction mixture to form a solid, and the resulting solid was filtered to obtain the desired compound as a brown solid. The resulting desired compound was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 304 [M+H] + ).

[0186] [Step 4] 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 )-5-Methylaniline 7-(5-(methoxy-d3)-2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine (1.0 eq.) prepared in step 3, ammonium chloride (0.45 eq.) and iron (4.5 eq.) were dissolved in ethanol-water solution (3:1), followed by stirring at 80° C. for 1 h. The mixture was filtered through a Celite filter and then concentrated to give the desired compound as a brown solid. The resulting desired compound was used in the next reaction without further purification (yield: 92%, MS (ESI): m / z 274 [M+H] + ).

[0187] [Step 5] N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of )-5-methylphenyl-7-methoxy-6-nitroquinazolin-4-amine 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylaniline (1.0 eq.) prepared in step 4 and 4-chloro-7-methoxy-6-nitroquinazoline (1.0 eq.) were dissolved in sec-BuOH (0.25 M), then 4M HCl (0.2 eq.) dissolved in 1,4-dioxane was added thereto, followed by stirring at 90° C. for 30 min. After adding methanol and ether to the reaction mixture, the desired compound was obtained after filtration as a yellow solid (yield: 65%, MS (ESI): m / z 477 [M+H] + ).

[0188] [Step 6]N 4 -(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of 5-methylphenyl-7-methoxyquinazoline-4,6-diamine N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)-7-methoxy-6-nitroquinazolin-4-amine (1.0 equiv.) prepared in step 5 and SnCl2.2H2O (6.0 equiv.) were dissolved in ethyl acetate (0.1 M) and the mixture was then stirred at 60° C. for 2 h. Aqueous ammonia was added to the reaction mixture, which was then concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid (yield: 64%, MS (ESI): m / z 447 [M+H] + ) was obtained.

[0189] [Step 7] Diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate 2-(diethoxyphosphoryl)-2-fluoroacetic acid (2.0 equiv.) and HATU (3.0 equiv.) were dissolved in DMF (0.5 M), followed by stirring at 50° C. for 30 min. 4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equiv.) and DIPEA (3.0 equiv.) were added to the mixture, followed by stirring at 50° C. for 1 h. Ice water was added to the reaction mixture to form a solid, which was then filtered to obtain the desired compound as a yellow solid (yield: 100%, MS (ESI): m / z 643 [M+H] + ) was obtained.

[0190] [Step 8] tert-Butyl (R,E / Z)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate Diethyl (2-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate (1.0 eq.) obtained in step 7 was dissolved in DMF (0.5M), and then tert-butyl (R)-2-formylpyrrolidine-1-carboxylate (1.5 eq.) and MgSO4 (1.5 eq.) were added thereto at 0°C, followed by stirring at room temperature for 1 hour. After adding water to the reaction mixture, the organic material was extracted with dichloromethane, and the water remaining in the collected organic layer was removed using Na2SO4, and the collected organic layer was concentrated. The desired compound obtained as a brown solid was used in the next reaction without further purification (yield: 100%, MS (ESI): m / z 688 [M+H] + ).

[0191] [Step 9] (R,E / Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide tert-Butyl (R,E / Z)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (1.0 eq.) obtained in step 8 was dissolved in dichloromethane (0.1 M), then TFA (20.0 eq.) was added thereto, the mixture was stirred at room temperature for 1 h, and then concentrated. The concentrated mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a brown liquid (yield: 100%, MS (ESI): m / z 588 [M+H] + ) was obtained.

[0192] [Step 10] (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 )-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide and (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d 3 Preparation of)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide (R,E / Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide (1.0 eq.) obtained in step 9 and 37% formaldehyde (5.0 eq.) were dissolved in DCE (0.2 M) and then stirred at room temperature for 1 h. Sodium triacetoxyborohydride (4.0 eq.) was added to the mixture, which was then stirred at 80° C. for 1 h. Saturated aqueous NaHCO3 and dichloromethane were added to the reaction mixture to extract the organic material, the remaining water was removed using MgSO4, and the organic layer was concentrated. The reaction mixture was purified using MPLC (dichloromethane:methanol) to give the desired compound as a yellow solid. ((R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide - yield: 11%, MS (ESI): m / z 602 [M+H] +, ((R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d3)-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide - yield: 4%, MS (ESI): m / z 602 [M+H] + ).

[0193] Preparation of the compounds of Examples 148, 151 and 152 The compounds of Examples 148, 151 and 152 of the present invention were prepared by a method similar to Preparation 15.

[0194] Chemical structures and names of the compounds of Examples 148 to 152 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 15 below.

[0195] [Table 15-1] [Table 15-2] (*: When "*" is to the right of the number in the last column, the number indicates the NMR purity.)

[0196] Preparation Example 16: Preparation of (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide (Example 155) and (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide (Example 157) [Reaction Scheme 18] [ka] (R,E / Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide (1.0 equivalent), prepared in a manner similar to Preparation 12, and K2CO3 (1.0 equivalent) were dissolved in ACN (0.13 M), and then iodomethane-d3 (1.0 equivalent) dissolved in ACN (0.5 M) was added thereto at 0° C., and the mixture was stirred at room temperature for 16 hours. The organic material was extracted by adding water and ethyl acetate to the reaction mixture, the remaining water was removed using MgSO4, and the organic layer was concentrated. The reaction mixture was purified using preparative HPLC to give the desired compound as a yellow solid. ((R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide - yield: 1%, MS (ESI): m / z 606 [M+H] + , (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d3)pyrrolidin-2-yl)acrylamide - yield: 1%, MS (ESI): m / z 606 [M+H] + ).

[0197] Preparation of the compounds of Examples 153, 154 and 156 The compounds of Examples 153, 154 and 156 of the present invention were prepared in a manner similar to Preparation 16.

[0198] Chemical structures and names of the compounds of Examples 153 to 157 1 The 1 H NMR, MS, yield, HPLC data and purity are summarized in Table 16 below.

[0199] [Table 16-1] [Table 16-2] (*: When "*" is to the right of the number in the last column, the number indicates the NMR purity.)

[0200] <Experimental Example> The example compounds prepared above were evaluated in the following experiments.

[0201] Experimental Example 1. Evaluation of HER2 enzyme inhibitory activity Biochemical kinase assays for HER2 were performed via Reaction Biology Corp. (San Diego, USA). Example compounds were diluted 3-fold from 10 μM to HER2 enzyme under ATP (10 μM) conditions, and IC values ​​were calculated at 10 doses. 50 The results are shown in Table 17 below. [Table 17] (A:IC 50 ≦50nM, B:50nM <IC 50 ≦100nM, C:100nM <IC 50 ≦500nM, D:500nM <IC 50 )

[0202] Experimental Example 2. Evaluation of BT-474 and N-87 cell proliferation inhibitory activity BT-474 cancer cells were cultured using RPMI-1640 medium containing 20% ​​FBS. BT-474 cancer cells were seeded at 5,000 cells / well in a white clear-bottom 96-well plate (Corning), and after 48 hours, BT-474 cancer cells were treated with the example compounds. The example compounds were diluted with dimethyl sulfoxide (3-fold dilution, total of 11 concentrations), and 1 μL of each was injected to give a final concentration of 0.2 nM to 10 μM. To measure viable cells, after treatment with the example compounds for the scheduled time (120 hours), the cells were placed at room temperature for 10 minutes using CellTiter-Glo cell viability reagent (Promega), and then the luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each test was repeated three times.

[0203] N-87 cancer cells were cultured using RPMI-1640 medium containing 10% FBS. N-87 cancer cells were seeded at 5,000 cells / well in a white clear-bottom 96-well plate (Corning), and 24 hours later, BT-474 cancer cells were treated with the example compounds. The example compounds were diluted with dimethyl sulfoxide (5-fold dilution, total of 11 concentrations), and 0.5 μL of each was injected to give a final concentration of 0.5 pM to 5 μM. To measure viable cells, after 72 hours of treatment with the example compounds, the cells were placed at room temperature for 10 minutes using CellTiter-Glo cell viability reagent (Promega), and then the luminescence intensity was measured using a reader (SynergyNeo, Biotek).

[0204] The resulting values ​​were calculated as the percentage of cell proliferation compared to the control group. Graphs were plotted and the GI 50 The values ​​were calculated using the GraphPad Prism version 8.0 program and the results are shown in Table 18 below. [Table 18] (A:GI 50 ≦50nM, B:50nM <GI 50 ≦100nM, C:100nM <GI 50 ≦500nM, D:500nM <GI50 )

[0205] Experimental Example 3. Evaluation of the inhibitory activity on the proliferation of transduced Ba / F3 cells The transduced Ba / F3 cells were cultured in 10% fetal bovine serum (FBS) medium (RPMI-1640) supplemented with 1 μg / mL puromycin (Invitrogen). 3,000 Ba / F3 HER2 WT cells were seeded in a white clear-bottom 96-well plate (Corning), and after 24 hours, the Ba / F3 HER2 WT cells were treated with the example compounds. 5,000 cells each of Ba / F3 HER2 L755S, Ba / F3 HER2 L755P, Ba / F3 HER2 T862A, and Ba / F3 HER2 L869R / T798I cells were added to a white clear-bottom 96-well plate (Corning), and after 24 hours, the cells were treated with the compounds. The example compounds were diluted with dimethyl sulfoxide (3-fold dilution, total of 11 concentrations), and 0.5 μL of each was injected to give a final concentration of 0.2 nM to 10 μM. For the measurement of viable cells, after 72 hours of treatment with example compounds, cells were incubated with CellTiter-Glo cell viability reagent (Promega) for 10 minutes at room temperature, and then luminescence intensity was measured using a reader (SynergyNeo, Biotek). Each experiment was repeated twice.

[0206] The resulting values ​​were calculated as the percentage of cell proliferation compared to the control group and expressed as the GI 50 The values ​​were calculated using software (GraphPad Prism version 8.0) and the results are shown in Table 19 below. [Table 19] (A:GI 50 ≦50nM, B:50nM <GI 50 ≦100nM, C:100nM <GI 50 ≦500nM, D:500 <GI 50 nM)

[0207] From the results of the Experimental Examples, it was confirmed that the Example compounds of the present invention exhibit high inhibitory activity against HER2 and inhibit the proliferation of HER2-activated cells.

[0208] Although the present invention has been described in detail with reference to preferred embodiments and experimental examples, it is understood that the scope of the present invention is not limited to the specific example compounds, but should be interpreted by the appended claims. Also, those skilled in the art will understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims

1. Formula (I): 【Chemistry 1】 [In the ceremony: Ring A is aromatic or non-aromatic C ６－１２ A carbocycle or a 5- to 12-membered heterocycle, where ring A is C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -CN, -NR Ａ１ R Ａ２ , -NO ２ , -OR Ａ３ , -C(=O)-NR Ａ１ R Ａ２ , -C(=O)-OR Ａ３ , -NH-C(=O)-(C １－６ alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C １－６ Alkyl, C １－６ Haloalkyl, C １－６ substituted with alkoxy or halo; R Ａ１ ~R Ａ３ are each independently H or C １－６ is alkyl; X １ is C １－６ Alkyl, deuterated C １－６ Alkyl, deuterated C １－６ Haloalkyl, C １－６ Haloalkyl, C ３－１２ cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C １－６ Alkyl or C １－６ substituted with haloalkyl; X ２ is H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -CN, -NR Ｂ１ R Ｂ２ , -NO ２ , -OR Ｂ３ or halo; R Ｂ１ ~R Ｂ３ are each independently H or C １－６ is alkyl; Y １ is CR １ or N; Y ２ is CR ２ , C(-L-Z) or N; Y ３ is CR ３ or N; R １ is H, C １－６ Alkyl, C １－６ alkylamino or -CN; R ２ is H, C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Alkylamino, C １－６ Haloalkyl, -CN, -NH ２ or halo; R ３ is H, halo, -OR ４ Or -NR ５ R ６ or R ３ combines with L to form a 5- to 6-membered heterocycle; R ４ is H, C １－６ Alkyl, -(CH ２ )n-O-(C １－６ Alkyl), C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -(CH ２ )n-(C ３－６ cycloalkyl), 3- to 6-membered heterocycloalkyl or -(CH ２ )n-(3- to 6-membered heterocycloalkyl), where cycloalkyl and heterocycloalkyl are C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -CN, -NR Ｃ１ R Ｃ２ , -NO ２ , -OR Ｃ３ with or without one or more substituents selected from the group consisting of: n is independently an integer from 1 to 4; R Ｃ１ ~R Ｃ３ are each independently H or C １－６ is alkyl; R ５ and R ６ are each independently H or C １－６ alkyl or R ５ and R ６ are joined together to form a 3- to 12-membered heterocycle, wherein the heterocycle is unsubstituted or １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -CN, -NR Ｄ１ R Ｄ２ , -NO ２ , -OR Ｄ３ , substituted with halo or 3-6 membered heterocycloalkyl; R Ｄ１ ~R Ｄ３ are each independently H or C １－６ is alkyl; L is -NH-, 【Chemistry 2】 or L is R ３ and combine with each other to form a 5- to 6-membered heterocycle, where ring B is a 3- to 8-membered heterocycle containing a N atom in the ring, and ring B is C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Alkylamino, C １－６ with or without one or more substituents selected from the group consisting of haloalkyl, -OH and halo; Z is 【Chemistry 3】 and Z １ is H, C １－６ Alkyl, C １－６ haloalkyl, -CN, halo, or 5-6 membered heteroaryl; Z ２ and Z ３ are each independently H, C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Alkylamino, C １－６ Haloalkyl, Halo, C ３－１２ Cycloalkyl, 3- to 12-membered heterocycloalkyl, -(CH ２ )m-(C １－６ alkylamino), -(CH ２ )m-(C ３－１２ Cycloalkyl), -(CH ２ )m-(3 to 12 membered heterocycloalkyl) or -(CH ２ )m-NH-(3- to 12-membered heterocycloalkyl), where -CH ２ -, cycloalkyl and heterocycloalkyl are C １－６ Alkyl, deuterated C １－６ Alkyl, deuterated C １－６ Haloalkyl, -OH, =O, -C(=O)-(C １－６ with or without one or more substituents selected from the group consisting of alkoxy and 3- to 6-membered heterocycloalkyl; m is independently an integer from 1 to 4; and The heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O. or a pharma- ceutically acceptable salt or stereoisomer thereof.

2. Ring A is aromatic C ６－１２ A carbocycle or an aromatic or non-aromatic 5- to 12-membered heterocycle, wherein ring A is C １－６ Alkyl, -NR Ａ１ R Ａ２ , -OR Ａ３ , -C(=O)-NR Ａ１ R Ａ２ , -C(=O)-OR Ａ３ , -NH-C(=O)-(C １－６ alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C １－６ Alkyl, C １－６ substituted with alkoxy or halo; R Ａ１ ~R Ａ３ are each independently H or C １－６ is alkyl; X １ C １－６ Alkyl, deuterated C １－６ Alkyl, C １－６ Haloalkyl, C ３－１２ cycloalkyl or 3- to 12-membered heterocycloalkyl, where cycloalkyl and heterocycloalkyl are unsubstituted or C １－６ Alkyl or C １－６ substituted with haloalkyl; X ２ H, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ Haloalkyl, -NR Ｂ１ R Ｂ２ or halo; R Ｂ１ and R Ｂ２ Each independently represents C １－６ is alkyl; and heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; 2. The compound of claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

3. Y １ is CR １ or N; Y ２ is CR ２ , C(-L-Z) or N; Y ３ is CR ３ or N; R １ is H or -CN; R ２ is H or halo; R ３ H, halo, -OR ４ Or -NR ５ R ６ or R ３ combines with L to form a 5- to 6-membered heterocycle; R ４ C １－６ Alkyl, -(CH ２ )n-O-(C １－６ Alkyl), C １－６ Haloalkyl, 3- to 6-membered heterocycloalkyl or -(CH ２ )n-(3- to 6-membered heterocycloalkyl), where cycloalkyl and heterocycloalkyl are C １－６ Alkyl, C １－６ Hydroxyalkyl, C １－６ Haloalkyl, -CN, -NR Ｃ１ R Ｃ２ , -NO ２ , -OR Ｃ３ with or without one or more substituents selected from the group consisting of: n is independently an integer from 1 to 4; R Ｃ１ ~R Ｃ３ are each independently H or C １－６ is alkyl; R ５ and R ６ are each independently H or C １－６ alkyl or R ５ and R ６ are joined together to form a 3-12 membered heterocycle, where the heterocycle is a 4-6 membered monocyclic ring or a 5-12 membered spirocycle, which heterocycle is unsubstituted or substituted with halo or a 3-6 membered heterocycloalkyl; and each heterocycle and heterocycloalkyl independently contains at least one heteroatom selected from the group consisting of N, S, and O; 2. The compound of claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

4. L is -NH-, 【Chemistry 4】 or L is R ３ and combine with each other to form a 5- to 6-membered heterocycle, where ring B is a 3- to 8-membered heterocycle containing a N atom in the ring, and ring B is C １－６ Alkyl, C １－６ with or without one or more substituents selected from the group consisting of haloalkyl and halo; Z 【Chemistry 5】 and Z １ is H, —CN, halo, or 5-6 membered heteroaryl; Z ２ and Z ３ are each independently H, C １－６ Alkyl, C １－６ Alkylamino, halo, C ３－１２ Cycloalkyl, 3- to 12-membered heterocycloalkyl, -(CH ２ )m-(C １－６ alkylamino), -(CH ２ )m-(C ３－１２ Cycloalkyl), -(CH ２ )m-(3 to 12 membered heterocycloalkyl) or -(CH ２ )m-NH-(3- to 12-membered heterocycloalkyl), where -CH ２ -, cycloalkyl and heterocycloalkyl are C １－６ Alkyl, deuterated C １－６ Alkyl, -OH, =O, -C(=O)-(C １－６ with or without one or more substituents selected from the group consisting of alkoxy and 3- to 6-membered heterocycloalkyl; m is independently an integer from 1 to 4 at each occurrence; and heterocycle, heteroaryl, and heterocycloalkyl each independently contain at least one heteroatom selected from the group consisting of N, S, and O; 2. The compound of claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

5. Ring A is 【Chemistry 6】 and A １ ~A ９ are each independently CH or N; B １ ~B ３ Each independently represents CH ２ , NH, O or S; Here, ring A is C １－６ Alkyl, -NR Ａ１ R Ａ２ , -OR Ａ３ , -C(=O)-NR Ａ１ R Ａ２ , -C(=O)-OR Ａ３ , -NH-C(=O)-(C １－６ alkyl), ═O, halo, and 5- to 6-membered heteroaryl, where heteroaryl is unsubstituted or C １－６ Alkyl, C １－６ substituted with alkoxy or halo; R Ａ１ ~R Ａ３ are each independently H or C １－６ is alkyl; and Heteroaryl contains at least one heteroatom selected from the group consisting of N, S and O; 2. The compound of claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

6. L is -NH-, 【Chemistry 7】 and wherein the N-containing heterocycle is C １－６ Alkyl, C １－６ with or without one or more substituents selected from the group consisting of haloalkyl and halo, L is R ３ to form a 5-6 membered heterocycle containing N; and N-containing heterocycles may or may not contain, in addition to N, at least one further heteroatom selected from S and O; 2. The compound of claim 1 or a pharma- ceutically acceptable salt or stereoisomer thereof.

7. 2. A compound according to claim 1, selected from the group consisting of: 1> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 2> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 3> 1-(4-((4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 4> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-((1-methylazetidin-3-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)piperidin-1-yl)prop-2-en-1-one; 5> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 6> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-3-fluoropiperidin-1-yl)prop-2-en-1-one; 7> 1-(4-((4-((4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 8> 1-(4-((4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 9> 1-(4-((4-((4-((1-(5-fluoro-6-methylpyridin-3-yl)-1H-pyrazol-3-yl)oxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 10> 1-(4-((7-methoxy-4-((2-methoxy-4-((1-(2-methoxypyrimidin-5-yl)-1H-pyrazol-3-yl)oxy)phenyl)amino)quinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 11> 1-(4-((4-((5-chloro-2-methoxy-4-(3-methoxyphenoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 12> 4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinoline-3-carbonitrile; 13> methyl 4-(4-((6-((1-acryloylpiperidin-4-yl)oxy)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)benzoate; 14> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-2-chloro-2-fluoroethan-1-one; 15> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one; 16> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-5-yl)oxy)-4,4-difluoropiperidin-1-yl)prop-2-en-1-one; 17> 1-(4-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrido[3,4-d]pyrimidin-6-yl)oxy)piperidin-1-yl)prop-2-en-1-one; 18> 1-(5-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-2-azabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one; 19> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 20> 1-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one; 21> 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7,8-dihydro-6H-[1,4]oxazino[3,2-g]quinazolin-6-yl)prop-2-en-1-one; 22> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)acrylamide; 23> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-morpholinoquinazolin-6-yl)acrylamide; 24> N-(4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)acrylamide; 25> (E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide; 26> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)but-2-enamide; 27> 1-(4-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)piperazin-1-yl)prop-2-en-1-one; 28> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)but-2-ynamide; 29> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 30> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 31> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(pyrrolidin-2-yl)acrylamide; 32> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 33> (R,E)-N-(4-((5-chloro-2-methoxy-4-(pyridin-2-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 34> (R,E)-N-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 35> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(2-methyl-2-azabicyclo[3.1.0]hexan-3-yl)acrylamide; 36> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpiperidin-2-yl)acrylamide; 37> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 38> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)amino)but-2-enamide; 39> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(5-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)but-2-enamide; 40> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)but-2-enamide; 41> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 42> (R,E)-N-(4-((5-chloro-4-(3-fluorophenoxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 43> (Z)—N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 44> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 45> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methyl-5-oxopyrrolidin-2-yl)acrylamide; 46> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 47> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 48> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 49> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 50> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 51> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 52> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-ethylpyrrolidin-2-yl)-2-fluoroacrylamide; 53> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 54> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-(trifluoromethyl)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 55> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 56> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 57> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 58> (R,Z)-N-(4-((5-chloro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 59> (R,E)-N-(4-((5-chloro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 60> (R,E)-2-fluoro-N-(4-((5-fluoro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 61> (R,Z)-2-fluoro-N-(4-((5-fluoro-2-methoxy-4-((1-methyl-1H-benzo[d]imidazol-5-yl)oxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 62> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinoxalin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 63> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinoxalin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 64> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(naphthalen-2-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 65> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(naphthalen-2-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 66> (R,E)-N-(4-((4-(benzo[d]oxazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 67> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((2-methylbenzo[d]oxazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 68> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((2-methylbenzo[d]oxazol-5-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 69> (E)-2-fluoro-N-(4-((4-((2-hydroxy-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 70> (Z)-2-fluoro-N-(4-((4-((2-hydroxy-2,3-dihydrobenzo[d]oxazol-5-yl)oxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 71> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 72> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 73> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 74> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-phenoxyphenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 75> (R,E)-2-fluoro-N-(4-((4-(imidazo[1,2-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 76> (R,Z)-2-fluoro-N-(4-((4-(imidazo[1,2-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 77> (R,E)-2-fluoro-N-(4-((4-(imidazo[1,2-c]pyrimidin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 78> (R,E)-N-(8-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 79> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 80> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(pyrazolo[1,5-a]pyrimidin-6-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 81> (R,E)-N-(4-((4-(benzo[d]thiazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 82> (R,Z)-N-(4-((4-(benzo[d]thiazol-6-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 83> (R,Z)-N-(4-((4-(benzo[d]thiazol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 84> (R,E)-N-(4-((4-(benzo[d]thiazol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 85> (R,E)-N-(4-((4-(benzo[d][1,3]dioxol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 86> (R,Z)-N-(4-((4-(benzo[d][1,3]dioxol-5-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 87> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinolin-7-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 88> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-(quinolin-7-yloxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 89> (R,E)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-indazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 90> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((1-methyl-1H-indazol-6-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 91> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 92> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 93> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 94> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 95> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 96> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 97> (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-2-fluoro-3-((R)-1-methylpyrrolidin-2-yl)acrylamide; 98> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 99> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 100> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 101> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 102> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-fluoroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 103> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-fluoroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 104> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-ethoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 105> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-(trifluoromethoxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 106> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-cyclopropoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 107> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-cyclopropoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 108> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-methyl-2-(oxetan-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 109> tert-butyl (R,E)-2-(3-((4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(oxetan-3-yloxy)phenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate; 110> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-((3R)-hexahydro-1H-pyrrolidin-3-yl)acrylamide; 111> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 112> (S,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 113> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4,4-difluoropiperidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 114> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(3,3-difluoroazetidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 115> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(4-morpholinopiperidin-1-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 116> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 117> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinazolin-6-yl)acrylamide; 118> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-(methylamino)quinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 119> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-6-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 120> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 121> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 122> (S,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 123> (R,E)-N-(4-((4-(4-(dimethylamino)phenoxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 124> methyl (R,E)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamido)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)benzoate; 125> (R,Z)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)-N,N-dimethylbenzamide; 126> (R,E)-4-(4-((6-(2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide)-7-methoxyquinazolin-4-yl)amino)-5-methoxy-2-methylphenoxy)-N,N-dimethylbenzamide; 127> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-(dimethylamino)-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 128> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 129> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-ethoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 130> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-morpholinoquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 131> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpiperidin-2-yl)acrylamide; 132> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 133> (R,Z)-N-(4-((4-(3-acetamidophenoxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 134> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 135> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidin-2-yl)acrylamide; 136> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-chloro-3-(1-methylpyrrolidin-2-yl)acrylamide; 137> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-cyclopropyl-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 138> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-cyclopropyl-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 139> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 140> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 141> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 142> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-5-chloroquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 143> (R,Z)-2-fluoro-N-(7-methoxy-4-((2-methoxy-5-methyl-4-((5-methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)oxy)phenyl)amino)quinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 144> (Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-cyano-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide; 145> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enamide; 146> (E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-4,4-dimethylpent-2-enamide; 147> N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-(1H-pyrazol-1-yl)acrylamide; 148> (R,E)-N-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d ３ )-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide; 149> (R,Z)-N-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d ３ )-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 150> (R,E)-N-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-(methoxy-d ３ )-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 151> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-(methoxy-d ３ )phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 152> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-(methoxy-d ３ )phenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidin-2-yl)acrylamide; 153> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-(methyl-d ３ )pyrrolidin-2-yl)acrylamide; 154> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-methoxy-5-methylphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d ３ )pyrrolidin-2-yl)acrylamide; 155> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d ３ )pyrrolidin-2-yl)acrylamide; 156> (R,Z)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-chloro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d ３ )pyrrolidin-2-yl)acrylamide; and 157> (R,E)-N-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-5-fluoro-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-(methyl-d ３ ) Pyrrolidin-2-yl) acrylamide.

8. A pharmaceutical composition for treating or preventing a human epidermal growth factor receptor 2 (HER2)-associated disease, comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt or stereoisomer thereof as an active ingredient.

9. The pharmaceutical composition of claim 8 , wherein the HER2-associated disease comprises cancer.

10. HER2-related diseases include pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal 9. The pharmaceutical composition of claim 8, wherein the cancer is selected from the group consisting of cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal region cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer.

11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt or stereoisomer thereof and a pharma- ceutically acceptable excipient.

12. Use of a compound of formula (I) as defined in any one of claims 1 to 7 or a pharma- ceutically acceptable salt or stereoisomer thereof for the treatment or prevention of a HER2-related disease.

13. Use of a compound of formula (I) as defined in any one of claims 1 to 7 or a pharma- ceutically acceptable salt or stereoisomer thereof for the manufacture of a medicament for the treatment or prevention of a HER2-related disease.

14. A method for treating or preventing a HER2-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined in any of claims 1 to 7 or a pharma- ceutically acceptable salt or stereoisomer thereof.

15. Pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, pulse Uveal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue tumor, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary 10. A method for treating or preventing at least one disease selected from the group consisting of cancer of unknown site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational choriocarcinoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, vestibular schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsillar cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal region cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer and thymic cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 7 or a pharmacologic acceptable salt or stereoisomer thereof.

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