Heteroaryl derivative compounds and their uses

Abstract

The present invention relates to a heteroaryl derivative compound and its use. The heteroaryl derivative of the present invention exhibits excellent inhibitory activity against HER2 and EGFR, and can therefore be usefully used as a therapeutic agent for the HER2 and / or EGFR-related diseases.

Description

[Technical Field]

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical applications. Specifically, the present invention relates to heteroaryl derivative compounds having HER2 and / or EGFR inhibitory activity. [Background technology]

[0002] Protein kinases act as molecular switches and are involved in signaling pathways, but they must smoothly regulate the conversion between the active and inactive states of target proteins within cells. If this conversion between active and inactive states is abnormally regulated, intracellular signaling becomes excessively activated or inactivated, inducing uncontrolled cell division and proliferation. In particular, abnormal activation due to mutations, amplification, and / or overexpression of protein kinase genes can cause the development and progression of various tumors and play a decisive role in the onset of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases.

[0003] In particular, HER2 (ErbB2) is a receptor tyrosine kinase of the ErbB family that forms homodimers or heterodimers with other EGFR receptors such as HER1 (EGFR, ErbB1), HER3 (ErbB3), or HER4 (ErbB4). It is activated by autophosphorylation at intracellular tyrosine residues and plays an important role in cell proliferation, differentiation, and survival in both normal and cancer cells (Di Fore PP, et al., Science. 1987; 237: 178-182). HER2 is known to be overexpressed in a variety of cancers, including breast cancer, gastric cancer, and ovarian cancer (Hardwick R, et al., Eur. J Surg Oncol. 1997 (23): 30-35; Korkaya H, et al., Oncogene. 2008; 27 (47): 6120-6130).

[0004] Furthermore, another ErbB family member, the epidermal growth factor receptor (EGFR), is abnormally activated in many epithelial cell tumors, including non-small cell lung cancer (NSCLC), breast cancer, glioma, head and neck squamous cell carcinoma, colorectal cancer, rectal adenocarcinoma, head and neck cancer, gastric cancer, and prostate cancer. It is known that activation of EGFR-tyrosine kinase leads to sustained cell proliferation, invasion into surrounding tissues, distant metastasis, and angiogenesis, thereby increasing cell survival.

[0005] Anticancer drugs that target HER2 and EGFR include apatinib (GILOTRIF) and trastuzumab (HERCEPTIN), but there are problems such as cancer recurrence after treatment and responses being observed only in a portion of the patient group. For example, in the case of trastuzumab, it has been reported that approximately 11.6% of HER2-overexpressing breast cancer patients who have received conventional anticancer treatment respond to trastuzumab, while the remaining approximately 88.4% of patients do not respond to trastuzumab or respond only weakly (Baselga et al., J. Clin. Oncol. 14:737-744 (1996)).

[0006] Thus, there is a growing unmet demand for novel compounds that can be usefully utilized in the treatment of HER2 and EGFR-related diseases by modulating HER2 and EGFR activity. [Overview of the project] [Problems that the invention aims to solve]

[0007] The object of the present invention is to provide a heteroaryl derivative with a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0009] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound. Specifically, a pharmaceutical composition for treating or preventing HER2 and / or EGFR-related diseases containing the heteroaryl derivative compound as an active ingredient, a use for treating or preventing HER2 and / or EGFR-related diseases using the compound, or a method for treating or preventing HER2 and / or EGFR-related diseases including the step of administering the compound.

Means for Solving the Problems

[0010] In order to achieve the above object, as a result of the research efforts of the present inventors, the present invention has been completed by confirming that a heteroaryl derivative compound represented by Chemical Formula 1 described below inhibits the growth of cells in which HER2 and / or EGFR is activated. <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1-6 The aminoalkyl, -(CH2)n-cycloalkyl, or -(CH2)n-heterocycloalkyl group {wherein one or more H atoms of the -(CH2)n-cycloalkyl or -(CH2)n-heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 They may be substituted with alkyl, -NO2, -OH, -halo, or heterocycloalkyl groups; n is 0, 1, 2, 3, or 4; R X3 and R X4 These are, independently, -H or -C 1-6 Alkyl, or R X3 and R X4 They are linked to each other, together with the N atom [ka] A ring is formed, and W1 and W2 are each independently CH2, NH, O, or S {where, [ka] One or more H atoms in the heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 They may be substituted with alkyl, -NO2, -OH, -halo, or heterocycloalkyl groups; a-d are, independently, 1, 2, or 3; R2 is -H, -C 1-6 Alkyl, -C 1-6 It is a haloalkyl, -CN, or -halo; L is -NH-, [ka] Here, ring B is a monocyclic or polycyclic ring containing an N atom, and one or more H atoms in ring B are -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 It may be substituted with alkyl, -NO2, -OH, =O, or -halo; R3 is -CZ 1 =CZ 2 Z 3, -C 1-6 Alkyl, -C 1-6 It is a haloalkyl or cycloalkyl; Z1 is -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 It is a haloalkyl, -CN, or -halo; Z2 and Z3 are independently -H and -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -halo, cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-cycloalkyl, or -C 1-6 It is an alkyl-heterocycloalkyl {wherein the cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-cycloalkyl, or -C 1-6One or more Hs of alkyl - heterocycloalkyl are -C 1-6 alkyl, -C 1-6 hydroxyalkyl, -C 1-6 aminoalkyl, -C 1-6 haloalkyl, -CN, -NH2, -NH - C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NO2, -OH, =O, or may be substituted with heterocycloalkyl}; [[ID=十六]]Y1 to Y3 are each independently N or CR[[ID=十七]] Y [[ID=十八]]and; [[ID=二十]]R[[ID=二十一]] Y [[ID=二十二]]is -H, -C[[ID=二十三]] 1-6 [[ID=二十四]]alkyl, -C[[ID=二十五]] 1-6 [[ID=二十六]]aminoalkyl, -C[[ID=二十七]] 1-6 [[ID=二十八]]hydroxyalkyl, -C[[ID=二十九]] 1-6 [[ID=三十]]haloalkyl, -CN, -NH2, -NH - C[[ID=三十一]] 1-6 [[ID=三十二]]alkyl, -N(C[[ID=三十三]] 1-6 [[ID=三十四]]alkyl)(C[[ID=三十五]] 1-6 [[ID=三十六]]alkyl), -NO2, -OH, or -halo;[[ID=三十七]] [[ID=三十八]]R4 is -C[[ID=三十九]] 1-6 [[ID=四十]]alkyl, -C[[ID=四十一]] 1-6 [[ID=四十二]]alkyl - O - C[[ID=四十三]] 1-6 [[ID=四十四]]alkyl, -C[[ID=四十五]] 1-6 [[ID=四十六]]haloalkyl, cycloalkyl, heterocycloalkyl, -C[[ID=四十七]] 1-6 [[ID=四十八]]alkyl - cycloalkyl, or -C[[ID=四十九]] 1-6 [[ID=五十]]alkyl - heterocycloalkyl {where one or more Hs of the cycloalkyl, heterocycloalkyl, -C[[ID=五十一]] 1-6 [[ID=五十二]]alkyl - cycloalkyl, or -C[[ID=五十三]] 1-6 [[ID=五十四]]alkyl - heterocycloalkyl may be substituted with -C[[ID=五十五]] 1-6 [[ID=五十六]]alkyl};[[ID=五十七]] [[ID=五十八]]Ring A is aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl {where one or more Hs of the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring are -C[[ID=五十九]] 1-6 [[ID=六十]]alkyl, -C[[ID=六十一]] 1-6 [[ID=六十二]]aminoalkyl, -C1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenil , -CN, -C(=O)-R A1 , -NO2, -NR A2 R A3 , -OR A4 , -S-C 1-6 alkyl, -halo, or heterocycloalkyl, and may be substituted [wherein one or more H of the heterocycloalkyl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, -halo, or heterocycloalkyl, and may be substituted], and the substituents of the aryl or heteroaryl ring may be linked to each other to form a 5- to 6-membered cycloalkyl or 5- to 6-membered heterocycloalkyl}; R A1 is -H, -C 1-6 alkyl, -NH2, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -NH-(CH2)m-aryl, -OH, or -O-C 1-6 alkyl {wherein one or more H of the -NH-(CH2)m-aryl ring is -C 1-6 alkyl, -C 1-6 haloalkyl, or -halo, and may be substituted}; m is 0, 1, 2, 3, or 4; R A2 and R A3 are each independently -H, -C 1-6 alkyl, -C(=O)-C 1-6 alkyl, -C(=O)-C 2-6 Alkenil , -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl {wherein one or more H of the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl ring is -C 1-6 alkyl, -C 1-6It may be substituted with haloalkyl, =O, -halo, or aryl; R A4 -H, -C 1-6 Alkyl, or -C 1-6 It is a haloalkyl group.

[0012] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: X is N or CR X1 and; R1 is -H, -OR X2 , or -NR X3 R X4 and; R X1 is -H or -CN; R X2 is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -C 1-6 Alkyl-O(C 1-6 Alkyl)-C 1-6 It is an aminoalkyl or -(CH2)n-heterocycloalkyl group, where one or more H atoms in the -(CH2)n-heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Alkyl-O(C 1-6} which may be substituted with alkyl or heterocycloalkyl groups; n is 0, 1, 2, 3, or 4; R X3 and R X4 These are, independently, -H or -C 1-6 Alkyl, or R X3 and R X4 They are linked to each other, together with the N atom [ka] A ring is formed, and W1 and W2 are each independently CH2, NH, or O {where, the above [ka] One or more hydrogen atoms in the ring may be substituted with a ¹-halo or a heterocycloalkyl group; a-d are each independently either 1 or 2; R2 is either -H or -HALO; L is -NH-, [ka] Here, ring B is a monocyclic or polycyclic ring containing an N atom, and one or more H atoms in ring B are -C 1-6 Alkyl, -C 1-6 It may be substituted with a haloalkyl, =O, or -halo; R3 is -CZ 1 =CZ 2 Z 3, -C 1-6 It is a haloalkyl or cycloalkyl; Z1 is -H, -C 1-6 It is aminoalkyl, -CN, or -halo; Z2 and Z3 are independently -H and -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -halo, -heterocycloalkyl, or -C 1-6 Alkyl-heterocycloalkyl {wherein -heterocycloalkyl, or -C} 1-6 One or more H atoms in an alkyl-heterocycloalkyl group are -C 1-6 It may be substituted with alkyl or heterocycloalkyl groups; Y1 to Y3 are each independently N or CR Y and; R Y -H, -C 1-6 Alkyl or -halo; R4 is -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 A haloalkyl, cycloalkyl, or heterocycloalkyl group {where one or more H in the cycloalkyl or heterocycloalkyl group is -C}. 1-6 It may be substituted with alkyl groups; Ring A is an aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl {wherein the aryl, heteroaryl 、 One or more H atoms in a heterocycloalkyl or heterocycloalkenyl ring are -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenil -CN, -C(=O)-R A1 -NO2, -NR A2 R A3 , -OR A4 -SC 1-6 It may be substituted with alkyl, -halo, or heterocycloalkyl [in this case, one or more H in the heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 The substituents of the aryl or heteroaryl ring may be substituted with haloalkyl, -halo, or heterocycloalkyl groups, and the substituents of the aryl or heteroaryl ring may be linked to each other to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group. R A1 These are -H, -NH-(CH2)m-aryl, -OH, or -OC 1-6 Alkyl {wherein one or more H atoms in the -NH-(CH2)m-aryl ring may be substituted with a -halo}; m is 0, 1, 2, 3, or 4; R A2 and R A3 These are -H and -C, respectively, independently. 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenil-C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl {wherein one or more H in the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl ring may be substituted with =O, -halo, or aryl}; R A4 -H, -C 1-6 Alkyl, or -C 1-6 It is a haloalkyl group.

[0013] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: X is N or CR X1 and; R1 is -H, -OR X2 , or -NR X3 R X4 and; R X1 is -H or -CN; R X2 is -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -C 1-6 Alkyl-O(C 1-6 Alkyl)-C 1-6 The aminoalkyl or -(CH2)n-heterocycloalkyl group {where the -(CH2)n-heterocycloalkyl ring has 4 to 6 members, and one or more H atoms in the -(CH2)n-heterocycloalkyl ring are -C 1-6 Alkyl, -C 1-6 Alkyl-O(C 1-6 (Alkyl) or may be substituted with a 4- to 6-membered heterocycloalkyl group; n is 0, 1, 2, or 3; R X3 and R X4 These are, independently, -H or -C 1-6 Alkyl, or R X3and R X4 They are linked to each other, together with the N atom [ka] The following is formed, where W1 and W2 are independently CH2 or O {where the above [ka] One or more hydrogen atoms in the ring may be substituted with a -halo or a 4- to 6-membered heterocycloalkyl group; a-d are each independently either 1 or 2; R2 is either -H or -halo.

[0014] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: L is -NH-, [ka] And {here, the above [ka] One or more H in the ring are -C 1-6 Alkyl, -C 1-6 It may be substituted with a haloalkyl, =O, or -halo; V1 and V2 are linked to each other, forming a double ring bridged by a single bond, a C1 alkyl, a C2 alkyl, or a C3 alkyl, or they are null; e~h are independently 1, 2, or 3.

[0015] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: R3 is -CZ 1 =CZ2 Z 3, -C 1-6 A haloalkyl or cycloalkyl group {where the cycloalkyl ring is monocyclic or polycyclic}; Z1 is -H, -C 1-6 It is aminoalkyl, -CN, or -halo; Z2 and Z3 are independently -H and -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Alkyl-O(C 1-6 Alkyl), -halo, heterocycloalkyl, or -C 1-6 The alkyl-heterocycloalkyl is {wherein the heterocycloalkyl or -C}. 1-6 The alkyl-heterocycloalkyl ring has 4 to 6 members, and the heterocycloalkyl or -C 1-6 One or more H atoms in an alkyl-heterocycloalkyl group are -C 1-6 It may be substituted with alkyl or 4-6 member heterocycloalkyl groups.

[0016] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: Y1 to Y3 are each independently N or CR Y and; R Y -H, -C 1-6 Alkyl or -halo; R4 is -C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 The elements are haloalkyl, 3-7 membered cycloalkyl, or 4-6 membered heterocycloalkyl {wherein one or more H of the 3-7 membered cycloalkyl or 4-6 membered heterocycloalkyl is -C 1-6 It may be substituted with alkyl.

[0017] According to a specific example of the present invention, the compound represented by chemical formula 1, its optical isomers, or pharmaceutically acceptable salts thereof may be within the following range: Ring A is phenyl, 5-10 member heteroaryl, 4-6 member heterocycloalkyl, or 4-6 member heterocycloalkenyl {wherein one or more H of the phenyl, 5-10 member heteroaryl, 4-6 member heterocycloalkyl, or 4-6 member heterocycloalkenyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 2-6 Alkenil -CN, -C(=O)-R A1 -NO2, -NR A2 R A3 , -OR A4 -SC 1-6 It may be substituted with alkyl, -halo, or 4-6 member heterocycloalkyl [in this case, one or more H of the 4-6 member heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 The substituents of the phenyl or 5-10 member heteroaryl ring may be substituted with haloalkyl, -halo, or heterocycloalkyl groups, and the substituents of the phenyl or 5-10 member heteroaryl ring may be linked to each other to form a 5-6 member cycloalkyl or 5-6 member heterocycloalkyl group; R A1 These are -H, -NH-(CH2)m-phenyl, -OH, or -OC 1-6 Alkyl {wherein one or more H atoms in the -NH-(CH2)m-phenyl ring may be substituted with -halo}; m is 0, 1, or 2; R A2 and R A3 These are -H and -C, respectively, independently. 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 2-6 Alkenil-C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-phenyl {wherein one or more H in the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-phenyl ring is -C 1-6 Alkyl, -C 1-6 It may be substituted with haloalkyl, =O, -halo, or phenyl; R A4 -H, -C 1-6 Alkyl, or -C 1-6 It is a haloalkyl group.

[0018] According to a specific example of the present invention, the compound represented by chemical formula 1 may be selected from the group consisting of the compounds listed in Table 1 below.

[0019] In the present invention, unless otherwise specified, "alkyl" may mean a linear or branched acyclic alkyl, a cyclic alkyl, or a saturated hydrocarbon formed by a combination thereof. For example, "C 1-6 "Alkyl" can mean an alkyl group containing 1 to 6 carbon atoms. Acyclic alkyls may include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, secondary (sec)-butyl, isobutyl, or tertiary (tert)-butyl. Cyclic alkyls may be used herein as a substitute for "cycloalkyl," and may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopeptyl, or cyclooctyl.

[0020] In the present invention, "alkoxy" refers to an alkyl ether group and can mean -(O-alkyl), where alkyl is as previously defined. For example, "C 1-6 "The alkoxy" is C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6Alkoxy can mean alkyl, and as an example, alkoxy can include, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0021] In the present invention, "halo" may be F, Cl, Br, or I.

[0022] In the present invention, "haloalkyl" can mean a linear or branched alkyl (hydrocarbon) having one or more carbon atoms substituted with a halo as defined herein. Examples of the haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl molecules independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0023] In the present invention, "hydroxyalkyl" can mean a linear or branched alkyl (hydrocarbon) having carbon atoms substituted with -hydroxy(-OH). Hydroxyalkyl Examples include, One or more -OH This includes, but is not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl independently substituted with these compounds.

[0024] In this specification, "aminoalkyl" may mean a linear or branched alkyl (hydrocarbon) having a carbon atom substituted with amino(NR'R''). Here, R' and R'' are, independently, hydrogen and C 1-6 The selected R' and R'' can be chosen from the group consisting of alkyl groups, and each of these selected R' and R'' may be independently substituted or unsubstituted.

[0025] In the present invention, "heterocycloalkyl" can mean a ring containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, and can be saturated or partially unsaturated. Here, if unsaturated, it can be called a heterocycloalkene. Unless otherwise specified, heterocycloalkyls can be monocyclic or multicyclic rings such as spiro, bridged, or fused rings. Also, "heterocycloalkyl of 3 to 12 atoms" can mean a heterocycloalkyl containing 3 to 12 ring-forming atoms, and as an example, heterocycloalkyls include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, and thi This could include, but is not limited to, omorfoline-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane.

[0026] In the present invention, "arene" can mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms in the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinquebenzene, sexibenzene, triphenylene, pyrene, benzofluorantene, and chrysene. In this specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl".

[0027] In the present invention, "heterearene" can be a ring containing one or more heteroatoms from O, N, P, Si, and S. The number of ring-forming carbon atoms in the heteroarene can be 2 to 30 or 2 to 20. The heteroarene can be a monocyclic heteroarene or a polycyclic heteroarene. A polycyclic heteroarene can have, for example, a bicyclic or tricyclic structure. Examples of heteroarenes include 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, imidazopyrazine Other examples include, but are not limited to, pyrazolopyridine, triazolopyridine, triazolopyrimidine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilol, and dibenzofuran. In one embodiment of the present invention, heteroarenes may also include bicyclic heterocycloarenes comprising an arene ring condensed to a heterocycloalkyl ring or a heteroarene condensed to a cycloalkyl ring. Hereinafter, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as a "heteroaryl".

[0028] In the present invention, the "ring" may be a single ring or a multiple ring, and the multiple ring may be in the form of a spiro ring, a bridged ring, or a fused ring.

[0029] In this invention, the term "optical isomer" means a compound or salt of the present invention having the same chemical or molecular formula but being sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of this invention. Unless otherwise specified, solid lines (-) representing bonds attached to a chiral carbon atom indicate a wedge-shaped bond, which represents the absolute configuration of the stereocenter. [ka] Or a dashed wedge-shaped connection [ka] It can include...

[0030] In this invention, the term "cis" refers to the case where the two substituents of a ring are bonded in the same direction, and the term "trans" refers to the case where the two substituents of a ring are bonded in different directions.

[0031] The compound of Chemical Formula 1 of the present invention can exist in the form of a "pharmaceutically acceptable salt." As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. In the present invention, the term "pharmaceutically acceptable salt" means any organic or inorganic acid addition salt of the compound at a concentration that has an effective effect that is relatively non-toxic and harmless to the patient, and in which the side effects caused by the salt do not reduce the effective efficacy of the compound represented by Chemical Formula 1.

[0032] Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of an excess amount of acid and precipitating the salt using a water-miscible organic solvent, such as methanol, ethanol, acetone, or acetonitrile. The same molar amount of the compound and the acid or alcohol in water are heated, and then the mixture is evaporated and dried, or the precipitated salt can be filtered by suction.

[0033] In this case, organic acids and inorganic acids can be used as free acids. As inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid can be used, and as organic acids, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid can be used. However, it is not limited to these.

[0034] Furthermore, pharmaceutically acceptable metal salts can be produced using bases. Alkali metal salts or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the insoluble compound salt, and then evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable as metal salts from a pharmaceutical perspective, but are not limited to these. Corresponding silver salts can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0035] Unless otherwise stated, the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of chemical formula 1. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of the hydroxyl group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts, which can be produced by salt production methods well known to those skilled in the art.

[0036] Applications of heteroaryl derivative compounds The present invention provides uses for compounds represented by the following chemical formula 1, their optical isomers, or pharmaceutically acceptable salts thereof.

[0037] [ka] Chemical formula 1 is defined as described above.

[0038] The compound represented by Chemical Formula 1 of the present invention, its optical isomers, or pharmaceutically acceptable salts thereof exhibit inhibitory activity against a variety of kinases.

[0039] According to one specific example of the present invention, the heteroaryl derivative represented by chemical formula 1 exhibits excellent inhibitory activity against HER2 and EGFR kinases, and can therefore be usefully used for the treatment or prevention of HER2 and / or EGFR-related diseases, particularly cancer. In particular, the heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against HER2 mutations (e.g., HER2 L869R, HER2 L755S, HER2 T798I, HER2 T862A, etc.) and EGFR mutations (e.g., EGFR G719A, EGFR L861Q, EGFR S768I, EGFR G719A / S768I, EGFR Del19 / T790M, etc.), and can therefore be usefully used for the treatment or prevention of cancers induced by HER2 and / or EGFR.

[0040] In the present invention, the cancers include all cancers for which therapeutic or prophylactic efficacy is achieved by inhibiting the activity of HER2 and / or EGFR kinase, and may be solid tumors or hematological cancers. For example, 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 carcinoma, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla carcinoma of Vater, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, The cancers may be one or more selected from the group consisting of malignant bone tumors, malignant lymphomas, malignant mesotheliomas, malignant melanomas, ocular cancers, vulvar cancers, ureteral cancers, urethral cancers, cancers of unknown primary origin, gastric lymphomas, gastric cancers, gastric carcinoid tumors, gastrointestinal stromal tumors, Wilms' tumors, breast cancers, sarcomas, penile cancers, pharyngeal cancers, gestational trophoblastic disease, cervical cancers, endometrial cancers, uterine sarcomas, prostate cancers, metastatic bone tumors, metastatic brain cancers, mediastinal cancers, rectal cancers, rectal carcinoid tumors, vaginal cancers, spinal cord cancers, acoustic neuromas, pancreatic cancers, salivary gland cancers, Kaposi's sarcoma, Paget's disease, tonsil cancers, squamous cell carcinomas, lung adenocarcinomas, lung cancers, lung squamous cell carcinomas, skin cancers, anal cancers, rhabdomyosarcomas, laryngeal cancers, pleural cancers, hematological cancers, and thymic cancers, but are not limited to these. Furthermore, the cancers include not only primary cancers but also metastatic cancers.

[0041] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for the treatment or prevention of HER2 and / or EGFR-related diseases, comprising as an active ingredient a compound represented by the chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Specifically, the HER2 and / or EGFR-related disease may be cancer. The types of cancer are as described above.

[0042] The pharmaceutical composition of the present invention may further contain, in addition to the compound represented by chemical formula 1, its optical isomer, or pharmaceutically acceptable salts thereof, one or more active ingredients exhibiting the same or similar pharmacological effects.

[0043] Furthermore, according to one specific example of the present invention, a method for treating or preventing HER2 and / or EGFR-related diseases is provided, comprising the step of administering a therapeutically effective amount of the compound represented by chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof to a subject in need. The subject may be a mammal, including a human.

[0044] The term "therapeutably effective amount" as used in this invention refers to the amount of the compound represented by chemical formula 1 that is effective in treating or preventing HER2 and / or EGFR-related diseases. Specifically, "therapeutably effective amount" means an amount sufficient to treat the disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined by factors including the individual's species and severity, age, sex, type of disease, drug activity, sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the pharmaceutical field. The pharmaceutical compositions of this invention can be administered as individual therapeutic agents or in combination with other therapeutic agents, and can be administered sequentially or concurrently with commercially available therapeutic agents. They can also be administered as a single dose or multiple doses. It is important to administer the amount that provides the greatest effect with the minimum amount without side effects, taking all of the above factors into consideration, and this can be easily determined by those skilled in the art. The dosage of the pharmaceutical compositions of this invention may be determined by a professional depending on various factors such as the patient's condition, age, sex, and comorbidities. The active ingredients of the pharmaceutical compositions of this invention are highly safe and can be used at doses higher than the specified dosage.

[0045] Furthermore, according to one specific example of the present invention, the present invention provides a use for the compound represented by chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicine for use in the treatment or prevention of HER2 and / or EGFR-related diseases. The compound represented by chemical formula 1 for manufacture of the medicine can be mixed with acceptable auxiliaries, diluents, carriers, etc., and manufactured as a compound formulation with other active ingredients, which can have a synergistic effect of the active ingredients.

[0046] The matters described in the uses, compositions, and therapeutic methods of the present invention shall apply equally, insofar as they do not contradict each other. [Effects of the Invention]

[0047] The heteroaryl derivative compounds of the present invention exhibit excellent inhibitory activity against HER2 and / or EGFR, and can therefore be usefully used for the treatment or prevention of HER2 and / or EGFR-related diseases. [Modes for carrying out the invention]

[0048] The present invention will be described in detail below with reference to examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and do not limit the scope of the present invention.

[0049] <Conditions for analysis and purification> 1. Conditions for HPLC analysis (a) Equipment name: Waters e2695 Column: Xbridge C18, 4.6 × 150 mm, 5 μm, 40°C Mobile phase: 20%->95% acetonitrile / H2O + 0.1% TFA Analysis time: 10 minutes, flow rate: 1mL / min UV detector: 254nm (b) Equipment name: Waters e2695 Column: YMC-Pack ODS-AM, 150 × 4.6 mm, 3 μm, 12 nm, 40°C Mobile phase: 10%->90% アセトニトリル / H2O+0.1%TFA Analysis time: 20 minutes, flow rate: 1 mL / min UV detector: 254nm

[0050] 2. Conditions for LC-MS analysis Machine Name: Waters ACQUITY UPLC Color: ACQUITY UPLC (Registered Trademark) BEH C18, 50×2.1mm, 5μm, 40℃ Mobile phase: アセトニトリル / H2O+0.1%TFA Flow rate: 0.6 mL / min UV detector: 254nm

[0051] 3. Conditions for MPLC purification Machine Name: CombiFlash (Registered Trademark) Rf+ UV detector: 254nm

[0052] 4. Conditions for Prep-HPLC purification (A) Machine Name: ACCQPrep HP125 Karam:XBridge (registered trademark) Prep Shield RP18, 250×19mm, 10μm Mobile phase: アセトニトリル / 0.1%TFA H2O Flow rate: 25 mL / min UV detector: 254nm

[0053] 5. Conditions for Prep-HPLC purification (B) Machine Name: ACCQPrep HP125 Karam:XBridge (registered trademark) Prep Shield RP18, 250×19mm, 10μm Mobile phase: アセトニトリル / 0.1%FA H2O Flow rate: 25 mL / min UV detector: 254nm

[0054] 6. 1 1H NMR Equipment name:Bruker Ascend TM 400 (400 MHz) The commercially available reagents used were used without further purification. In this invention, room temperature refers to a temperature of 15 to 25°C. Concentration or solvent removal under reduced pressure was performed using a rotary evaporator.

[0055] Manufacturing Example 1. Preparation of N-(2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide [ka] 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equivalent) and anhydride acetic acid (2.81 equivalents) were dissolved in acetic acid (15.4 equivalents), DMAP (0.02 equivalents) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the ivory-colored solid obtained was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 298[M+1]). + ).

[0056] Example 1. Preparation of N-(3'-((6-((1-acryloylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-2,4-difluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)acetamide [ka]

[0057] [Step 1] Preparation of tert-butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate 4-Chloro-7-methoxyquinazolin-6-ol (1.0 equivalent), tert-butyl 4-hydroxypiperidine-1-carboxylate (2.0 equivalents), and triphenylphosphine (1.5 equivalents) were dissolved in DCM. DTBAD (1.5 equivalents) was then slowly added at 5°C, and the mixture was stirred at room temperature for 16 hours. After concentrating the reaction mixture, it was purified using MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 52%, MS(ESI): m / z 394[M+1]). + ).

[0058] [Step 2] Preparation of tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate The tert-butyl 4-((4-chloro-7-methoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.2 equivalents) obtained in step 1 were dissolved in sec-BuOH. 4.0 M HCl dissolved in dioxane was added to the reaction mixture, and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, ethyl ether was added to produce a solid. The target compound was then obtained as an ivory-colored solid through filtration (yield: 96%, MS(ESI): m / z 559[M+1]). + ).

[0059] [Step 3] Preparation of N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-(piperidine-4-yloxy)quinazoline-4-amine The tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) obtained in step 2 was dissolved in DCM, and trifluoroacetic acid (50 equivalents) was added. The mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, it was purified by MPLC (DCM:MeOH) to obtain the target compound as a pale yellow solid (yield: 97%, MS(ESI): m / z 459[M+1]). + ).

[0060] [Step-4] Manufacturing of 1-(4-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-yl)propa-2en-1one In step 3, N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-(piperidine-4-yloxy)quinazoline-4-amine (1.0 equivalent) and saturated NaHCO3 aqueous solution (5.0 equivalents) were dissolved in THF. Acryloyl chloride (1.0 equivalent) was then added at 0°C and the mixture was stirred for 1 hour. After concentrating the reaction mixture, water was added, and organic matter was extracted by DCM. The collected organic layer was concentrated after removing the remaining water using MgSO4. The reaction mixture was purified by MPLC (DCM: MeOH) to obtain the target compound as a white solid (yield: 60%, MS(ESI): m / z 513[M+1]). + ).

[0061] [Step 5] Preparation of N-(3'-((6-((1-acryloylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-2,4-difluoro-4'-methoxy-[1,1'-biphenyl]-3-yl)acetamide 1-(4-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-yl)propa-2-en-1-one (1.0 equivalent) obtained in step 4, and N-(2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (2.3 equivalents) and K3PO4 (3.5 equivalents) obtained in Preparation Example 1 were dissolved in dioxane:water (5:1). After degassing with nitro gas, Xphos Pd G2 (0.1 equivalent) was added at 80°C, and then the mixture was stirred at 100°C for 30 minutes. After filtration through a Celite filter, the mixture was concentrated. The reaction mixture was purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 96%, MS(ESI): m / z 604[M+1]). + ).

[0062] Examples 2-231: Preparation of Compounds Compounds of Examples 2 to 231 according to the present invention were prepared by the same method as in Example 1. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 1.

[0063] [Table 1] TIFF0007893421000018.tif216161 TIFF0007893421000019.tif236161 TIFF0007893421000020.tif229161 TIFF0007893421000021.tif237161 TIFF0007893421000022.tif236161 TIFF0007893421000023.tif204161 TIFF0007893421000024.tif202161 TIFF0007893421000025.tif221161 TIFF0007893421000026.tif217161 TIFF0007893421000027.tif223161 TIFF0007893421000028.tif212161 TIFF0007893421000029.tif230161 TIFF0007893421000030.tif235161 TIFF0007893421000031.tif235161 TIFF0007893421000032.tif236161 TIFF0007893421000033.tif235161 TIFF0007893421000034.tif235161 TIFF0007893421000035.tif237161 TIFF0007893421000036.tif236161 TIFF0007893421000037.tif205161 TIFF0007893421000038.tif236161 TIFF0007893421000039.tif234161 TIFF0007893421000040.tif223161 TIFF0007893421000041.tif203161 TIFF0007893421000042.tif229161 TIFF0007893421000043.tif211161 TIFF0007893421000044.tif217161 TIFF0007893421000045.tif234161 TIFF0007893421000046.tif235161 TIFF0007893421000047.tif237161 TIFF0007893421000048.tif225161 TIFF0007893421000049.tif238161 TIFF0007893421000050.tif204161 TIFF0007893421000051.tif209161 TIFF0007893421000052.tif234161 TIFF0007893421000053.tif229161 TIFF0007893421000054.tif235161 TIFF0007893421000055.tif236161 TIFF0007893421000056.tif235161 TIFF0007893421000057.tif235161 TIFF0007893421000058.tif217161 TIFF0007893421000059.tif212161 TIFF0007893421000060.tif224161 TIFF0007893421000061.tif237161 TIFF0007893421000062.tif230161 TIFF0007893421000063.tif222161 TIFF0007893421000064.tif216161 TIFF0007893421000065.tif204161 TIFF0007893421000066.tif221161 TIFF0007893421000067.tif234161 TIFF0007893421000068.tif235161 TIFF0007893421000069.tif229161 TIFF0007893421000070.tif237161 TIFF0007893421000071.tif236161 TIFF0007893421000072.tif235161 TIFF0007893421000073.tif234161 TIFF0007893421000074.tif222161 TIFF0007893421000075.tif234161 TIFF0007893421000076.tif236161 TIFF0007893421000077.tif228161 TIFF0007893421000078.tif236161 TIFF0007893421000079.tif234161 TIFF0007893421000080.tif224161 TIFF0007893421000081.tif236161 TIFF0007893421000082.tif216161 TIFF0007893421000083.tif217161 TIFF0007893421000084.tif217161 TIFF0007893421000085.tif236161 TIFF0007893421000086.tif216161 TIFF0007893421000087.tif217161 TIFF0007893421000088.tif236161 TIFF0007893421000089.tif237161 TIFF0007893421000090.tif205161 TIFF0007893421000091.tif229161 TIFF0007893421000092.tif217161 TIFF0007893421000093.tif234161 TIFF0007893421000094.tif224161 TIFF0007893421000095.tif237161 TIFF0007893421000096.tif237161 TIFF0007893421000097.tif234161 TIFF0007893421000098.tif235161 TIFF0007893421000099.tif222161 TIFF0007893421000100.tif237161 TIFF0007893421000101.tif229161 TIFF0007893421000102.tif229161 TIFF0007893421000103.tif237161 TIFF0007893421000104.tif236161 TIFF0007893421000105.tif237161 TIFF0007893421000106.tif224161 TIFF0007893421000107.tif237161 TIFF0007893421000108.tif237161 TIFF0007893421000109.tif236161 TIFF0007893421000110.tif236161 TIFF0007893421000111.tif223161 TIFF0007893421000112.tif237161 TIFF0007893421000113.tif212161 TIFF0007893421000114.tif236161 TIFF0007893421000115.tif237161 TIFF0007893421000116.tif211161 TIFF0007893421000117.tif237161 TIFF0007893421000118.tif237161 TIFF0007893421000119.tif237161 TIFF0007893421000120.tif223161 TIFF0007893421000121.tif236161 TIFF0007893421000122.tif235161 TIFF0007893421000123.tif236161 TIFF0007893421000124.tif204161 TIFF0007893421000125.tif62161

[0064] Example 231. Preparation of 4-(3-((6-((1-acryloylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4-methoxyphenyl)-N-(3-fluorophenethyl)thiophene-2-carboxamide [ka]

[0065] [Step 1] Production of methyl 4-(4-methoxy-3-nitrophenyl)thiophene-2-carboxylate 4-Bromo-1-methoxy-2-nitrobenzene (1.0 equivalent), (5-(methoxycarbonyl)thiophen-3-yl)boronic acid (2.0 equivalents), and K3PO4 (2.2 equivalents) were dissolved in 1,4-dioxane (0.1 M) and water (0.5 M). After degassing with nitro gas, Xphos Pd G2 (0.13 equivalents) was added at 80°C, and the mixture was stirred at 100°C for 1 hour. After filtration through a Celite filter, the mixture was concentrated. The reaction mixture was purified by MPLC (DCM / MeOH) to obtain the target compound as a yellow solid (yield: 100%, MS(ESI): m / z 294[M+1]). + ).

[0066] [Step 2] Production of 4-(4-methoxy-3-nitrophenyl)thiophene-2-carboxylic acid The methyl 4-(4-methoxy-3-nitrophenyl)thiophene-2-carboxylate (1.0 equivalent) obtained in step 1 was dissolved in THF (0.05 M) and MeOH (0.05 M), and then 5 M KOH (1.2 equivalents) dissolved in distilled water was added, and the mixture was stirred at 60°C for 2 hours. The mixture was vacuum-dried at 50°C to obtain the target compound as a white solid (yield: 100%, MS(ESI): m / z 280[M+1]). + ).

[0067] [Step 3] Production of 4-(3-amino-4-methoxyphenyl)thiophene-2-carboxylic acid The 4-(4-methoxy-3-nitrophenyl)thiophene-2-carboxylic acid (1.0 equivalent) obtained in step 2 was dissolved in THF (0.3 M) at 0°C, and then acetic acid (20 equivalents) and zinc (10 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through a Celite filter and concentrated. After neutralization with saturated NaHCO3 aqueous solution at 0°C, organic matter was extracted by DCM, and the collected organic layer was concentrated after removing the remaining water with Na2SO4. The mixture was purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 84%, MS(ESI): m / z 250[M+1]). + ).

[0068] [Step-4] Production of 4-(3-((6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4-methoxyphenyl)thiophene-2-carboxylic acid The 4-(3-amino-4-methoxyphenyl)thiophene-2-carboxylic acid (1.2 equivalents) and tert-butyl 4-((4-chloro-7-methoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) obtained in step 3 were dissolved in sec-BuOH (0.1 M). Then, 4 M HCl (0.2 equivalents) dissolved in 1,4-dioxane was added, and the mixture was stirred at 80°C for 2 hours before being concentrated. The reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 100%, MS(ESI): m / z 607[M+1]). + ).

[0069] [Step 5] Preparation of tert-butyl 4-((4-((5-(5-((3-fluorophenethyl)carbamoyl)thiophen-3-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate In step 4, 4-(3-((6-((1-(tert-butoxycarbonyl)piperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4-methoxyphenyl)thiophene-2-carboxylic acid (1.0 equivalent) and 2-(3-fluorophenyl)ethane-1-amine (1.0 equivalent) obtained were dissolved in acetonitrile (0.1 M), then HATU (2.0 equivalents) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at room temperature for 5 hours before being concentrated. The reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 100%, MS(ESI): m / z 728[M+1]). + ).

[0070] [Step 6] Preparation of N-(3-fluorophenethyl)-4-(4-methoxy-3-((7-methoxy-6-(piperidine-4-yloxy)quinazoline-4-yl)amino)phenyl)thiophen-2-carboxamide The tert-butyl 4-((4-((5-(5-((3-fluorophenethyl)carbamoyl)thiophen-3-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) obtained in step 5 was dissolved in DCM (0.1 M), then TFA (10 equivalents) was added, and the mixture was stirred at room temperature for 1 hour before being concentrated. The reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 95%, MS (ESI): m / z 628 [M+1]). + ).

[0071] [Step 7] Preparation of 4-(3-((6-((1-acryloylpiperidine-4-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4-methoxyphenyl)-N-(3-fluorophenethyl)thiophene-2-carboxamide In step 6, 1.0 equivalent of N-(3-fluorophenethyl)-4-(4-methoxy-3-((7-methoxy-6-(piperidine-4-yloxy)quinazolin-4-yl)amino)phenyl)thiophene-2-carboxamide was dissolved in 5.0 equivalents of saturated NaHCO3 aqueous solution in 0.1 M THF. Acryloyl chloride (1.0 equivalent) was then added at 0°C, and the mixture was stirred for 10 minutes before being concentrated. The reaction mixture was purified using prep-HPLC to obtain the target compound as a pale yellow solid (yield: 13%, MS(ESI): m / z 682[M+1]). + ).

[0072] Examples 232-235: Preparation of Compounds The compounds of Examples 232 to 235 according to the present invention were produced in the same manner as in Example 231. The chemical structural formula, compound name, 1 1H NMR, MS, HPLC data and yield are summarized in Table 2 below.

[0073]

Table 2

[0074] Example 236. (R)-N-(3'-((6-((1-acryloylazetidine-3-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-4-phenyloxazolidine-3-carboxamide

Chemical formula

[0075] [Step 1] Preparation of tert-butyl 3-((4-((3'-amino-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)oxy)azetidine-1-carboxylate tert-Butyl 3-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)azetidine-1-carboxylate (1.0 equivalent), (3-aminophenyl)boronic acid (3.0 equivalents), and K3PO4 (2.0 equivalents) were dissolved in 1,4-dioxane:distilled water = 5:1 (v / v) (0.1 M), degassed with nitrogen, and then stirred at 100 °C for 3 minutes under nitrogen. Then, Xphos Pd G2 (0.13 equivalent) was added at 100 °C, stirred for 1 hour, and then concentrated. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a pale yellow solid (yield: 63%, MS (ESI): m / z 544 [M+1] + ).

[0076] [Step 2] Preparation of tert-butyl 3-((7-methoxy-4-((4-methoxy-3'-(((4-nitrophenoxy)carbonyl)amino)-[1,1'-biphenyl]-3-yl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate The tert-butyl 3-((4-((3'-amino-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)oxy)azetidine-1-carboxylate (1.0 equivalent) obtained in step 1 was dissolved in DCM (0.1 M), and then pyridine (3.0 equivalents) was added. After cooling to 0°C, 4-nitrophenyl chloroformate (1.5 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. The resulting brown solid of the target compound was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 709[M+1]). + ).

[0077] [Step 3] Preparation of tert-butyl(R)-3-((7-methoxy-4-((4-methoxy-3'-(2-oxo-4-phenyloxazolidine-3-carboxamide)-[1,1'-biphenyl]-3-yl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate (R)-4-phenyloxazolidine-2-one (2.2 equivalents) was dissolved in DMF (0.1M), then NaH (2.2 equivalents) was added and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was added to the tert-butyl 3-((7-methoxy-4-((4-methoxy-3'-(((4-nitrophenoxy)carbonyl)amino)-[1,1'-biphenyl]-3-yl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate obtained in step 2, and the mixture was stirred at room temperature for 15 minutes. Organic matter was extracted from the reaction mixture with saturated NaHCO3 and EA, and the collected organic layer was concentrated by removing the remaining water with MgSO4. The target compound obtained as a brown solid was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 733[M+1]). + ).

[0078] [Step-4](R)-N-(3'-((6-(azetidine-3-yloxy)-7-methoxyquinazoline-4-yl)amino)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-4-phenyloxazolidine-3-carboxamide The tert-butyl(R)-3-((7-methoxy-4-((4-methoxy-3'-(2-oxo-4-phenyloxazolidine-3-carboxamide)-[1,1'-biphenyl]-3-yl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate (1.0 equivalent) obtained in step 3 was dissolved in DCM:TFA (10:1 v / v) solution (0.1M) and stirred at room temperature for 2 hours. After concentrating the reaction mixture, it was purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 38%, MS(ESI): m / z 633[M+1]). + ).

[0079] [Step 5] Preparation of (R)-N-(3'-((6-((1-acryloylazetidine-3-yl)oxy)-7-methoxyquinazoline-4-yl)amino)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-4-phenyloxazolidine-3-carboxamide (R)-N-(3'-((6-(azetidine-3-yloxy)-7-methoxyquinazoline-4-yl)amino)-4'-methoxy-[1,1'-biphenyl]-3-yl)-2-oxo-4-phenyloxazolidine-3-carboxamide (1.0 equivalent) obtained in step 4 was dissolved in THF (0.1 M) and cooled to 0°C. After adding 1 M NaHCO3 solution (2.0 equivalents), acryloyl chloride (1.2 equivalents) was added and the mixture was stirred at 0°C for 30 minutes. After adding saturated NaHCO3 aqueous solution to the reaction mixture, organic matter was extracted with EA, and the collected organic layer was concentrated by removing the remaining water with MgSO4. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 49%, MS(ESI): m / z 687[M+1]). + ).

[0080] Example 237: Preparation of the compound The compound of Example 237 according to the present invention was prepared by the same method as in Example 236. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 3.

[0081] [Table 3]

[0082] Example 238. Preparation of 1-(4-((7-ethoxy-4-((5-(furan-2-yl)-2-methoxyphenyl)amino)quinazoline-6-yl)oxy)piperidine-1-yl)propa-2-en-1-one [ka]

[0083] [Step 1] Preparation of methyl 3,4-dihydroxybenzoate 3,4-Dihydroxybenzoic acid (1.0 equivalent) and thionyl chloride (1.0 equivalent) were added to methanol (0.5 M). The mixture was heated at 70°C for 2 hours and then concentrated. The residue was diluted with ethyl acetate and washed with sat.NaHCO3 solution and brine. The collected organic layer was concentrated after removing the remaining water with MgSO4. The resulting white solid of the target compound was used in the next reaction without further purification (yield: 98%).

[0084] [Step 2] Preparation of methyl 4-ethoxy-3-hydroxybenzoate The methyl 3,4-dihydroxybenzoate (1.0 equivalent) and K2CO3 (1.0 equivalent) obtained in step 1 were added to DMF (0.2 M). The mixture was stirred at 0°C for 20 minutes, and iodoethane (4.0 equivalents) was added dropwise. After the addition was complete, the mixture was stirred at 0°C for a further 12 hours. The desired product was confirmed by LC-MS. The mixture was passed through a Celite filter, and the DMF was removed under reduced pressure. The residue was redissolved in ethyl acetate and washed with 1 M HCl. The collected organic layer was concentrated after removing the remaining water with MgSO4. The resulting white solid of the target compound was used in the next reaction without further purification (yield: 37%, MS(ESI): m / z 197[M+1]). + ).

[0085] [Step 3] Preparation of methyl 3-(benzyloxy)-4-ethoxybenzoate Methyl 4-ethoxy-3-hydroxybenzoate, K2CO3 (1.5 equivalents), and benzyl bromide (1.1 equivalents) obtained in step 2 were added to DMF (0.2 M). The mixture was heated at 100°C for 12 hours. After cooling to room temperature, water was added, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated by removing the remaining water with MgSO4. The resulting white solid target compound was used in the next reaction without further purification (yield: 91%, MS(ESI): m / z 287[M+1]). + ).

[0086] [Step 4] Preparation of methyl 5-(benzyloxy)-4-ethoxy-2-nitrobenzoate The methyl 3-(benzyloxy)-4-ethoxybenzoate (1.0 equivalent) obtained in step 3 was dissolved in the minimum amount of acetic acid. Concentrated nitric acid (2.9 equivalents, 70%) was added to this solution. The mixture was stirred at 50°C for 1 hour, then ice water was poured over it to wash the resulting solid with water, and it was vacuum-dried to obtain the target compound as a yellow solid (yield: 92%).

[0087] [Step 5] Preparation of methyl 2-amino-4-ethoxy-5-hydroxybenzoate The methyl 5-(benzyloxy)-4-ethoxy-2-nitrobenzoate (1.0 equivalent) obtained in step 4 was dissolved in methanol (0.1 M), and then Pd / C (10% purity, 0.05 equivalents) was added. The mixture was stirred at room temperature for 1 hour under hydrogen. After filtration through a Celite filter and washing with metalol, the filtrate was concentrated. The resulting white solid of the target compound was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 212[M+1]). + ).

[0088] [Step 6] Production of 7-ethoxyquinazoline-4,6-diol The methyl 2-amino-4-ethoxy-5-hydroxybenzoate (1.0 equivalent) and formamidine acetate (2.0 equivalents) obtained in step 5 were dissolved in 2-methoxyethanol (0.1 M), and the mixture was stirred at 120°C for 1 hour. The solvent was concentrated, washed with water, and dried. The resulting light brown solid of the target compound was used in the next reaction without further purification (yield: 77%, MS(ESI): m / z 207[M+1]). + ).

[0089] [Step 7] Preparation of 7-ethoxy-4-hydroxyquinazoline-6-ylacetate After adding pyridine (2.5 equivalents) to the 7-ethoxyquinazoline-4,6-diol (1.0 equivalent) and anhydride acetate (1.1 equivalents) obtained in step 6, the mixture was heated at 120°C for 4 hours. After adding ice water to the reaction mixture, the mixture was filtered, and the resulting solid was vacuum-dried. The target compound, obtained as a light brown solid, was used in the next reaction without further purification (yield: 91%, MS(ESI): m / z 249[M+1]). + ).

[0090] [Step 8] Preparation of 4-chloro-7-ethoxyquinazoline-6-ylacetate The 7-ethoxy-4-hydroxyquinazoline-6-yl acetate (1.0 equivalent) and thionyl chloride (20.0 equivalents) obtained in step 7 were dissolved in DMF (0.3 M) and heated at 120°C for 2 hours. The excess thionyl chloride was removed under reduced pressure, and the reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 47%, MS(ESI): m / z 267[M+1]). + ).

[0091] [Step 9] Production of 4-chloro-7-ethoxyquinazolin-6-ol The 4-chloro-7-ethoxyquinazoline-6-yl acetate (1.0 equivalent) obtained in step 8 and an ammonia solution (65 equivalents, 28% in water) were dissolved in MeOH (0.1 M) and stirred at room temperature for 1 hour. After concentrating the reaction mixture, ethyl ether was added, and the resulting solid was filtered. The obtained solid was vacuum-dried at 60°C to obtain the target compound as a white solid (yield: 52%, MS(ESI): m / z 225[M+1]).+ ).

[0092] [Step-10] Preparation of tert-butyl 4-((4-chloro-7-ethoxyquinazolin-6-yl)oxy)piperidine-1-carboxylate The 4-chloro-7-ethoxyquinazolin-6-ol (1.0 equivalent), tert-butyl-4-hydroxypiperidine-1-carboxylate (2.0 equivalents), and triphenylphosphine (1.5 equivalents) obtained in step 9 were dissolved in DCM (0.1 M), and then DTBAD (1.5 equivalents) was added at 0°C. The mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, it was purified using MPLC to obtain the target compound as a white solid (yield: 73%, MS(ESI): m / z 408[M+1]). + ).

[0093] [Step-11] Preparation of tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-ethoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate The tert-butyl 4-((4-chloro-7-ethoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.2 equivalents) obtained in step-10 were dissolved in sec-BuOH (0.1 M), and then 4 M HCl (0.2 equivalents) dissolved in dioxane was added, and the mixture was stirred at 100°C for 1 hour. Ethyl ether was added to the mixture to produce a solid, which was filtered and washed with ethyl ether. The resulting white solid of the target compound was used in the next reaction without further purification (yield: 94%, MS(ESI): m / z 574[M+1]). + ).

[0094] [Step-12] Preparation of N-(5-bromo-2-methoxyphenyl)-7-ethoxy-6-(piperidine-4-yloxy)quinazoline-4-amine The tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-ethoxyquinazoline-6-yl)oxy)piperidine-1-carboxylate (1.0 equivalent) obtained in step 11 was dissolved in DCM (0.1 M), then TFA (10 equivalents) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 94%, MS (ESI): m / z 474 [M+1]). + ).

[0095] [Step-13] Preparation of 7-ethoxy-N-(5-(furan-2-yl)-2-methoxyphenyl)-6-(piperidine-4-yloxy)quinazoline-4-amine The N-(5-bromo-2-methoxyphenyl)-7-ethoxy-6-(piperidine-4-yloxy)quinazoline-4-amine (1.0 equivalent), furan-2-ylboronic acid (2.2 equivalents), and K3PO4 (2.0 equivalents) obtained in step-12 were dissolved in dioxane (0.1 M) and water (0.5 M). After degassing with nitro gas, Xphos Pd G2 (0.13 equivalents) was added at 80°C, and the mixture was stirred at 90°C for 20 minutes. The mixture was filtered through a Celite filter, and after concentrating the filtrate, the resulting brown solid of the target compound was used in the next reaction without further purification (MS(ESI): m / z 461[M+1]). + ).

[0096] [Step-14] Manufacture of 1-(4-((7-ethoxy-4-((5-(furan-2-yl)-2-methoxyphenyl)amino)quinazoline-6-yl)oxy)piperidine-1-yl)propa-2-en-1-one 7-ethoxy-N-(5-(furan-2-yl)-2-methoxyphenyl)-6-(piperidine-4-yloxy)quinazoline-4-amine (1.0 equivalent) obtained in step-13 was dissolved in saturated NaHCO3 aqueous solution (5.0 equivalents) in THF (0.1 M), and then acryloyl chloride (1.0 equivalent) was added at 0°C and the mixture was stirred for 10 minutes. After concentrating the reaction mixture, it was purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 22%, MS(ESI): m / z 515[M+1]). + ).

[0097] Example 239: Preparation of Compound The compound of Example 239 according to the present invention was prepared in the same manner as in Example 238. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 4.

[0098] [Table 4]

[0099] Manufacturing Example 2. Production of 2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)aniline [ka]

[0100] [Step 1] Production of 1-methylpyrrolidine-3-ylmethanesulfonate 1-Methylpyrrolidine-3-ol (1.0 equivalent) was dissolved in DCM (1.0 M) at 0°C, and then DIPEA (1.2 equivalents) and methylsulfonyl chloride (1.1 equivalents) were added. The reaction mixture was stirred at 0°C for 1 hour, and then stirred at room temperature for 16 hours. After confirming the reaction by TLC, water was added to the reaction mixture, and the organic matter was extracted with DCM. The collected organic layer was concentrated after removing the remaining water with Na2SO4. The resulting brown solid of the target compound was used in the next reaction without further purification (yield: 80%).

[0101] [Step 2] Preparation of 3-(4-bromo-2-nitrophenoxy)-1-methylpyrrolidine The 1-methylpyrrolidine-3-ylmethanesulfonate (1.0 equivalent), 4-bromo-2-nitrophenol (1.5 equivalents), and K2CO3 (2.0 equivalents) obtained in step 1 were dissolved in DMF (0.6 M) and stirred at 100°C for 16 hours. Water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated by removing the remaining water with Na2SO4. The reaction mixture was purified using MPLC (Hexane: EA) to obtain the target compound as a brown solid (yield: 80%, MS (ESI): m / z 301 [M+1]). + ).

[0102] [Step 3] Production of 5-bromo-2-((1-methylpyrrolidine-3-yl)oxy)aniline 3-(4-bromo-2-nitrophenoxy)-1-methylpyrrolidine (1.0 equivalent) obtained in step 2 was dissolved in THF (0.3 M) at 0°C, and then acetic acid (20 equivalents) and zinc (10 equivalents) were added. The reaction mixture was stirred at room temperature for 2 hours. After dilution with methanol, the mixture was filtered through a Celite filter and concentrated. Saturated NaHCO3 aqueous solution was added at 0°C to neutralize the mixture, and organic matter was extracted by DCM. The collected organic layer was concentrated after removing the remaining water using Na2SO4. The mixture was purified using MPLC (DCM: MeOH) to obtain the target compound as a yellow solid (yield: 77%, MS(ESI): m / z 271[M+1]).+ ).

[0103] [Step 4] Production of 2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)aniline 5-bromo-2-((1-methylpyrrolidine-3-yl)oxy)aniline (1.0 equivalent), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (2.0 equivalents), and K3PO4 (2.0 equivalents) obtained in step 3 were dissolved in dioxane (0.1 M) and water (0.5 M). After degassing with nitrous oxide, Xphos Pd G2 (0.13 equivalents) was added at 80°C, and the mixture was stirred at 100°C for 1 hour. The mixture was filtered through a Celite filter, and the filtrate was concentrated. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a brown solid (yield: 64%, MS(ESI): m / z 275[M+1]). + ).

[0104] Example 240. Preparation of 1-(3-((7-methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazoline-6-yl)oxy)azetidine-1-yl)propa-2-en-1-one [ka]

[0105] [Step 1] Production of 7-Methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazolin-6-ol 2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)aniline (1.2 equivalents) and 4-chloro-7-methoxyquinazolin-6-ol (1.0 equivalent) obtained in Preparation Example 2 were dissolved in sec-BuOH (0.1 M), and 4 M HCl (0.2 equivalents) dissolved in 1,4-dioxane was added. The mixture was stirred at 100°C for 16 hours. Ethyl ether was added to the mixture, the resulting solid was filtered, washed with ethyl ether, and the target compound was obtained as a yellow solid (yield: 84%, MS(ESI): m / z 449[M+1]). + ).

[0106] [ Step 2] Production of tert-butyl 3-((7-methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate The 7-methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazolin-6-ol (1.0 equivalent), tert-butyl3-(tosyloxy)azetidine-1-carboxylate (1.2 equivalents), and K2CO3 (2.0 equivalents) obtained in step 1 were dissolved in DMF (0.1 M) and stirred at 100°C for 16 hours. The solution was cooled to room temperature, DCM and brine were added, and organic matter was extracted. The collected organic layer was concentrated by removing the remaining water with Na2SO4. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 33%, MS(ESI): m / z 604[M+1]). + ).

[0107] [Step 3] Preparation of 6-(azetidine-3-yloxy)-7-methoxy-N-(2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)quinazoline-4-amine The tert-butyl 3-((7-methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazoline-6-yl)oxy)azetidine-1-carboxylate (1.0 equivalent) obtained in step 2 was dissolved in DCM (0.2 M), then TFA (50.0 equivalents) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 92%, MS(ESI): m / z 504[M+1]). + ).

[0108] [Step 4] Manufacturing of 1-(3-((7-Methoxy-4-((2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)amino)quinazoline-6-yl)oxy)azetidine-1-yl)propa-2-en-1-one The 6-(azetidine-3-yloxy)-7-methoxy-N-(2-((1-methylpyrrolidine-3-yl)oxy)-5-(thiophen-2-yl)phenyl)quinazoline-4-amine (1.0 equivalent) obtained in step 3 and saturated NaHCO3 aqueous solution (5.0 equivalents) were dissolved in THF (0.1 M), and then acryloyl chloride (1.0 equivalent) was added at 0°C and the mixture was stirred for 30 minutes. After concentrating the reaction mixture, it was purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 30%, MS(ESI): m / z 558[M+1]). + ).

[0109] Examples 241-261: Preparation of Compounds Compounds of Examples 241-261 according to the present invention were prepared in the same manner as in Example 240. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 5.

[0110] [Table 5] TIFF0007893421000137.tif228161 TIFF0007893421000138.tif227161 TIFF0007893421000139.tif227161 TIFF0007893421000140.tif220161 TIFF0007893421000141.tif227161 TIFF0007893421000142.tif227161 TIFF0007893421000143.tif226161 TIFF0007893421000144.tif219161 TIFF0007893421000145.tif112161

[0111] Example 262. Preparation of 1-(4-((4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one [ka]

[0112] [Step-1] Production of 7-(2-methoxyethoxy)-6-nitroquinazoline-4(1H)-one 2-methoxyethane-1-ol (1.0 equivalent) was dissolved in anhydrous THF (1.5 M), cooled to 0°C under nitrogen, then NaH (0.68 equivalents) was added and the mixture was stirred at room temperature for 1 hour. 7-fluoro-6-nitroquinazoline-4(1H)-one (0.3 equivalents) was added to the reaction mixture and the mixture was stirred at 75°C for 12 hours. The reaction mixture was adjusted to pH 7 with saturated NaHCO3 aqueous solution, and organic matter was extracted with chloroform. The collected organic layer was concentrated by removing the remaining water using MgSO4. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 54%, MS(ESI): m / z 266[M+1]). + ).

[0113] [Step 2] Preparation of 4-chloro-7-(2-methoxyethoxy)-6-nitroquinazoline To the 7-(2-methoxyethoxy)-6-nitroquinazoline-4(1H)-one (1.0 equivalent) obtained in step 1, SOCl2 (0.4 M) and DMF (0.2 equivalents) were added, and the mixture was stirred at 120°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the target compound as a yellow solid, which was used in the next reaction without further purification (yield: 70%, MS(ESI): m / z 284[M+1]). + ).

[0114] [Step 3] Preparation of N-(5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)-6-nitroquinazoline-4-amine 4-chloro-7-(2-methoxyethoxy)-6-nitroquinazoline (1.0 equivalent) obtained in step 2 was dissolved in isopropyl alcohol (0.2 M), then 5-bromo-2-methoxyaniline (1.0 equivalent) was added, and the mixture was stirred at 60°C for 2 hours. After concentrating the reaction mixture, it was purified through MPLC (DCM:MeOH) to obtain the target compound as a pale yellow solid (yield: 80%, MS(ESI): m / z 450[M+1]). + ).

[0115] [Stage-4]N 4 Preparation of (5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)quinazoline-4,6-diamine N-(5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)-6-nitroquinazoline-4-amine (1.0 equivalent) obtained in step 3 was dissolved in EA (0.2 M), then tin(II) chloride dihydrate (5.0 equivalents) was added, and the mixture was stirred at 60°C for 3 hours. After the reaction mixture was cooled to room temperature, aqueous ammonia was added and the mixture was concentrated. The reaction mixture was purified by MPLC (DCM:MeOH) and the target compound was obtained as a white solid (yield: 86%, MS (ESI): m / z 420 [M+1]). + ).

[0116] [Step 5] Preparation of tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)amino)piperidine-1-carboxylate N obtained in step 4 4 -(5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)quinazoline-4,6-diamine (1.0 equivalent) was dissolved in AcOH (0.2 M), and then tert-butyl 4-oxopiperidine-1-carboxylate (2.0 equivalents) was added. After stirring at room temperature for 2 hours, sodium triacetoxyborohydride (1.2 equivalents) was added, and the mixture was stirred at room temperature for 12 hours. After adding saturated aqueous NaHCO3, organic matter was extracted with EA, and the collected organic layer was concentrated by removing the remaining water with MgSO4. The reaction mixture was purified by MPLC (DCM:MeOH) to obtain the target compound as a pale yellow solid (yield: 58%, MS(ESI): m / z 603[M+1]). + ).

[0117] [Stage-6]N 4 -(5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)-N 6 - Preparation of (piperidine-4-yl)quinazoline-4,6-diamine The tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)amino)piperidine-1-carboxylate (1.0 equivalent) obtained in step 5 was dissolved in DCM:TFA (10:1 v / v) (0.2M) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by MPLC (DCM:MeOH) to obtain the target compound as a pale yellow solid (yield: 99%, MS(ESI): m / z 503[M+1]). + ).

[0118] [Stage-7]N 4 -(5-(furan-2-yl)-2-methoxyphenyl)-7-(2-methoxyethoxy)-N 6 - Preparation of (piperidine-4-yl)quinazoline-4,6-diamine N obtained in step 6 4 -(5-bromo-2-methoxyphenyl)-7-(2-methoxyethoxy)-N 6 (Piperidine-4-yl)quinazoline-4,6-diamine (1.0 equivalent), furan-2-ylboronic acid (2.2 equivalents), and K3PO4 (3.0 equivalents) were dissolved in 1,4-dioxane:distilled water = 5:1 (v / v) (0.2M), and then degassed with nitrogen. The mixture was heated at 100°C for 5 minutes under nitrogen, Xphos Pd G2 (0.1 equivalent) was added, and the mixture was stirred for 1 hour. The reaction mixture was concentrated and purified by MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 98%, MS (ESI): m / z 490 [M+1]). + ).

[0119] [Step-8] Manufacture of 1-(4-((4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one N manufactured in stage -7 4 -(5-(furan-2-yl)-2-methoxyphenyl)-7-(2-methoxyethoxy)-N 6 (Piperidin-4-yl)quinazoline-4,6-diamine (1.0 equivalent) was dissolved in THF (0.1 M), cooled to 0°C, and then 1.5 equivalents of 1 M NaHCO3 aqueous solution and acryloyl chloride (1.0 equivalent) were added. The mixture was then stirred at 0°C for 30 minutes. The reaction mixture was concentrated and purified by prep-HPLC to obtain the target compound as a yellow solid (yield: 40%, MS(ESI): m / z 544[M+1]). + ).

[0120] Examples 263-286: Preparation of Compounds Compounds of Examples 263-286 according to the present invention were prepared in the same manner as in Example 262. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 6.

[0121] [Table 6] TIFF0007893421000148.tif216161 TIFF0007893421000149.tif226161 TIFF0007893421000150.tif226161 TIFF0007893421000151.tif227161 TIFF0007893421000152.tif226161 TIFF0007893421000153.tif226161 TIFF0007893421000154.tif227161 TIFF0007893421000155.tif227161 TIFF0007893421000156.tif226161 TIFF0007893421000157.tif221161 TIFF0007893421000158.tif132161

[0122] Example 287. Preparation of N-(4-((5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)acrylamide [ka]

[0123] [Step 1] Production of 7-methoxy-6-nitroquinazoline-4(3H)-one 7-Fluoro-6-nitroquinazoline-4(3H)-one (1.0 equivalent) and sodium methoxide (2.0 equivalents) were dissolved in MeOH (0.2 M), and the mixture was stirred at 70°C for 2 hours. 1N HCl was added, and the resulting solid was filtered. The target compound obtained as a white solid was used in the next reaction without further purification (yield: 78%, MS(ESI): m / z 222[M+1]). + ).

[0124] [Step 2] Production of 4-chloro-7-methoxy-6-nitroquinazoline To the 7-methoxy-6-nitroquinazoline-4(3H)-one (1.0 equivalent) obtained in step 1, thionyl chloride (30.0 equivalents) and DMF (1 drop) were added under nitrogen. The mixture was stirred at 100°C for 4 hours and then concentrated. The target compound obtained from the clear oil was used in the next reaction without further purification (yield: 92%, MS(ESI): m / z 240[M+1]). + ).

[0125] [Step 3] Preparation of N-(5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine 4-chloro-7-methoxy-6-nitroquinazoline (3.0 equivalents) and 5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyaniline (1.0 equivalent) obtained in step 2 were dissolved in sec-BuOH (0.1 M), and then 4 M HCl (0.2 equivalents) dissolved in 1,4-dioxane was added, and the mixture was stirred at 80°C for 2 hours. Ethyl ether was added to the reaction mixture to form a solid, and the formed solid was filtered and washed with ethyl ether. The target compound obtained as a white solid was used in the next reaction without further purification (yield: 39%, MS(ESI): m / z 444[M+1]). + ).

[0126] [Stage-4]N 4 -(5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine preparation The N-(5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine (1.0 equivalent) obtained in step 3 and tin(II) chloride dihydrate (5.0 equivalents) were dissolved in ethyl acetate (0.1 M), and the mixture was stirred at 55°C for 1 hour. The desired product was confirmed by LC-MS. The mixture was filtered through a Celite filter, and the target compound, obtained as a white solid after concentration, was used in the next reaction without further purification (MS(ESI): m / z 414[M+1]). + ).

[0127] [Step 5] Preparation of N-(4-((5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)acrylamide N obtained in step 4 4(5-([1,2,4]triazolo[1,5-a]pyridine-7-yl)-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equivalent) and DIPEA (2.5 equivalents) were dissolved in DMF (0.1 M), and then acryloyl chloride (1.0 equivalent) was added at 0°C and the mixture was stirred at 0°C for 20 minutes. The reaction mixture was concentrated under vacuum and purified using prep-HPLC to obtain the target compound as a white solid (yield: 15%, MS(ESI): m / z 468[M+1]). + ).

[0128] Examples 288-296: Preparation of Compounds Compounds of Examples 288-296 according to the present invention were prepared in the same manner as in Example 287. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 7.

[0129] [Table 7] TIFF0007893421000161.tif226161 TIFF0007893421000162.tif208161 TIFF0007893421000163.tif189161

[0130] Example 297. Preparation of 1-(4-((4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-(difluoromethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one [ka]

[0131] [Step 1] Preparation of N-(5-bromo-2-methoxyphenyl)-7-fluoro-6-nitroquinazoline-4-amine 4-Chloro-7-fluoro-6-nitroquinazoline (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.0 equivalent) were dissolved in isopropyl alcohol (0.2 M) and stirred at 50°C for 10 minutes. Ethyl ether was added to produce a solid compound, and the resulting solid was filtered to obtain the target compound as a yellow solid (yield: 72%, MS(ESI): m / z 393[M+1]). + ).

[0132] [Step 2] Production of 4-((5-bromo-2-methoxyphenyl)amino)-6-nitroquinazoline-7-ol N-(5-bromo-2-methoxyphenyl)-7-fluoro-6-nitroquinazoline-4-amine (1.0 equivalent) obtained in step 1 was dissolved in 1,4-dioxane, and then 50% NaOH aqueous solution (12.5 equivalents) was added and the mixture was stirred at 110°C for 4 hours. After acidification by adding 10% sulfuric acid aqueous solution, organic matter was extracted using EA. The collected organic layer was concentrated after removing the remaining water with Na2SO4. The resulting yellow solid target compound was used in the next reaction without further purification (yield: 74%, MS(ESI): m / z 391[M+1]). + ).

[0133] [Step 3] Preparation of N-(5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)-6-nitroquinazoline-4-amine The 4-((5-bromo-2-methoxyphenyl)amino)-6-nitroquinazolin-7-ol (1.0 equivalent), 2-chloro-2,2-difluoro-1-phenylethane-1-one (2.0 equivalents), and K2CO3 (2.0 equivalents) obtained in step 2 were dissolved in ACN:H2O (5:1) and stirred at 80°C for 16 hours. Water was added, and organic matter was extracted using EA. The collected organic layer was concentrated after removing the remaining water with Na2SO4. The reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 37%, MS(ESI): m / z 441[M+1]). + ).

[0134] [Stage-4]N 4 Preparation of (5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)quinazoline-4,6-diamine The N-(5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)-6-nitroquinazoline-4-amine (1.0 equivalent) and tin(II) chloride dihydrate (5.0 equivalents) obtained in step 3 were dissolved in ethyl acetate (0.1 M), and the mixture was stirred at 60°C for 2 hours. After adding aqueous ammonia to the reaction mixture, it was concentrated and then purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 49%, MS(ESI): m / z 411[M+1]). + ).

[0135] [Step 5] Preparation of tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(difluoromethoxy)quinazoline-6-yl)amino)piperidine-1-carboxylate N obtained in step 4 4 -(5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)quinazoline-4,6-diamine (1.0 equivalent) and tert-butyl 4-oxopiperidine-1-carboxylate (3.0 equivalents) were dissolved in acetic acid (0.1 M) and stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (3.0 equivalents) was added, and the mixture was stirred at room temperature for 16 hours. After adding 2 M NaOH aqueous solution, organic matter was extracted using DCM. The collected organic layer was concentrated after removing the remaining water with MgSO4. The resulting yellow solid of the target compound was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 594[M+1]). + ).

[0136] [Stage-6]N 4 -(5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)-N 6 - Preparation of (piperidine-4-yl)quinazoline-4,6-diamine The tert-butyl 4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)amino)piperidine-1-carboxylate (1.0 equivalent) obtained in step 5 was dissolved in DCM, TFA (50.0 equivalents) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, it was purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 97%, MS(ESI): m / z 494[M+1]). + ).

[0137] [Step-7] Manufacturing of 1-(4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one N obtained in step 6 4 -(5-bromo-2-methoxyphenyl)-7-(difluoromethoxy)-N 6(Piperidin-4-yl)quinazoline-4,6-diamine (1.0 equivalent) and saturated NaHCO3 aqueous solution (5.0 equivalents) were dissolved in THF, and then acryloyl chloride (1.0 equivalent) was added at 0°C and the mixture was stirred for 10 minutes. The reaction mixture was concentrated, and the resulting brown solid of the target compound was used in the next reaction without further purification (yield: 100%, MS(ESI): m / z 548[M+1]). + ).

[0138] [Step-8] Preparation of 1-(4-((4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-(difluoromethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one The 1-(4-((4-((5-bromo-2-methoxyphenyl)amino)-7-(difluoromethoxy)quinazolin-6-yl)amino)piperidine-1-yl)propa-2-en-1-one (1.0 equivalent), (2,4-difluorophenyl)boric acid (2.2 equivalents), and K3PO4 (2.0 equivalents) obtained in step 7 were dissolved in 1,4-dioxane:water (5:1). After degassing with nitrous oxide, Xphos Pd G2 (0.1 equivalent) was added at 100°C and the mixture was stirred at 100°C for 10 minutes. The mixture was filtered through a Celite filter and the filtrate was concentrated. The reaction mixture was purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 7%, MS(ESI): m / z 582[M+1]). + ).

[0139] Examples 298-303: Compound Preparation Compounds of Examples 298-303 according to the present invention were prepared by the same method as in Example 297. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 8.

[0140] [Table 8] TIFF0007893421000166.tif220161 TIFF0007893421000167.tif227161 TIFF0007893421000168.tif215161

[0141] Example 304. Preparation of (R,E)-N-(4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide [ka]

[0142] [Step 1] Preparation of N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine 4-chloro-7-methoxy-6-nitroquinazoline (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.0 equivalent) were dissolved in sec-BuOH (0.2 M), then 4 M HCl (0.2 equivalent) dissolved in 1,4-dioxane was added, and the mixture was stirred at 90°C for 2 hours. Ethyl ether was added to the reaction mixture, the resulting solid was filtered, washed with ethyl ether, and the target compound was obtained as a yellow solid (yield: 99%, MS(ESI): m / z 406[M+1]). + ).

[0143] [Stage-2]N 4 Preparation of (5-bromo-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine The N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine (1.0 equivalent) obtained in step 1 and tin(II) chloride dihydrate (5.0 equivalents) were dissolved in ethyl acetate (0.1 M), and the mixture was stirred at 60°C for 1 hour. The mixture was filtered through a Celite filter and concentrated. The resulting brown solid of the target compound was used in the next reaction without further purification (MS(ESI): m / z 376 [M+1]). + ).

[0144] [Step 3] Preparation of diethyl(2-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate 2-(diethoxyphosphoryl)-2-fluoroacetic acid (2.0 equivalents) was dissolved in DMF (0.5 M), then HATU (3.0 equivalents) was added and the mixture was stirred at 50°C for 1 hour. The N obtained in step 2 was added to the reaction mixture. 4 (5-bromo-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equivalent) and DIPEA (3.0 equivalents) were added, and the mixture was stirred at 50°C for 1 hour. Ice water was added, the resulting solid was filtered, washed with distilled water, and the target compound was obtained as a yellow solid (yield: 30%, MS(ESI): m / z 572[M+1]).+ ).

[0145] [Step 4] Preparation of tert-butyl(R,E)-2-(3-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate Diethyl (2-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-1-fluoro-2-oxoethyl)phosphonate (1.0 equivalent) obtained in step 3 was mixed with ethanol (0.02 M) and NaOH (8.0 equivalents) dissolved in distilled water (0.2 M), and the mixture was stirred for 30 minutes. Tert-butyl(R)-2-formylpyrrolidine-1-carboxylate (2.0 equivalents) was added to the reaction mixture at 0°C and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and organic matter was extracted with EA. The collected organic layer was concentrated after removing the remaining water using Na2SO4. The resulting yellow solid of the target compound was used in the next reaction without further purification (yield: 91%, MS(ESI): m / z 616[M+1]). + ).

[0146] [Step 5] Preparation of (R,E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-2-fluoro-3-(pyrrolidine-2-yl)acrylamide The tert-butyl(R,E)-2-(3-((4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)pyrrolidine-1-carboxylate (1.0 equivalent) obtained in step 4 was dissolved in DCM (0.1 M), TFA (10.0 equivalents) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, it was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 97%, MS(ESI): m / z 516[M+1]). + ).

[0147] [Step 6] Preparation of (R,E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide (R,E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(pyrrolidine-2-yl)acrylamide (1.0 equivalent) obtained in step 5 was dissolved in DCE (0.1 M), and 37% formaldehyde (5.0 equivalents) dissolved in distilled water was added. The mixture was stirred at room temperature for 1 hour, then NaBH(OAc)3 (7.0 equivalents) was added, and the mixture was stirred at 80°C for 1 hour. After concentrating the reaction mixture, it was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 56%, MS(ESI): m / z 530[M+1]). + ).

[0148] [Step 7] Preparation of (R,E)-N-(4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide The (R,E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2-fluoro-3-(1-methylpyrrolidine-2-yl)acrylamide (1.0 equivalent), (2,4-difluorophenyl)boronic acid (2.2 equivalents), and K3PO4 (2.0 equivalents) obtained in step 6 were dissolved in 1,4-dioxane (0.1 M) and water (0.5 M). After degassing with nitrous oxide, Xphos Pd G2 (0.13 equivalents) was added at 80°C, and the mixture was stirred at 90°C for 10 minutes. The reaction mixture was concentrated and purified by prep-HPLC to obtain the target compound as a pale yellow solid (yield: 22%, MS(ESI): m / z 564[M+1]). + ).

[0149] Examples 305-313: Preparation of Compounds Compounds of Examples 305-313 according to the present invention were prepared in the same manner as in Example 304. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 9.

[0150] [Table 9] TIFF0007893421000171.tif226161 TIFF0007893421000172.tif226161 TIFF0007893421000173.tif215161 TIFF0007893421000174.tif62161

[0151] Example 314. (E)-N-(4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-4-(4-methylpiperazine-1-yl)buto-2-enamide [ka]

[0152] [Step 1] Preparation of N-(5-(furan-2-yl)-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine 4-Chloro-7-methoxy-6-nitroquinazoline (1.0 equivalent) and 5-(furan-2-yl)-2-methoxyaniline (1.1 equivalents) were dissolved in isopropyl alcohol (0.1 M), and then 80 o The mixture was stirred in 1C for 2 hours. After the reaction mixture was cooled to room temperature, the solid was filtered and washed with ethyl ether. The resulting yellow solid of the target compound was used in the next reaction without further purification (yield: 96%, MS(ESI): m / z 393[M+1]). + ).

[0153] [Stage-2]N 4 Preparation of (5-(furan-2-yl)-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine N-(5-(furan-2-yl)-2-methoxyphenyl)-7-methoxy-6-nitroquinazoline-4-amine (1.0 equivalent) obtained in step 1 was dissolved in EA (0.1 M), then tin(II) chloride dihydrate (6.0 equivalents) was added, and the mixture was stirred at 60°C for 3 hours. After the reaction mixture was cooled to room temperature, aqueous ammonia was added until the reaction solution turned white. The reaction mixture was concentrated and purified using MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 68%, MS(ESI): m / z 363[M+1]). + ).

[0154] [Step 3] Production of (E)-4-bromo-N-(4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)buto-2-enamide N obtained in step 2 4-(5-(furan-2-yl)-2-methoxyphenyl)-7-methoxyquinazoline-4,6-diamine (1.0 equivalent), (E)-4-bromobut-2-enoic acid (2.0 equivalents), DIPEA (4.5 equivalents), and HATU (3.0 equivalents) were dissolved in DMF (0.2 M) and stirred at 40°C for 16 hours. Water and brine were added, and organic matter was extracted by DCM. The collected organic layer was concentrated after removing the remaining water with Na2SO4. The reaction mixture was purified by MPLC (DCM: MeOH) to obtain the target compound as a yellow solid (yield: 7%, MS(ESI): m / z 510[M+1]). + ).

[0155] [Step 4] Preparation of (E)-N-(4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-4-(4-methylpiperazine-1-yl)buto-2-enamide The (E)-4-bromo-N-(4-((5-(furan-2-yl)-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)but-2-enamide obtained in step 3 was dissolved in DMF (0.1M), then K2CO3 (2.3 equivalents), KI (1.8 equivalents), and 1-methylpiperazine (4.0 equivalents) were added, and the mixture was stirred at 40°C for 1 hour. Water and brine were added, and organic matter was extracted by DCM. The collected organic layer was concentrated after removing the remaining water using MgSO4. The reaction mixture was purified by prep-HPLC to obtain the target compound as a white solid (yield: 19%, MS(ESI): m / z 529[M+1]). + ).

[0156] Examples 315-319: Preparation of Compounds Compounds of Examples 315-319 according to the present invention were prepared in the same manner as in Example 314. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 10.

[0157] [Table 10] TIFF0007893421000177.tif227161 TIFF0007893421000178.tif106161

[0158] Example 320. Preparation of (E)-N-(5-chloro-4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)quinazolin-6-yl)-4-(dimethylamino)buto-2-enamide [ka]

[0159] [Step 1] Preparation of 4-(1H-benzo[d][1,2,3]triazole-1-yl)-5-chloroquinazoline-6-amine 6-amino-5-chloroquinazoline-4(3H)-one (1.0 equivalent) and BOP (1.5 equivalents) were dissolved in acetonitrile (0.1 M), then DBU (2.0 equivalents) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, it was purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 100%, MS(ESI): m / z 296[M+1]). + ).

[0160] [Stage-2]N 4 Preparation of (5-bromo-2-methoxyphenyl)-5-chloroquinazoline-4,6-diamine 4-(1H-benzo[d][1,2,3]triazole-1-yl)-5-chloroquinazoline-6-amine (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.2 equivalents), obtained in step 1, were dissolved in isopropyl alcohol and stirred at 90°C for 10 minutes. Then, p-toluenesulfonic acid monohydrate (0.1 equivalent) was added and the mixture was stirred at 90°C for 1 hour. The reaction mixture was cooled to room temperature, water was added, and a solid was formed. The target compound was obtained as a yellow solid through a filter (yield: 39%, MS(ESI): m / z 379[M+1]). + ).

[0161] [Step 3] Preparation of (E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)but-2-enamide N obtained in step 2 4 (5-bromo-2-methoxyphenyl)-5-chloroquinazoline-4,6-diamine (1.0 equivalent) was dissolved in NMP (0.1 M), and then (E)-4-(dimethylamino)buto-2-enoyl chloride (1.0 equivalent) was added under nitrogen and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 44%, MS (ESI): m / z 490 [M+1]).+ ).

[0162] [Step 4] Preparation of (E)-N-(5-chloro-4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)quinazolin-6-yl)-4-(dimethylamino)buto-2-enamide The (E)-N-(4-((5-bromo-2-methoxyphenyl)amino)-5-chloroquinazolin-6-yl)-4-(dimethylamino)buto-2-enamide (1.0 equivalent), (2,4-difluorophenyl)boric acid (2.2 equivalents), and K3PO4 (2.0 equivalents) obtained in step 3 were dissolved in dioxane:water (5:1, 0.1M). After degassing with nitrous oxide, Xphos Pd G2 (0.13 equivalents) was added at 80°C, and the mixture was stirred at 90°C for 10 minutes. The mixture was filtered through a Celite filter, concentrated, and purified using prep-HPLC to obtain the target compound as a yellow solid (yield: 8%, MS(ESI): m / z 524[M+1]). + ).

[0163] Example 321: Preparation of the compound The compound of Example 321 according to the present invention was prepared in the same manner as in Example 320. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data and yields are summarized in Table 11.

[0164] [Table 11]

[0165] Example 322. Preparation of 1-(2-(4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)-2,6-diazaspiro[3.5]nonane-6-yl)propa-2-en-1-one [ka]

[0166] [Step 1] Preparation of 5-fluoro-4-methoxy-2-nitrobenzonitrile 1-Bromo-5-fluoro-4-methoxy-2-nitrobenzene (1.0 equivalent) and CuCN (1.5 equivalents) were dissolved in DMF (0.2 M) and stirred at 180°C for 2 hours. Ice water was added to the reaction mixture to form a solid, and the resulting solid was filtered to obtain the target compound as a yellow solid (yield: 90%).

[0167] [Step 2] Preparation of tert-butyl 2-(5-cyano-2-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate The 5-fluoro-4-methoxy-2-nitrobenzonitrile (1.0 equivalent), tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 equivalent), and DIPEA (4.0 equivalents) obtained in step 1 were dissolved in DMSO (0.1 M) and stirred at 120°C for 1 hour. Water was added to the reaction mixture to produce a solid compound, and the target compound was obtained as a yellow solid by filtration (yield: 51%, MS(ESI): m / z 347[M+1]). + ).

[0168] [Step 3] Preparation of tert-butyl 2-(4-amino-5-cyano-2-methoxyphenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate The tert-butyl 2-(5-cyano-2-methoxy-4-nitrophenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 equivalent) obtained in step 2 was dissolved in MeOH (0.1 M), and then Pd / C (10% purity, 0.1 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour under hydrogen. After filtering through Celite, the filtrate was concentrated. The resulting yellow solid of the target compound was used in the next reaction without further purification (yield: 98%, MS(ESI): m / z 373[M+1]). + ).

[0169] [Step 4] Preparation of tert-butyl(Z)-2-(5-cyano-4-(((dimethylamino)methylene)amino)-2-methoxyphenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate The tert-butyl 2-(4-amino-5-cyano-2-methoxyphenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 equivalent) and N,N-dimethylformamide dimethyl acetal (5.0 equivalents) obtained in step 3 were dissolved in toluene (0.1 M), stirred at 100°C for 1 hour, and then concentrated. The reaction mixture was purified using MPLC (DCM:MeOH) to obtain the target compound as a yellow solid (yield: 81%, MS(ESI): m / z 428[M+1]). + ).

[0170] [Step 5] Preparation of tert-butyl 2-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate The tert-butyl(Z)-2-(5-cyano-4-(((dimethylamino)methylene)amino)-2-methoxyphenyl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 equivalent) and 5-bromo-2-methoxyaniline (1.1 equivalents) obtained in step 4 were dissolved in acetic acid (0.1 M) and stirred at 120°C for 1 hour. After cooling to room temperature, saturated NaHCO3 aqueous solution was added to bring the reaction mixture to pH 8, and the organic layer was extracted by DCM. The collected organic layer was concentrated after removing the remaining water with MgSO4. The resulting brown solid of the target compound was used in the next reaction without further purification (yield: 30%, MS(ESI): m / z 584[M+1]). + ).

[0171] [Step 6] Preparation of N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-(2,6-diazaspiro[3.5]nonan-2-yl)quinazoline-4-amine The tert-butyl 2-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazoline-6-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (1.0 equivalent) obtained in step 5 was dissolved in DCM, and an excess amount of TFA was added. The reaction mixture was stirred at room temperature for 1 hour. After confirming the desired product by LC-MS, the mixture was concentrated and purified by MPLC (DCM:MeOH) to obtain the target compound as a white solid (yield: 100%, MS(ESI): m / z 484[M+1]). + ).

[0172] [Step-7] Manufacture of 1-(2-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2,6-diazaspiro[3.5]nonan-6-yl)propa-2-en-1-one N-(5-bromo-2-methoxyphenyl)-7-methoxy-6-(2,6-diazaspiro[3.5]nonan-2-yl)quinazoline-4-amine (1.0 equivalent) obtained in step 6 was dissolved in saturated NaHCO3 aqueous solution (5.0 equivalents) in THF (0.1 M), and then acryloyl chloride (1.0 equivalent) was added at 0°C and the mixture was stirred for 30 minutes. The reaction mixture was concentrated, water was added, and the organic layer was extracted with DCM. The collected organic layer was concentrated after removing the remaining water with MgSO4. The resulting white solid of the target compound was used in the next reaction without further purification (yield: 42%, MS(ESI): m / z 538[M+1]). + ).

[0173] [Step-8] Preparation of 1-(2-(4-((2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)-7-methoxyquinazoline-6-yl)-2,6-diazaspiro[3.5]nonan-6-yl)propa-2-en-1-one The 1-(2-(4-((5-bromo-2-methoxyphenyl)amino)-7-methoxyquinazolin-6-yl)-2,6-diazaspiro[3.5]nonan-6-yl)propa-2-en-1-one (1.0 equivalent), (2,4-difluorophenyl)boric acid (1.1 equivalent), and K3PO4 (2.5 equivalents) obtained in step 7 were dissolved in dioxane:water (5:1, 0.006 M). After degassing with nitrous oxide, Xphos Pd G2 (0.1 equivalent) was added at 80°C, and the mixture was stirred at 100°C for 1 hour. The mixture was filtered through Celite, and the filtrate was concentrated and purified by prep-HPLC to obtain the target compound as a yellow solid (yield: 64%, MS(ESI): m / z 572[M+1]). + ).

[0174] Examples 323-330: Compound Preparation Compounds of Examples 323-330 according to the present invention were prepared in the same manner as in Example 322. The chemical structural formula and compound name of each example are provided. 1 The 1H NMR, MS, and HPLC data, as well as the yields, are summarized in Table 12.

[0175] [Table 12] TIFF0007893421000183.tif227161 TIFF0007893421000184.tif201161 TIFF0007893421000185.tif201161 TIFF0007893421000186.tif123161

[0176] <Experimental Example 1> Evaluation of HER2 and EGFR enzyme inhibitory activity Biochemical kinase assays for HER2 and EGFR were performed through Reaction Biology Corp (San Diego, USA). Compounds were diluted 3-fold from 10 μM against HER2 and EGFR enzymes under ATP (10 μM) conditions, and IC50 was performed at 10-dose. 50 The following measurements were taken. The results are shown in Table 13.

[0177] [Table 13]

[0178] <Experimental Example 2> Evaluation of the cell proliferation inhibitory activity of SK-BR-3, BT-474, N-87, and HaCaT To evaluate the cell proliferation inhibitory activity of the compounds according to the present invention against HER2 and EGFR kinases, the following methods were used with HER2 overexpressing cell lines (SK-BR-3, BT-474, N-87) and EGFR expressing cell line (HaCaT).

[0179] SK-BR-3 cells were cultured in McCoy's 5A medium supplemented with 10% FBS, BT-474 cancer cells in RPMI-1640 medium supplemented with 20% FBS, and N-87 cancer cells in RPMI-1640 medium supplemented with 10% FBS. HaCaT cells were cultured in DMEM medium supplemented with 10% FBS.

[0180] SK-BR-3 cells were dispensed into each well of a white clear-bottom 96-well plate (Corning) 48 hours before treatment with the example compound. BT-474 cells were dispensed into each well of a white clear-bottom 96-well plate (Corning) 48 hours before treatment with the example compound. N-87 cells were dispensed into each well of a white clear-bottom 96-well plate (Corning) 24 hours before treatment with the example compound. HaCaT cells were dispensed into each well of a white clear-bottom 96-well plate (Corning) 24 hours before treatment with the example compound. For SK-BR-3 and BT-474 cells, the example compound was diluted with dimethyl sulfoxide (diluted 3-fold, for a total of 11 concentrations), and 1 μl was injected at a time to achieve a final concentration of 0.2 nM to 10 μM. For N-87 cells, the example compound was diluted with dimethyl sulfoxide (5-fold dilution, totaling 11 concentrations), and 0.5 µl was injected into each cell to achieve a final concentration of 0.5 pM to 5 µM. For HaCaT cells, the example compound was diluted with dimethyl sulfoxide (3-fold dilution, totaling 11 concentrations), and 0.5 µl was injected into each cell to achieve a final concentration of 0.8 nM to 45 µM. To measure the viability of living cells, after treatment with the example compound, a certain period of time (SK-BR-3: 120 hours, BT-474: 120 hours, N-87: 72 hours, HaCaT: 72 hours) was observed. The cells were then stored at room temperature for 10 minutes using CellTiter-Glo cell viability reagent (Promega), and the luminescence intensity was measured using a plate reader (SynergyNeo, Biotek). Each test was repeated three times.

[0181] The result values ​​were calculated as the percentage of cell growth compared to the control group. Graphs were plotted using the GraphPad Prism version 5.0 program, and GI was calculated. 50 The values ​​were calculated. The results are shown in Table 14.

[0182] [Table 14] TIFF0007893421000189.tif226161 TIFF0007893421000190.tif226161 TIFF0007893421000191.tif225161 TIFF0007893421000192.tif227161 TIFF0007893421000193.tif225161 TIFF0007893421000194.tif225161 TIFF0007893421000195.tif226161 TIFF0007893421000196.tif94161

[0183] <Experimental Example 3> Evaluation of the inhibitory activity of transduced Ba / F3 cells in cell proliferation. Ba / F3 cells were cultured in RPMI-1640 containing 10% FBS and 5 ng / ml IL-3 (R&D Systems). Transduced Ba / F3 cells were further cultured in the same medium with 1 ug / ml puromycin (Invitrogen).

[0184] Cells were aliquoted into each well of a white clear-bottom 96-well plate (Corning) 24 hours before treatment with the example compound. The example compound was diluted with dimethyl sulfoxide (3-fold dilution, totaling 12 concentrations), and 1 μl was injected at a time to achieve a final concentration of 0.2 nM to 5 μM. Live cells were measured 72 hours after compound treatment using CellTiter-Glo luminescentcell-viability reagent (Promega). After storage at room temperature for 10 minutes, the luminescence intensity was measured using a plate reader (SynergyNeo, Biotek). Each test was repeated three times. The results were calculated as the percentage of cell growth compared to the control group. Graphs were plotted using the GraphPad Prism version 8.3.0 program, and GI was calculated. 50 The value was calculated.

[0185] Table 15 lists L869R, which expresses rare (or uncommon) and drug resistance mutations in HER2. L755S This shows the results of evaluating the proliferation inhibitory activity of Ba / F3 cells with T798I, T862A, and G719A, L861Q, S768I, G719A / S768I, and Del19 / T790M, which express rare or uncommon EGFR and drug resistance mutations.

[0186] [Table 15]

Claims

1. The compound represented by the following chemical formula 1, its optical isomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 29】 In the above formula 1, X is N or CR Ｘ１ And; R １ is -H, -OR Ｘ２ , or -NR Ｘ３ R Ｘ４ And; R Ｘ１ is -H, -C １－６ Alkyl, -C １－６ It is a haloalkyl, -CN, or -halo; R Ｘ２ is -H, -C １－６ alkyl, -C １－６ hydroxyalkyl, -C １－６ aminoalkyl, -C １－６ haloalkyl, -C １－６ alkyl -O(C １－６ alkyl), -C １－６ alkyl -O(C １－６ alkyl)-C １－６ aminoalkyl, -(CH ２ )n -cycloalkyl, or -(CH ２ )n -heterocycloalkyl {where one or more H of said -(CH ２ )n -cycloalkyl or -(CH ２ )n -heterocycloalkyl ring may be substituted with -C １－６ alkyl, -C １－６ hydroxyalkyl, -C １－６ aminoalkyl, -C １－６ haloalkyl, -C １－６ alkyl -O(C １－６ alkyl), -CN, -NH ２ , -NH -C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -NO ２ , -OH, -halo, or heterocycloalkyl}; n is 0, 1, 2, 3, or 4; R Ｘ３ and R Ｘ４ These are, independently, -H or -C １－６ Alkyl, or R Ｘ３ and R Ｘ４ They are linked to each other, together with the N atom 【Transformation 30】 Forming a ring, the W １ and W ２ Each is independent of CH ２ , NH, O, or S {where, the above 【Chemistry 31】 One or more H atoms in the heterocycloalkyl ring are -C １－６ Alkyl, -C １－６ Hydroxyalkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -CN, -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ (Alkyl) (C １－６ Alkyl), -NO ２ , may be substituted with -OH, -halo, or heterocycloalkyl; a to d are each independently 1, 2, or 3; R ２ is -H, -C １－６ Alkyl, -C １－６ It is a haloalkyl, -CN, or -halo; L is -NH-, 【Chemistry 32】 Here, ring B is a monocyclic or polycyclic ring containing an N atom, and one or more H atoms in ring B are -C １－６ Alkyl, -C １－６ Hydroxyalkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -CN, -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ (Alkyl) (C １－６ Alkyl), -NO ２ , -OH, =O, or -halo may be substituted; R ３ is -CZ 1 =CZ 2 Z 3, -C １－６ Alkyl, -C １－６ It is a haloalkyl or cycloalkyl; Z １ is -H, -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, -C １－６ It is a haloalkyl, -CN, or -halo; Z ２ and Z ３ are each independently, -H, -C １－６ alkyl, -C １－６ hydroxyalkyl, -C １－６ aminoalkyl, -C １－６ haloalkyl, -C １－６ alkyl-O(C<� １－６ alkyl), -halo, cycloalkyl, heterocycloalkyl, -C １－６ alkyl-cycloalkyl, or -C １－６ alkyl-heterocycloalkyl provided that one or more H of said cycloalkyl, heterocycloalkyl, -C １－６ alkyl-cycloalkyl, or -C １－６ alkyl-heterocycloalkyl may be substituted with -C １－６ alkyl, -C １－６ hydroxyalkyl, -C １－６ aminoalkyl, -C １－６ haloalkyl, -CN, -NH ２ , -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -NOis]] ２ , -OH, =O, or heterocycloalkyl}}; It should be noted that there seems to be an error in the original text where "<� １－６ " is likely an incorrect tag. I have translated it as best as possible while maintaining the integrity of the text. Y １ ~Y ３ These are, independently, N or CR Ｙ And; R Ｙ is -H, -C １－６ alkyl, -C １－６ aminoalkyl, -C １－６ hydroxyalkyl, -C １－６ haloalkyl, -CN, -NH ２ , -NH-C １－６ alkyl, -N(C １－６ alkyl)(C １－６ alkyl), -NO ２ , -OH, or -halo; R ４ is, -C １－６ Alkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ Haloalkyl, cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-cycloalkyl, or -C １－６ It is an alkyl-heterocycloalkyl {wherein the cycloalkyl, heterocycloalkyl, -C}. １－６ Alkyl-cycloalkyl, or -C １－６ One or more H atoms in an alkyl-heterocycloalkyl group are -C １－６ It may be substituted with alkyl; Ring A is an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring {wherein one or more H atoms in the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl ring are -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Hydroxyalkyl, -C １－６ Haloalkyl, -C2-6 alkenyl, -CN, -C(=O)-R Ａ１ , -NO ２ , -NR Ａ２ R Ａ３ , -OR Ａ４ , -S-C １－６ It may be substituted with alkyl, -halo, or heterocycloalkyl [in this case, one or more H in the heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ The substituents of the aryl or heteroaryl ring may be substituted with haloalkyl, -halo, or heterocycloalkyl groups, and the substituents of the aryl or heteroaryl ring may be linked to each other to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group. R Ａ１ is -H, -C １－６ Alkyl, -NH ２ , -NH-C １－６ Alkyl, -N(C) １－６ (Alkyl) (C １－６ Alkyl), -NH- (CH ２ ) m-aryl, -OH, or -O-C １－６ It is an alkyl group {where the -NH-(CH ２ ) One or more H atoms in the m-aryl ring are -C １－６ Alkyl, -C １－６ } May be substituted with a haloalkyl or -halo; m is 0, 1, 2, 3, or 4; R Ａ２ and R Ａ３ These are independently -H and -C １－６ Alkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C2-6 alkenyl, -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl {wherein one or more H in the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl ring is -C １－６ Alkyl, -C １－６ {May be substituted with haloalkyl, =O, -halo, or aryl}; R Ａ４ is -H, -C １－６ Alkyl, or -C １－６ It is a haloalkyl group.

2. X is N or CR Ｘ１ And; R １ is -H, -OR Ｘ２ , or -NR Ｘ３ R Ｘ４ And; R Ｘ１ is -H or -CN; R Ｘ２ is, -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -C １－６ Alkyl-O(C) １－６ Alkyl), -C １－６ Alkyl-O(C) １－６ Alkyl)-C １－６ Aminoalkyl, or -(CH ２ ) is an n-heterocycloalkyl {where the above-(CH ２ ) One or more H atoms in the n-heterocycloalkyl ring are -C １－６ Alkyl, -C １－６ Alkyl-O(C) １－６ } which may be substituted with alkyl, or heterocycloalkyl; n is 0, 1, 2, 3, or 4; R Ｘ３ and R Ｘ４ These are, independently, -H or -C １－６ Alkyl, or R Ｘ３ and R Ｘ４ They are linked to each other, together with the N atom 【Transformation 33】 Forming a ring, W １ and W ２ Each is independent of CH ２ , NH, or O {where the above 【Transformation 34】 One or more hydrogen atoms in the ring may be substituted with a -halo or a heterocycloalkyl group. a to d are each independently either 1 or 2; R ２ is -H or -HALO; L is -NH-, 【Chemistry 35】 Here, ring B is a monocyclic or polycyclic ring containing an N atom, and one or more H atoms in ring B are -C １－６ Alkyl, -C １－６ } May be substituted with a haloalkyl, =O, or -halo; R ３ is -CZ 1 =CZ 2 Z 3, -C １－６ It is a haloalkyl or cycloalkyl; Z １ is -H, -C １－６ It is an aminoalkyl, -CN, or -halo; Z ２ and Z ３ These are independently -H and -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Alkyl-O(C) １－６ Alkyl), -halo, -heterocycloalkyl, or -C １－６ It is an alkyl-heterocycloalkyl group {wherein the -heterocycloalkyl group, or -C}. １－６ One or more H atoms in an alkyl-heterocycloalkyl group are -C １－６ They may be substituted with alkyl or heterocycloalkyl groups. Y １ ~Y ３ These are, independently, N or CR Ｙ And; R Ｙ is -H, -C １－６ Alkyl or -halo; R ４ is, -C １－６ Alkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ A haloalkyl, cycloalkyl, or heterocycloalkyl group {wherein one or more H of the cycloalkyl or heterocycloalkyl group is -C}. １－６ It may be substituted with alkyl; Ring A is an aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring {wherein one or more H atoms in the aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl ring are -C}. １－６ Alkyl, -C １－６ Haloalkyl, -C2-6 alkenyl, -CN, -C(=O)-R Ａ１ , -NO ２ , -NR Ａ２ R Ａ３ , -OR Ａ４ , -S-C １－６ It may be substituted with alkyl, -halo, or heterocycloalkyl [in this case, one or more H in the heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ The substituents of the aryl or heteroaryl ring may be substituted with haloalkyl, -halo, or heterocycloalkyl groups, and the substituents of the aryl or heteroaryl ring may be linked to each other to form a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group. R Ａ１ is -H, -NH- (CH ２ ) m-aryl, -OH, or -O-C １－６ It is an alkyl group {where the -NH-(CH ２ ) One or more H atoms in the m-aryl ring may be substituted with a -halo; m is 0, 1, 2, 3, or 4; R Ａ２ and R Ａ３ These are independently -H and -C １－６ Alkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C2-6 alkenyl, -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl {wherein one or more H in the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-aryl ring may be substituted with =O, -halo, or aryl}; R Ａ４ is -H, -C １－６ Alkyl, or -C １－６ It is a haloalkyl; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

3. X is N or CR Ｘ１ And; R １ is -H, -OR Ｘ２ , or -NR Ｘ３ R Ｘ４ And; R Ｘ１ is -H or -CN; R Ｘ２ is, -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Haloalkyl, -C １－６ Alkyl-O(C) １－６ Alkyl), -C １－６ Alkyl-O(C) １－６ Alkyl)-C １－６ Aminoalkyl, or -(CH ２ ) is an n-heterocycloalkyl {where the above-(CH ２ The n-heterocycloalkyl ring has 4 to 6 members, and the -(CH ２ ) One or more H atoms in the n-heterocycloalkyl ring are -C １－６ Alkyl, -C １－６ Alkyl-O(C) １－６ Alkyl), or may be substituted with a 4- to 6-membered heterocycloalkyl group; n is 0, 1, 2, or 3; R Ｘ３ and R Ｘ４ These are, independently, -H or -C １－６ Alkyl, or R Ｘ３ and R Ｘ４ They are linked to each other, together with the N atom 【Transformation 36】 Forms W １ and W ２ Each is independent of CH ２ or O {where the above 【Chemistry 37】 One or more hydrogen atoms in the ring may be substituted with a -halo or a 4- to 6-membered heterocycloalkyl group. a to d are each independently either 1 or 2; R ２ is -H or -HALO; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. L is -NH-, 【Transformation 38】 And {Here, the above 【Chemistry 39】 One or more H in the ring are -C １－６ Alkyl, -C １－６ } May be substituted with a haloalkyl, =O, or -halo; V １ and V ２ They are connected to each other, single bonds, C １ Alkyl, C ２ Alkyl, or C ３ It forms a biring cross-linked with alkyl, or it is null; e to h are each independently 1, 2, or 3; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

5. R ３ is -CZ 1 =CZ 2 Z 3, -C １－６ A haloalkyl or cycloalkyl group {where the cycloalkyl ring is monocyclic or polycyclic}; Z １ is -H, -C １－６ It is an aminoalkyl, -CN, or -halo; Z ２ and Z ３ These are independently -H and -C １－６ Alkyl, -C １－６ Aminoalkyl, -C １－６ Alkyl-O(C) １－６ Alkyl), -halo, heterocycloalkyl, or -C １－６ It is an alkyl-heterocycloalkyl {wherein the heterocycloalkyl or -C}. １－６ The alkyl-heterocycloalkyl ring has 4 to 6 members, and the heterocycloalkyl or -C １－６ One or more H atoms in an alkyl-heterocycloalkyl group are -C １－６ They may be substituted with alkyl groups or 4-6 member heterocycloalkyl groups. A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

6. Y １ ~Y ３ These are, independently, N or CR Ｙ And; R Ｙ is -H, -C １－６ Alkyl or -halo; R ４ is, -C １－６ Alkyl, -C １－６ Alkyl-O-C １－６ Alkyl, -C １－６ The member is a haloalkyl, a 3-7 membered cycloalkyl, or a 4-6 membered heterocycloalkyl {wherein one or more H of the 3-7 membered cycloalkyl or 4-6 membered heterocycloalkyl is -C １－６ It may be substituted with alkyl; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

7. Ring A is phenyl, 5-10 member heteroaryl, 4-6 member heterocycloalkyl, or 4-6 member heterocycloalkenyl {wherein one or more H in the phenyl, 5-10 member heteroaryl, 4-6 member heterocycloalkyl, or 4-6 member heterocycloalkenyl ring is -C １－６ Alkyl, -C １－６ Haloalkyl, -C2-6 alkenyl, -CN, -C(=O)-R Ａ１ , -NO ２ , -NR Ａ２ R Ａ３ , -OR Ａ４ , -S-C １－６ It may be substituted with alkyl, -halo, or 4-6 membered heterocycloalkyl [in this case, one or more H in the 4-6 membered heterocycloalkyl ring is -C １－６ Alkyl, -C １－６ The substituents of the phenyl or 5-10 member heteroaryl ring may be substituted with haloalkyl, -halo, or heterocycloalkyl groups, and the substituents of the phenyl or 5-10 member heteroaryl ring may be linked to each other to form a 5-6 member cycloalkyl or 5-6 member heterocycloalkyl group; R Ａ１ is -H, -NH- (CH ２ ) m-phenyl, -OH, or -O-C １－６ It is an alkyl group {where the -NH-(CH ２ ) One or more H atoms in the m-phenyl ring may be substituted with a -halo; m is 0, 1, or 2; R Ａ２ and R Ａ３ These are independently -H and -C １－６ Alkyl, -C(=O)-C １－６ Alkyl, -C(=O)-C2-6 alkenyl, -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-phenyl {wherein one or more H in the -C(=O)-cycloalkyl, -C(=O)-heterocycloalkyl, or -C(=O)-phenyl ring is -C １－６ Alkyl, -C １－６ {May be substituted with haloalkyl, =O, -halo, or phenyl}; R Ａ４ is -H, -C １－６ Alkyl, or -C １－６ It is a haloalkyl; A compound represented by chemical formula 1 as described in claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, an optical isomer thereof, and a pharmaceutically acceptable salt thereof, wherein the compound represented by chemical formula 1 is selected from the group consisting of the following compounds: Table 16

9. A pharmaceutical composition for the prevention or treatment of cancer, comprising a compound according to any one of claims 1 to 8, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient.

10. The pharmaceutical composition according to claim 9, which inhibits HER2 and / or EGFR.

11. The pharmaceutical composition according to claim 10, which inhibits one or more selected from the group consisting of HER2 L869R, HER2 L755S, HER2 T798I, HER2 T862A, EGFR G719A, EGFR L861Q, EGFR S768I, EGFR G719A / S768I, and EGFR Del19 / T790M.

12. The aforementioned cancers 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 carcinoma, ovarian germ cell tumor, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain tumor, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, and malignant soft tissue tumors. The pharmaceutical composition according to claim 9, comprising one or more selected from the group consisting of uterine cancer, malignant bone tumor, malignant lymphoma, malignant mesothelioma, malignant melanoma, ocular cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary origin, gastric lymphoma, gastric cancer, gastric carcinoid tumor, gastrointestinal stromal tumor, Wilms' tumor, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone tumor, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymic cancer.

13. Use of a compound according to any one of claims 1 to 8, an optical isomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug used for the treatment or prevention of cancer.

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