NOVEL QUINAZOLINE DERIVATIVES AS SOS1 INHIBITORS AND USE THEREOF

Abstract

The present invention relates to novel quinazoline derivative compounds as inhibitors of SOS1 and their uses, and more particularly to novel quinazoline derivative compounds having inhibitory activity against the binding of SOS1 to RAS family proteins and / or RAC1, pharmacologically acceptable salts thereof, or pharmaceutical compositions containing such compounds.

Description

[Technical Field]

[0001] The present invention relates to novel quinazoline derivative compounds as inhibitors of SOS1 and their uses, and more particularly to novel quinazoline derivative compounds having the activity of inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, their pharmacologically acceptable salts, or pharmaceutical compositions containing such compounds. [Background technology]

[0002] RAS family proteins are found in 20-30% of human cancers and are known to include KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey rat sarcoma viral oncogene). RAS regulates cell proliferation through the RAF / MEK / ERK pathway, which leads to activation of mitogen-activated protein kinase (MAPK), and the PI3K / Akt / mTOR pathway, which involves PI3K. Cancer-associated mutations in RAS family proteins inhibit the activity of intrinsic GAP-induced GTPases (GTPases), increasing the population of GTP-bound / active RAS family proteins.

[0003] Meanwhile, RAS proteins act as molecular switches, allowing GTP and GDP to exist in active (GTP-bound) and inactive (GDP-bound) states within cells. Activated, GTP-bound RAS recruits other proteins through the binding of their cognate RAS-binding domains (RBDs), activating effector proteins and then generating downstream signals for various functions. The activity state of RAS is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Binding of GTPase-activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS family proteins.

[0004] Binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promotes GDP release from RAS family proteins, allowing them to bind and activate with GTP. Son of Sevenless (SOS) proteins exist in two isoforms, SOS1 and SOS2, and only SOS1 is phosphorylated by ERK. Growth factor-induced phosphorylation of SOS1 is mostly mediated by ERK, which phosphorylates at least four serine residues in the C-terminal region of SOS1. This suggests that SOS1 plays an important role in negative feedback regulation of the KRAS pathway.

[0005] The SOS1 protein consists of 1,333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HDs) followed by a Dbl homology domain (DH), a pleckstrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins: a catalytic site that binds to GDP-bound RAS family proteins and promotes guanine nucleotide exchange, and an allosteric site that binds to GTP-bound RAS family proteins, causing a further increase in SOS1's catalytic GEF function. Selective pharmacological inhibition of SOS1 catalytic site binding to RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins in the GTP-bound form.

[0006] Such SOS1 inhibitor compounds are expected to inhibit downstream signal transduction (e.g., ERK phosphorylation) of RAS-family proteins. Novel SOS1 inhibitor compounds have been developed that bind to the SOS1 catalytic site (confirmed by crystallography) and simultaneously prevent the binding and activation of RAS family proteins. These compounds exhibit significant inhibitory effects (low IC 50 There are agents in development that have potent potency (potency) and consequently induce a marked decrease in ERK phosphorylation in KRAS-mutant cancer cell lines.

[0007] The present inventors have confirmed that novel quinazoline derivative compounds as SOS1 inhibitors have the activity of inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, and have thereby completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide novel quinazoline derivative compounds that have excellent activity in inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the above compound in a therapeutically effective amount. [Means for solving the problem]

[0010] According to one embodiment of the present invention, there is provided a compound selected from the group consisting of a compound of the following Chemical Formula 1, and pharmaceutically acceptable salts, optical isomers, partial stereoisomers, hydrates, and solvates thereof: [Chemical formula 1] [ka] In the above chemical formula 1, R1 is hydrogen or C 1-4 is alkyl; R2 is hydrogen, C1-4 Alkyl, HaloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 is alkynyl; R3 is R 3a or [ka] and; Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo (=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, HaloC 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a , -(CH2) r -NR a R b and R a and R b are each independently hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -CF2H and C 3-8 carbocyclyl; r is an integer from 0 to 1; m is an integer from 0 to 5; L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and; p is an integer from 0 to 3; q is an integer from 0 to 2; [ka] are each independently 6-10Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 bicyclic heterocyclyl, wherein [ka] C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 A bicyclic heterocyclyl may be unsubstituted or may contain one or more R 3a may be substituted with; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyls include halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -ORc , -NR c R d may be substituted or unsubstituted with, where R c and R d are each independently hydrogen or C 1-6 is alkyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 bridged heterocyclyl, wherein said C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 The bridged heterocyclyl may be unsubstituted or may be substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f wherein R e and R f are each independently hydrogen or C 1-6 is alkyl, Alternatively, the -N(R5)(R6) may be a C group in which R5 and R6 are linked to each other to form a ring together with the nitrogen atom in -N(R5)(R6). 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused Heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 heteroaryl, wherein said C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused Heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl may be unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h wherein R g and R h are each independently hydrogen, C1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy or C 3-8 is a carbocyclyl; L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer from 0 to 2; [ka] is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 bridged heterocyclyl, wherein said C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 The bridged heterocyclyl may be unsubstituted or may be substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i and -NR i R j wherein R i and R j are each independently hydrogen or C1-6 It is alkyl.

[0011] According to another embodiment of the present invention, pharmaceutical compositions and pharmaceutical formulations for the prevention or treatment of various diseases associated with the inhibition of binding of SOS1 to RAS family proteins and / or RAC1 are provided, which contain the above-mentioned compounds in a therapeutically effective amount.

[0012] According to another embodiment of the present invention, there is provided a method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in a subject or cell, comprising administering a pharmaceutically effective amount of the above compound to the subject.

[0013] According to yet another embodiment of the present invention, there is provided a method for inhibiting tyrosine kinase in a subject or cell, comprising administering to the subject a pharmaceutically effective amount of the compound described above.

[0014] According to yet another embodiment of the present invention, there is provided a method for preventing or treating cancer in a subject, comprising administering a pharmaceutically effective amount of the compound described above to the subject.

[0015] According to another embodiment of the present invention, there is provided a use of the compound or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer or tumor. [Effects of the Invention]

[0016] The quinazoline derivative compound of Chemical Formula 1 in the present invention has excellent activity in inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, and has anticancer activity against cancers associated with cell proliferation due to abnormal SOS1 activity, and can be usefully used as a therapeutic agent therefor.

[0017] Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those of ordinary skill in the art related to the present invention. Although preferred methods and samples are described herein, similar or equivalent methods and samples are also included within the scope of the present invention. Numerical values ​​described herein are considered to include the meaning of "about" even if not explicitly stated. The contents of all publications referenced herein are incorporated by reference in their entirety.

[0018] In the above Chemical Formula 1, the residues listed as R1 to R6 are used in the sense that they are commonly understood by those skilled in the art.

[0019] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, unless otherwise specified, and specifically includes, but is not limited to, fluorine and chlorine.

[0020] As used herein, the term "alkyl", unless otherwise specified, refers to a saturated, straight-chain or branched monovalent hydrocarbon radical.

[0021] As used herein, the term "alkenyl," unless otherwise specified, refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, each of which can have an E- or Z-configuration.

[0022] As used herein, the term "alkynyl," unless otherwise specified, refers to a monovalent group derived from an unsaturated, linear or branched hydrocarbon moiety having at least one carbon-carbon triple bond.

[0023] Such alkyl, alkenyl, and alkynyl groups may be linear, i.e., straight-chained, or branched. Depending on their respective definitions, the number of carbon atoms in an alkyl group may be 1, 2, 3, 4, 5, or 6, or 1, 2, 3, or 4. Examples of alkyl are methyl, ethyl, propyl, including n-propyl and isopropyl, butyl, including n-butyl, sec-butyl, isobutyl, and tert-butyl, pentyl, including n-pentyl, 1-methylbutyl, isopentyl, neopentyl, and tert-pentyl, and hexyl, including n-hexyl, 3,3-dimethylbutyl, and isohexyl. The double and triple bonds between the alkenyl and alkynyl groups may be in any position. Examples of alkenyl and alkynyl include ethenyl, prop-1-enyl, prop-2-enyl (allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl, and hex-5-ynyl, although substituted alkyl, alkenyl, and alkynyl groups may be substituted at any position as long as the respective compounds are sufficiently stable and suitable for the desired purpose, such as use as a pharmaceutical substance.

[0024] The term "carbocyclyl" as used herein, unless otherwise specified, refers to a substituted or unsubstituted cyclic alkyl, and may refer to a mono- or bicycloaliphatic. Preferably, carbocyclyl includes, but is not limited to, aryl, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl. More preferably, carbocyclyl may include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, or any possible isomer thereof.

[0025] In the present invention, the term "heterocyclyl," unless otherwise specified, may refer to a monocyclic, bicyclic or higher substituted or unsubstituted cyclic alkyl containing one or more heteroatoms, specifically 1 to 4 heteroatoms, selected from O, N, and S. Preferably, heterocyclyl includes, but is not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl. More preferably, heterocyclyl includes, but is not limited to, piperazinyl, piperidinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspirooctanyl, and similar groups. For example, C 2-10 In the case of heterocyclyl, the number of carbon atoms is indicated by C 2-10 means a ring size of 3 or more members containing one or more heteroatoms.

[0026] In the present invention, the term "aryl", unless otherwise specified, refers to a substituted or unsubstituted aromatic group, and can include, for example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof, without limitation.

[0027] The term "heteroaryl," as used herein, unless otherwise specified, refers to a monocyclic or bicyclic or higher aromatic group containing one or more, e.g., one to four, heteroatoms selected from O, N, and S. Preferred examples of monocyclic heteroaryls include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups. Preferred examples of bicyclic heteroaryls include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl, and similar groups.

[0028] In the present invention, a numerical range indicated using the term "to" means a range that includes the numerical values ​​stated before and after the term "to" as the lower and upper limits, respectively.

[0029] As used herein, the term "SOS1 binding to RAS family proteins and / or RAC1" refers to the binding of SOS1 to the catalytic site of a RAS family protein, and "activity inhibiting binding" refers to preventing SOS1-mediated activation of a RAS family protein in its GTP-bound form.

[0030] The term "SOS1 inhibitor compound" as used in the present invention means a compound that inhibits signal transmission to downstream cells by RAS-family proteins, such as ERK phosphorylation, and specifically, "SOS1 inhibitor compound" means a compound that binds to the SOS1 catalytic site and prevents binding to and activation of RAS-family proteins.

[0031] The term "optical isomer" as used herein refers to various stereoisomers and geometric isomers that may exist for a compound according to the present invention, unless otherwise specified. The compound of Formula 1 according to one embodiment of the present invention may have an asymmetric carbon center (chiral carbon) and therefore may exist as an enantiomer (R or S isomer), a racemate, a partial stereoisomer, or any mixture thereof, and all of these isomers and mixtures are included within the scope of the present invention. The optically active (R)- and (S)-isomers can be resolved using conventional techniques or prepared using chiral synthons or chiral reagents. When a compound contains a double bond, the substituent may be E or Z. When a compound contains a disubstituted carbocyclyl, it may be cis or trans. Furthermore, when a compound of Formula 1 contains a bridged ring, it may exist as an exo or endo isomer. All tautomeric forms are also included.

[0032] The term "asymmetric carbon atom" as used herein means, unless otherwise specified, a carbon atom in a molecule that is bonded to four different atoms, atomic groups, or functional groups. Compounds containing such asymmetric carbon atoms have optical rotation or optical isomers. Specifically, the compound having the structure of Chemical Formula 1 and having the asymmetric carbon atom may be a compound having the structure of Chemical Formula 1a or Chemical Formula 1b below. Meanwhile, a 1:1 mixture of a pair of enantiomers is referred to as a "racemic" mixture.

[0033] [Chemical formula 1a] [ka]

[0034] In the above chemical formula 1a, [ka] , R1 to R3, X1, L1, [ka] , m and n are defined as in Chemical Formula 1.

[0035] [Formula 1b] [ka]

[0036] In the above chemical formula 1b, [ka] , R1 to R3, X1, L1, [ka] , m and n are defined as in Chemical Formula 1.

[0037] The compound of Formula 1 according to one embodiment above, its optical isomers, and its partial stereoisomers may exist in the form of a solvate. The term "solvate" may also include a molecular complex containing the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. A complex in which the solvent molecule is water is also called a "hydrate."

[0038] The compounds of Formula 1 according to one embodiment above, their optical isomers, their partial stereoisomers and their solvates may exist in the form of pharmaceutically acceptable salts.

[0039] The term "pharmaceutically acceptable salt" as used herein means a salt that has low toxicity to the human body and does not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts between pharmaceutically acceptable free acids and base compounds of Chemical Formula 1, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts), organic base addition salts between organic bases and the carboxylic acid structure of Chemical Formula 1, and amino acid addition salts.

[0040] Preferred salt forms of the compounds according to the present invention include salts with inorganic or organic acids. In this case, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and bromic acid may be used. Organic acids such as acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, and glutamic acid may be used. Organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used to prepare amino acid addition salts include natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases can be used in addition to the inorganic acids, organic acids, organic bases, and amino acids listed above.

[0041] The salts can be prepared by a conventional method, for example, by dissolving the compound of Formula 1 in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, adding a free acid or free base, and then crystallizing the solution.

[0042] The details of the above-mentioned prevention or treatment method may be applied to the above-mentioned explanation for the pharmaceutical composition according to one embodiment of the present invention.

[0043] In the present invention, the term "treatment" is used as a concept that includes all of the treatment, improvement, amelioration, and management of a disease.

[0044] The term "prevent" or "prevention" as used herein means preventing a disease, for example, preventing a disease, condition or disorder in an individual who may be prone to the disease, condition or disorder, but who has not yet experienced or exhibited the pathology or symptoms of the disease.

[0045] As used herein, the term "individual" or "patient" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and humans.

[0046] The present invention will now be described in more detail.

[0047] [Chemical formula 1] [ka]

[0048] In the above chemical formula 1, R1 is hydrogen or C 1-4 is alkyl; R2 is hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 is alkynyl; R3 is R 3a or -L2- [ka] and; Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo (=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, HaloC 1-6Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and R a and R b are each independently hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -CF2H and C 3-8 carbocyclyl; r is an integer from 0 to 1; m is an integer from 0 to 5; L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and; p is an integer from 0 to 3; q is an integer from 0 to 2; [ka] are each independently 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 bicyclic heterocyclyl, wherein [ka] C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 A bicyclic heterocyclyl may be unsubstituted or may contain one or more R 3a may be substituted with; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyls include halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d may be substituted or unsubstituted with, where R c and R d are each independently hydrogen or C 1-6 is alkyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 bridged heterocyclyl, wherein said C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused Carbocyclyl, C 6-14 Fused Heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 The bridged heterocyclyl may be unsubstituted or may be substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f wherein R e and R f are each independently hydrogen or C 1-6 is alkyl, Alternatively, the -N(R5)(R6) may be a C group in which R5 and R6 are linked to each other to form a ring together with the nitrogen atom in -N(R5)(R6). 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused Heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 heteroaryl, wherein said C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused Heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl may be unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h wherein R g and R h are each independently hydrogen, C 1-6 Alkyl, Hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy or C 3-8 is a carbocyclyl; L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer from 0 to 2; [ka] is C3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 bridged heterocyclyl, wherein said C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 The bridged heterocyclyl may be unsubstituted or may be substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i and -NR i R j wherein R i and R j are each independently hydrogen or C 1-6 It is alkyl.

[0049] Preferably, the compound of the present invention selected from the compounds of formula 1, pharmaceutically acceptable salts, optical isomers, partial stereoisomers, hydrates and solvates thereof is [ka] are each independently, C 6-10 Aryl or C 4-10 It may also be heteroaryl.

[0050] Preferably, in the compound of the present invention selected from the compounds of formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof, R 3a are each independently halogen, hydroxy, cyano, amino, amine, nitro, C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, -CF2H, C 6-10 Aryl, C 3-6 Cyclyl, -(CH2) r -C 2-6 Heterocyclyl, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b where R a and R b are each independently hydrogen, C 1-6 It may be alkyl, -CF3 or -CF2H.

[0051] Preferably, in the compound of the present invention selected from the compounds of formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof, R4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 heterocyclyl; R and R are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 heterocyclyl, or the -N(R5)(R6) is C 2-9 It may also be a heterocyclyl.

[0052] According to another embodiment of the present invention, the compound represented by Formula 1 may be represented by Formula 2 below: [Chemical formula 2] [ka]

[0053] In the above chemical formula 2, L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3, or -NH2, except when both Z1 and Z2 are hydrogen; R 4a is hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 is heterocyclyl; [ka] is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl is unsubstituted or optionally substituted with one or more functional groups selected from the group consisting of halogen or —CH.

[0054] According to another embodiment of the present invention, the compound represented by Formula 1 may be represented by Formula 3: [Chemical formula 3] [ka]

[0055] In the above chemical formula 3, L3 is a direct bond or -C(O)-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3, or -NH2, except when both Z1 and Z2 are hydrogen; R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 is heterocyclyl, Alternatively, the -N(R 5a )(R 5b ) is R 5a and R 5b are connected to each other and -N(R 5a )(R 5b C that forms a ring with the nitrogen atom in 2-9 is heterocyclyl; [ka] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl is unsubstituted or optionally substituted with one or more functional groups selected from the group consisting of halogen or —CH. According to another embodiment of the present invention, the compound represented by Formula 2 may be represented by Formula 4: [Chemical formula 4] [ka]

[0056] In the above chemical formula 4, L4 is a direct bond, -C(O)- or -O-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3, or -NH2, except when both Z1 and Z2 are hydrogen; [ka] is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, or tetrahydropyranyl, wherein said morpholinyl, piperazinyl, thiazolidinyl, or tetrahydropyranyl is unsubstituted or optionally substituted with one or more functional groups selected from the group consisting of halogen or —CH3. According to another embodiment of the present invention, the compound represented by Formula 3 may be represented by Formula 5: [Chemical formula 5] [ka]

[0057] In the above chemical formula 5, L5 is a direct bond or -C(O)-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3, or -NH2, except when both Z1 and Z2 are hydrogen; [ka] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or optionally substituted with one or more functional groups selected from the group consisting of halogen or —CH.

[0058] In addition, preferred examples of the compound of the above Chemical Formula 1 according to the present invention are as follows, but are not limited to these: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone; (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone; (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone; (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone; (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile; (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine; (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine; (R)—N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; and (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 -(Tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine.

[0059] The method for preparing the compound of Formula 1 in the present invention is not particularly limited, but it can be synthesized, for example, by the preparation method of Reaction Scheme 1 or Reaction Scheme 2 below:

[0060] [Reaction Scheme 1] [ka]

[0061] In the above reaction formula 1, [ka] , R1, R2, R3, R4, m and [ka] is as defined in Chemical Formula 1 above, but is not limited thereto.

[0062] [Step-1] 2-Bromoterephthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5 to 5°C and refluxed for 4 to 6 minutes. After mixing sulfuric acid and nitric acid, this mixture was slowly added dropwise to the reaction mixture at 0 to 5°C. After the addition was complete, the mixture was refluxed at 95-110°C for 1 to 3 hours. Upon completion of the reaction, the mixture was cooled to room temperature and refluxed at room temperature for 11 to 13 hours. Ice water was slowly added dropwise to the reaction mixture. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting solution was concentrated under reduced pressure to obtain the title compound.

[0063] [Step 2] B (1 equivalent) prepared in Step 1 above, sodium acetate (2.2 equivalents), sodium hydroxide (3 equivalents), and copper (0.01 equivalents) were dissolved in distilled water and refluxed at 110-130°C for 1.5-3 hours under microwave irradiation. Upon completion of the reaction, the solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with water. The filtered aqueous layer was acidified with 6N hydrochloric acid to a pH of 1-2. The acidified aqueous layer was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0064] [Step-3] C (1 equivalent) obtained in Step 2 above and sulfuric acid (1 equivalent) were dissolved in methanol and refluxed at 65-75°C for 60-70 hours with stirring. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. This was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0065] [Step-4] D (1 equivalent) obtained in Step 3 above, methyl iodide (8 equivalents), and potassium carbonate (8 equivalents) were dissolved in acetone and refluxed at 50-70°C for 16-24 hours with stirring. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in distilled water and ethyl acetate, extracted three times with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0066] [Step-5] E (1 equivalent) prepared in Step 4 above was dissolved in ethyl acetate:ethanol and Pd / C was added. The reaction solution was stirred at 45-55°C under hydrogen gas for 16-24 hours. Upon completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC to obtain the title compound.

[0067] [Step-6] The F (1 equivalent) obtained in Step 5 above was dissolved in tetrahydrofuran, and 4% potassium hydroxide was slowly added dropwise. The mixture was stirred at 65-75°C for 2-4 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic layer, and the resulting aqueous layer was acidified with 1N hydrochloric acid to a pH of 1-2 to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with distilled water. The filtered solid was dried in an oven dryer at 50-60°C to obtain the title compound.

[0068] [Step-7] G (1 equivalent) obtained in Step 6 above, acetamidine hydrochloride (2 equivalents), and sodium acetate (2 equivalents) were dissolved in 2-methoxyethanol and stirred under reflux at 140-160°C for 12-20 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature, and distilled water was added dropwise. The mixture was stirred at 0-5°C for 0.5-1 hour to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with distilled water. The filtered solid was dried in an oven dryer at 50-60°C to obtain the title compound.

[0069] [Step-8] The H (1 equivalent) obtained in Step 7 above, amine (1.5 equivalents), HATU (3 equivalents), and DIPEA (5 equivalents) were dissolved in DMF and refluxed at room temperature for 2-3 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with ethyl acetate to obtain the title compound.

[0070] [Step-9] The I (1 equivalent) obtained in Step 8 above was dissolved in phosphoryl chloride and refluxed at 105-114°C for 1-2.5 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound.

[0071] [Step-10] J (1 equivalent) prepared in Step 9 above, aniline (1.1 equivalents), and DIPEA (4 equivalents) were dissolved in DMF and refluxed at 95-110°C for 12-15 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0072] [Reaction Scheme 2] [ka]

[0073] In the above reaction scheme 2, [ka] , R1, R2, R3, R4, m and [ka] is as defined in Chemical Formula 1 above, but is not limited thereto.

[0074] [Step-1] Methyl 3-methoxy-4-methylbenzoate (1 equivalent) was mixed with acetic acid and water, and then bromine (1.1 equivalents) was added dropwise. After the addition was complete, the mixture was refluxed and stirred at 50-60°C for 1-2 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. The aqueous solution was extracted with a hexane / ether solution, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered solution was concentrated under reduced pressure to obtain the title compound.

[0075] [Step 2] B (1 equivalent) obtained in Step 1 above, N-bromosuccinimide (0.9 equivalents), and azobisisobutyronitrile (0.2 equivalents) were dissolved in chloroform and refluxed at 65-70°C for 1.5-3 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. After extraction with ethyl acetate, the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0076] [Step-3] C (1 equivalent) obtained in [Step 2] above, amine (1.1 equivalents), and potassium carbonate (2 equivalents) were dissolved in acetonitrile and stirred at 20-30°C for 17-20 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. After extraction with ethyl acetate, the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC to obtain the title compound.

[0077] [Step-4] The D (1 equivalent) obtained in Step 3 above, tert-butyl carbamate (1.1 equivalents), xanthophos (0.2 equivalents), Pd2(dba)3dba (0.1 equivalents), and cesium carbonate (3 equivalents) were dissolved in 1,4-dioxane and stirred at 100-120 °C for 1-3 hours. Upon completion of the reaction, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC to obtain the title compound.

[0078] [Step-5] E (1 equivalent) obtained in Step 4 above was dissolved in acetonitrile, and a 4N solution of hydrogen chloride in dioxane was added dropwise. The mixture was refluxed and stirred at 70-90°C for 1-3 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding an aqueous solution of sodium bicarbonate dropwise. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to obtain the title compound.

[0079] [Step-6] The F (1 equivalent) obtained in Step 5 above, aniline (1.5 equivalents), PyBOP (1.5 equivalents), and DBU (2.5 equivalents) were dissolved in acetonitrile and stirred at 75-85°C for 4-6 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0080] In addition, the method for preparing the compound of Formula 1 in the present invention is not particularly limited, but it can be synthesized, for example, by the preparation method of Reaction Scheme 3 below:

[0081] [Reaction Scheme 3] [ka]

[0082] In the above reaction scheme 3, [ka] , R1, R2, R3, R5, R6, m and [ka] is as defined in Chemical Formula 1 above, but is not limited thereto.

[0083] [Step-1] 2-Bromoterephthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5 to 5°C and refluxed for 4 to 6 minutes. After mixing sulfuric acid and nitric acid, this mixture was slowly added dropwise to the reaction mixture at 0 to 5°C. After the addition was complete, the mixture was refluxed at 95 to 110°C for 1 to 3 hours. Upon completion of the reaction, the mixture was cooled to room temperature and refluxed at room temperature for 11 to 13 hours. Ice water was slowly added dropwise to the reaction mixture. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting solution was concentrated under reduced pressure to obtain the title compound.

[0084] [Step 2] The B (1 equivalent) obtained in Step 1 above and sulfuric acid (1 equivalent) were dissolved in methanol and refluxed at 65-75°C for 60-70 hours with stirring. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. This was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0085] [Step-3] C (1 equivalent) obtained in Step 2 above, amine (5 equivalents), and DIPEA (10 equivalents) were dissolved in DMF and refluxed at 95-105°C for 1-2 hours with stirring. Upon completion of the reaction, the reaction solution was cooled to room temperature and added dropwise to distilled water. The mixture was filtered under reduced pressure to obtain the title compound.

[0086] [Step-4] The D (1 equivalent) obtained in Step 3 above and zinc dust (3.5 equivalents) were dissolved in a dioxane:distilled water mixture and refluxed at 25-30°C for 0.5-1 hour. After stirring, the reaction mixture was cooled to 0-5°C, and then ammonium chloride (5 equivalents) was added dropwise. After the dropwise addition, the mixture was refluxed and stirred at 25-30°C for 1-3 hours. Upon completion of the reaction, the reaction mixture was filtered through a filter filled with Celite and washed with ethyl acetate. This was dissolved in distilled water and ethyl acetate, extracted three times with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0087] [Step-5] E (1 equivalent) prepared in Step 4 above and acetonitrile (8 equivalents) were dissolved in 4N hydrochloric acid solution in dioxane, and the reaction solution was stirred at 85-95°C for 2.5-3.5 hours using a sealed tube. Upon completion of the reaction, the reaction solution was filtered and washed with hexane. The filtered solid was neutralized with aqueous sodium bicarbonate solution and then filtered under reduced pressure to obtain the title compound.

[0088] [Step-6] The F (1 equivalent) obtained in Step 5 above was dissolved in phosphoryl chloride and stirred at 110-130°C for 2-4 hours. Upon completion of the reaction, the organic layer was removed by concentration under reduced pressure. The resulting residue was dissolved in dichloromethane and neutralized with aqueous sodium bicarbonate at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0089] [Step-7] G (1 equivalent) obtained in Step 6 above, aniline (1.3 equivalents), and DIPEA (3 equivalents) were dissolved in DMF and refluxed at 85-100°C for 12-15 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0090] [Step-8] The H (1 equiv.) obtained in [Step 7] above was dissolved in a mixture of tetrahydrofuran:methanol:water, and sodium hydroxide (5 equiv.) was added. The mixture was refluxed at 25-30°C for 1-3 hours. Upon completion of the reaction, 2N aqueous HCl was added dropwise to the mixture, the pH was adjusted to 5-6, and the mixture was washed with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The title compound was obtained without further purification. The amine (1.1 equiv.), HATU (1.3 equiv.), and DIPEA (3 equiv.) were dissolved in DMF and refluxed at 25-30°C for 1-3 hours. Upon completion of the reaction, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain the title compound.

[0091] Although the preparation method of Chemical Formula 1 has been described as a specific example, specific reaction conditions, such as the reaction solvent, base, amount of reactants, etc., are not limited to those described herein and should not be construed as limiting the scope of the present invention in any manner.

[0092] The pharmaceutical composition of the present invention is also useful for preventing or treating various diseases associated with RAS family proteins and / or RAC1, since the compound of Chemical Formula 1 contained therein inhibits the binding of SOS1 to RAS family proteins and / or RAC1.

[0093] In one embodiment, the compounds of the present invention have little inhibitory effect on cytochrome P450 enzyme (CYP) subtypes, thereby reducing side effects such as drug-drug interactions that may occur due to decreased activity of P450 enzyme (CYP) subtypes, making them useful when administering multiple drug combinations. In a specific embodiment, the compounds of the present invention have a structure of Chemical Formula 2 or Chemical Formula 3 and have little inhibitory effect on cytochrome P450 enzyme subtypes. In a more specific embodiment, the compounds of the present invention have a structure of Chemical Formula 4 or Chemical Formula 5 and are excellent in maintaining activity against cytochrome P450 enzyme subtypes. For example, the inhibition of cytochrome P450 enzyme (CYP) subtype activity by the compounds of Chemical Formula 4 or 5 of the present invention is observed at IC 50 The value may be at least 20 μM or greater.

[0094] According to another embodiment of the present invention, there is provided a pharmaceutical composition for prevention or treatment comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0095] According to another embodiment of the present invention, there is provided a pharmaceutical formulation comprising the above-described pharmaceutical composition.

[0096] The pharmaceutical formulations of the present invention may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or parenteral dosage forms such as injections for intramuscular, intravenous or subcutaneous administration, preferably oral dosage forms.

[0097] In addition, the pharmaceutical preparation may contain, in addition to the active ingredient, conventional non-toxic pharmaceutically acceptable additives, such as one or more selected from the group consisting of carriers, reinforcing agents, and excipients, and may be formulated by conventional methods.

[0098] Excipients that can be used in the pharmaceutical formulation of the present invention include, but are not limited to, sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonicity agents, adsorbents, disintegrants, antioxidants, preservatives, fluidizing agents, fillers, flavoring agents, etc. For example, excipients that may be used include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0099] When the pharmaceutical preparation of the present invention is of oral administration type, examples of the carrier to be used include, but are not limited to, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, etc.

[0100] When the pharmaceutical preparation of the present invention is in the form of an injection, the carrier may include, but is not limited to, water, saline, aqueous glucose solution, aqueous sugar analogue solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0101] For use of the compounds according to the present invention as medicines, the latter are prepared in the form of pharmaceutical preparations, which contain, in addition to the active ingredient for oral or parenteral administration, suitable pharmaceutical organic or inorganic inert carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oils, polyalkylene glycols, etc. Pharmaceutical preparations can be in solid form, for example, tablets, dragees, suppositories, or capsules, or in liquid form, for example, as solutions, suspensions, or emulsions. They may also contain optional auxiliary substances, such as preservatives, stabilizers, wetting agents, or emulsifiers; salts for changing osmotic pressure, or buffers.

[0102] For parenteral administration, injectable solutions or suspensions are particularly preferred.

[0103] As carrier systems, surfactants such as bile salts or animal or plant phospholipids, or mixtures thereof, and liposomes or components thereof may also be used.

[0104] For oral administration, tablets, dragees or capsules containing talc and / or a hydrocarbon vehicle or binder, such as lactose, corn or potato starch, are particularly suitable, but they may also be administered in liquid form, for example as a juice to which sweeteners have been added.

[0105] In addition, the dosage of the compound of Formula 1 according to the present invention to the human body is preferably in the range of 0.1 mg / day to 2,000 mg / day for an adult patient weighing 70 kg. The compound according to the present invention can be administered once or in several divided doses per day. However, the above dosage may vary depending on the patient's health condition, age, weight, and sex, as well as the dosage form and the severity of the disease, and therefore the scope of the present invention is not limited to the above dosage.

[0106] According to another embodiment of the present invention, there is provided a use of a compound selected from the compound of Chemical Formula 1 of the present invention, its pharmaceutically acceptable salt, optical isomer, partial stereoisomer, hydrate and solvate, or a pharmacologically acceptable salt thereof for the prevention or treatment of cancer or tumor.

[0107] According to another embodiment of the present invention, there is provided a method for preventing or treating cancer, comprising administering to a subject a compound selected from the group consisting of the compound of Formula 1, its pharmaceutically acceptable salt, optical isomer, partial stereoisomer, hydrate and solvate, or a pharmacologically acceptable salt thereof. Preferably, the subject refers to, but is not limited to, an individual or a patient.

[0108] According to another embodiment of the present invention, there is provided a method for treating cancer in a subject in need of administration of a therapeutic standard formulation containing a compound selected from the compound of Chemical Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a partial stereoisomer, a hydrate, and a solvate thereof, or a pharmacologically acceptable salt thereof, comprising administering a therapeutically effective amount of a therapeutic standard formulation containing an inhibitor of the compound and a therapeutic standard formulation.

[0109] According to another embodiment of the present invention, there is provided a method for treating cancer in a subject in need of administration of a composition comprising a compound selected from the group consisting of the compound of Chemical Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a partial stereoisomer, a hydrate, and a solvate thereof, or a pharmacologically acceptable salt thereof, in a therapeutically effective amount.

[0110] According to another embodiment of the present invention, there is provided a method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in a subject or cell, comprising administering to a subject a compound selected from the compound of Chemical Formula 1 of the present invention, its pharmaceutically acceptable salt, optical isomer, partial stereoisomer, hydrate and solvate, or a pharmacologically acceptable salt thereof.

[0111] According to yet another embodiment of the present invention, there is provided a method for inhibiting tyrosine kinase in a subject or cell, comprising administering to the subject a compound selected from the compound of Chemical Formula 1 of the present invention, its pharmaceutically acceptable salt, optical isomer, partial stereoisomer, hydrate and solvate, or a pharmacologically acceptable salt thereof.

[0112] According to another embodiment of the present invention, there is provided a method for preventing or treating cancer in a subject, comprising administering to the subject a compound selected from the compound of Chemical Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a partial stereoisomer, a hydrate, and a solvate thereof, or a pharmacologically acceptable salt thereof.

[0113] According to another embodiment of the present invention, there is provided a method for preventing or treating cancer, which can be prevented or treated by inhibiting the binding of SOS1 protein to RAS family proteins and / or RAC1 in a subject or cell, comprising administering to a subject a compound selected from the compound of Chemical Formula 1 of the present invention, its pharmaceutically acceptable salt, optical isomer, partial stereoisomer, hydrate and solvate, or a pharmacologically acceptable salt thereof.

[0114] The present invention will be described in more detail below with reference to the following examples and experimental examples. However, these examples and experimental examples are intended to aid in understanding the present invention and are not intended to limit the scope of the present invention in any way.

[0115] Example 1: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid [ka] 2-Bromoterephthalic acid (13.8 g, 56.32 mmol) was slowly added dropwise to 78 mL of sulfuric acid at 0°C and stirred for 5 minutes. 7.5 mL of sulfuric acid and 17.5 mL of nitric acid were mixed and then slowly added dropwise to the reaction solution at 0°C. After the addition was complete, the mixture was refluxed and stirred at 100°C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted three times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered solution was concentrated under reduced pressure to obtain 16 g of the title compound without further purification. 1 H-NMR (300MHz, DMSO-d6): δ8.34(s,1H), 8.17(s,1H).

[0116] [Step 2] Production of 2-hydroxy-5-nitroterephthalic acid [ka] 2-Bromo-5-nitroterephthalic acid (10.5 g, 36.21 mmol), sodium acetate (6.6 g, 79.65 mmol), sodium hydroxide (4.35 g, 108.63 mmol), and copper (46.5 mg, 0.72 mmol) prepared in Step 1 above were dissolved in 60 mL of distilled water and refluxed at 120 °C for 2 hours under microwave irradiation. Upon completion of the reaction, the solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with water. The filtered aqueous layer was acidified with 6 N hydrochloric acid to a pH of 1-2. The acidified aqueous solution was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the title compound (7 g) in 85% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.42(s,1H), 7.15(s,1H).

[0117] [Step 3] Preparation of dimethyl 2-hydroxy-5-nitroterephthalate [ka] 2-Hydroxy-5-nitroterephthalic acid (7 g, 30.82 mmol) obtained in Step 2 above and sulfuric acid (35 mL, 653.04 mmol) were dissolved in 330 mL of methanol and refluxed with stirring at 70°C for 65 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. This was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain 7.9 g of the title compound without further purification. 1 H-NMR (300MHz, DMSO-d6): δ8.43(s,1H), 6.85(s,1H), 3.83(s,6H). [Step 4] Preparation of dimethyl 2-methoxy-5-nitroterephthalate [ka] Dimethyl 2-hydroxy-5-nitroterephthalate (7.9 g, 30.82 mmol) obtained in Step 3 above, methyl iodide (15.3 mL, 246.56 mmol), and potassium carbonate (34 g, 246.56 mmol) were dissolved in 310 mL of acetone and refluxed at 60 °C for 21 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in distilled water and ethyl acetate (1:1 vol / vol) and extracted three times with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 6.1 g of the title compound in 73% yield.

[0118] 1 H-NMR (300MHz, CDCl3): δ8.57(s,1H), 7.15(s,1H), 4.05(s,3H), 3.98(s,3H), 3.96(s,3H).

[0119] [Step 5] Preparation of dimethyl 2-amino-5-methoxy terephthalate [ka] Dimethyl 2-methoxy-5-nitroterephthalate (6.1 g, 22.50 mmol) prepared in Step 4 above was dissolved in 122 mL of ethyl acetate:ethanol (1:4, vol / vol), and Pd / C (600 mg, 10 wt%) was added. The reaction solution was stirred at 50 °C under hydrogen gas for 20 h. Upon completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give the title compound 5 g in 93% yield. 1 H-NMR (300MHz, CDCl3): δ7.38(s,1H), 7.05(s,1H), 5.50(s,2H), 3.86(s,6H), 3.80(s,3H).

[0120] [Step 6] Preparation of 2-amino-5-methoxyterephthalic acid [ka] Dimethyl 2-amino-5-methoxyterephthalate (5 g, 20.93 mmol) obtained in Step 5 above was dissolved in 115 mL of tetrahydrofuran, and 115 mL of 4% potassium hydroxide was slowly added dropwise. The mixture was stirred at 70 °C for 3 hours. Upon completion of the reaction, the organic layer was removed by concentration under reduced pressure, and the resulting aqueous layer was acidified with 1N hydrochloric acid to a pH of 1-2 to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with distilled water. The filtered solid was dried in an oven dryer at 55 °C to obtain 4.3 g of the title compound in 98% yield. 1 H-NMR (300MHz, DMSO-d6): δ7.30(s,1H), 7.01(s,1H), 3.70(s,3H).

[0121] [Step-7] Preparation of 6-methoxy-2-methyl-4-oxo-1,4-dihydroquinazoline-7-carboxylic acid [ka] 2-Amino-5-methoxyterephthalic acid (4.3 g, 20.51 mmol) obtained in Step 6 above, acetamide hydrochloride (3.86 g, 41.02 mmol), and sodium acetate (3.38 g, 40.77 mmol) were dissolved in 86 mL of 2-methoxyethanol and refluxed at 150 °C for 15 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature, and distilled water was added dropwise. The mixture was stirred at 0 °C for 0.5 hours to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with distilled water. The filtered solid was dried in an oven at 55 °C to obtain 3.3 g of the title compound in 69% yield. 1 H-NMR (300MHz, DMSO-d6): δ13.19(s,1H), 12.26(s,1H), 7.70(s,1H), 7.57(s,1H), 3.90(s,3H), 2.34(s,3H).

[0122] [Step-8] Preparation of 6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1H)-one [ka] 6-Methoxy-2-methyl-4-oxo-1,4-dihydroquinazoline-7-carboxylic acid (300 mg, 1.28 mmol) obtained in Step 7 above, morpholine (0.18 mL, 1.92 mmol), HATU (1.44 g, 3.84 mmol), and DIPEA (1.2 mL, 6.40 mmol) were dissolved in 4.5 mL of DMF and refluxed at room temperature for 2.5 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature to obtain a solid product. The resulting solid was filtered under reduced pressure and washed with ethyl acetate to obtain 255 mg of the title compound in 66% yield. 1 H-NMR (300MHz, DMSO-d6): δ12.24(s,1H), 7.55(s,1H), 7.41(s,1H), 3.90(s,3H), 3.68(m,4H), 3.52(m,2H), 3.11(m,2H), 2.51(s,3H).

[0123] [Step-9] Preparation of (4-chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholine)methanone [ka] 6-Methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1H)-one (255 mg, 0.84 mmol) obtained in Step 8 above was dissolved in 14 mL of phosphoryl chloride and refluxed at 110°C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 25:1 to 10:1 (v / v)) to give 221 mg of the title compound in 82% yield. 1 H-NMR (300MHz, DMSO-d6): δ7.86(s,1H), 7.52(s,1H), 4.01(s,3H), 3.67(m,4H), 3.50(m,2H), 3.14(m,2H), 2.50(s,3H).

[0124] [Step-10] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] (4-Chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholine)methanone (70 mg, 0.22 mmol) prepared in Step 9 above, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (57 mg, 0.24 mmol) synthesized by the method proposed in WO2018115380, and DIPEA (0.15 mL, 0.88 mmol) were dissolved in 1 mL of DMF and refluxed at 100 °C for 13 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to obtain 60 mg of the title compound in 56% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.29(d,1H), 7.85(s,1H), 7.40(s,1H), 6.90(d,2H), 6.71(s,1H), 5.62( m,1H), 5.57(s,2H), 3.94(s,3H), 3.50(m,4H), 3.37(m,2H), 3.11(m,2H), 2.50(s,3H), 1.58(m,3H). MS (ESI+, m / z): 490.2 [M+H] +

[0125] Example 2: (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone [Step 1] Preparation of (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that 1-(4-bromothiophen-2-yl)ethan-1-amine (100 mg, 0.47 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, and DMAc was used instead of DMF, to obtain 156 mg of the title compound in 68% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.40(d,1H), 7.77(s,1H), 7.51(s,1H), 7.43(s,1H), 7.10(s,1H) , 5.90(m,1H), 3.91(s,3H), 3.65(m,4H), 3.48(m,2H), 3.11(m,2H), 2.49(m,3H), 1.72(m,3H).

[0126] [Step 2] Preparation of 2-(5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde [ka] (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (156 mg, 0.32 mmol) prepared in Step 1 above, (2-formylphenyl)boronic acid (57 mg, 0.38 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), and potassium carbonate (177 mg, 1.28 mmol) were dissolved in 3 mL of dioxane:water (5:1) and stirred at 100 °C for 5 h. Upon completion of the reaction, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. Water was added dropwise to the combined organic layer, which was then extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=100:1 to 10:1 (v / v)) to give 143 mg of the title compound in 88% yield. 1H-NMR (300MHz, DMSO-d6): δ10.08(s,1H), 8.40(m,1H), 7.90(d,1H), 7.87(s,1H), 7.73(m,1H), 7.70(m,3H), 7.51 (s,1H), 7.32(s,1H), 6.00(m,1H), 4.09(s,3H), 3.65(m,4H), 3.50(m,2H), 3.11(m,2H), 2.49(m,3H), 1.79(m,3H).

[0127] [Step 3] Preparation of (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone [ka] 2-(5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde (143 mg, 0.28 mmol) prepared in Step 2 above, 2.0 M methylamine (0.3 mL, 0.55 mmol), acetic acid (0.03 mL, 0.55 mmol), and sodium triacetoxyborohydride (117 mg, 0.55 mmol) were dissolved in 2 mL of dichloroethane and stirred at room temperature for 16 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by the dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol=50:1 to 7:1 (v / v)) to give 80 mg of the title compound in 56% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.45(m,1H), 7.81(s,1H), 7.48(m,3H), 7.29(m,4H), 6.00(m,1H), 4.09(m,3H) , 3.65(m,4H), 3.58(m,2H), 3.50(m,2H), 3.11(m,2H), 2.51(m,3H), 2.23(s,3H), 1.94(m,1H), 1.71(m,3H). MS (ESI +, m / z): 532.2 [M + H] +

[0128] Example 3: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone [ka] The process of Example 1 was repeated except that cis-2,6-dimethylpiperazine (270 mg, 2.34 mmol) was used instead of morpholine in [Step-8] of Example 1, to obtain 14 mg of the title compound in 34% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.28(d,1H), 7.84(m,1H), 7.36(d,1H), 6.93(m,2H), 6.72(s,1H), 5.62(m,3H), 4.41( m,1H), 3.92(s,3H), 3.07(m,1H), 2.68(m,3H), 2.40(d,3H), 2.28(m,3H), 1.60(m,3H), 1.03(d,3H), 0.82(m,3H). MS (ESI +, m / z): 517.3 [M + H] +

[0129] Example 4: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone [ka] The process of Example 1 was repeated except that thiomorpholine (0.24 mL, 2.56 mmol) was used instead of morpholine in [Step-8] of Example 1, to give 60 mg of the title compound in 56% yield. 1H-NMR (300MHz, DMSO-d6): δ8.27(d,1H), 7.85(d,1H), 7.41(s,1H), 6.88(m,2H), 6.71(s,1H) , 5.59(m,3H), 3.88(m,5H), 3.36(m,2H), 2.73(m,2H), 2.50(m,2H), 2.38(s,3H), 1.58(m,3H). MS (ESI +, m / z): 506.2 [M + H] +

[0130] Example 5: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone [ka] The process of Example 1 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (159 mg, 1.41 mmol) was used instead of morpholine in Step 8 of Example 1, to give 9.2 mg of the title compound in 9% yield. 1 H-NMR (300MHz, CD3OD): δ7.82(s,1H), 7.52(s,1H), 7.00(m,2H), 6.83(s,1H), 5.66(m,1H), 4.02 (s,3H), 3.94(m,2H), 3.84(m,2H), 3.66(m,2H), 3.18(m,4H), 2.49(s,3H), 1.67(d,J=6.9Hz,3H). MS (ESI+, m / z): 516.2 [M+H] +

[0131] Example 6: (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (25 mg, 0.11 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 8 mg of the title compound in a yield of 17%. 1 H-NMR (300MHz, DMSO-d6): δ8.40(m,1H), 7.89(s,1H), 7.68(m,1H), 7.66(m,1H), 7.50(s,1H), 7.40-7. 06(m,2H), 5.82(m,1H), 3.97(s,3H), 3.50(m,4H), 3.42(m,2H), 3.29(m,2H), 2.33(s,3H), 1.64(m,3H). MS (ESI+, m / z): 475.2 [M+H] +

[0132] Example 7: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone [ka] The process of Example 1 was repeated except that azetidine (0.1 mL, 1.40 mmol) was used instead of morpholine in [Step-8] of Example 1, to give 28 mg of the title compound in 15% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.28(d,1H), 7.83(s,1H), 7.43(s,1H), 6.90(d,2H), 6.71(s,1H) , 5.64(m,3H), 4.06(m,2H), 3.95(s,3H), 3.88(m,2H), 2.42(s,3H), 2.28(m,2H), 1.59(d,3H). MS (ESI +, m / z): 460.2 [M + H] +

[0133] Example 8: (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 2 was repeated except that (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)boronic acid (74 mg, 0.27 mmol) was used instead of (2-formylphenyl)boronic acid in Step 2 of Example 2, to give 30 mg of the title compound in 48% yield. 1 H-NMR (300MHz, CD3OD): δ7.77(s,1H), 7.54(s,1H), 7.13(m,5H), 6.00(m,1H), 4.13(s,3H), 3.82(m,4H), 3.61(m,2H), 3.32(m,2H), 3.13(m,2H), 2.87(m,4H), 2.57(s,3H), 1.83(m,3H). MS (ESI +, m / z): 544.2 [M + H] +

[0134] Example 9: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone [ka] The process of Example 1 was repeated except that piperazine (26 mg, 0.41 mmol) was used instead of morpholine in [Step-8] of Example 1, to give 5 mg of the title compound in 9% yield. 1 H-NMR (300MHz, CD3OD): δ8.09(s,1H), 7.61(s,1H), 6.98(m,2H), 6.84(s,2H), 5.79(m ,1H), 4.06(m,5H), 3.54(m,2H), 3.34(m,2H), 3.20(m,2H), 2.65(s,3H), 1.74(d,3H). MS (ESI +, m / z): 489.2 [M + H] +

[0135] Example 10: (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide [ka] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (30 mg, 0.061 mmol) obtained in Example 1 [Step 10] above, trifluoroacetic anhydride (14 mg, 0.067 mmol), and DIPEA (10 mg, 0.078 mmol) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 3.5 hours. Upon completion of the reaction, aqueous ammonium chloride solution was added dropwise to neutralize the mixture. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 50:1 to 10:1 (v / v)) to obtain 7 mg of the title compound in 20% yield. 1 H-NMR (300MHz, CD3OD): δ8.11-8.08(d,1H), 7.91-7.88(d,1H), 7.88(s,1H), 7.66(s,1H), 7.52(s,1H), 5 .74(m,1H), 4.86(s,6H), 4.03(s,3H), 3.79(m,4H), 3.63(m,2H), 3.32(m,2H), 2.47(s,3H), 1.76(d,3H). MS (ESI +, m / z): 586.2 [M + H] +

[0136] Example 11: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone [ka] The process of Example 1 was repeated except that 3-fluoroazetidine (258 mg, 1.07 mmol) was used instead of morpholine in [Step-8] of Example 1, to give 30 mg of the title compound in 9% yield. 1 H-NMR (300MHz, CD3OD): δ8.03(s,1H), 7.64(s,1H), 7.00(m,2H), 6.85(s,1H), 5.78( m,1H), 5.34(m,1H), 4.51(m,1H), 4.28(m,3H), 4.08(s,3H), 2.63(s,3H), 1.74(d,3H) MS (ESI +, m / z): 478.2 [M + H] +

[0137] Example 12: (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 2 was repeated except that 2.0 M dimethylamine (0.16 ml, 0.32 mmol) was used instead of 2.0 M methylamine in [Step-3] of Example 2 above, to obtain 307 mg of the title compound in 8% yield. 1 H-NMR (300MHz, CD3OD): δ7.77(s,1H), 7.49(m,2H), 7.39(m,3H), 7.26(s,1H), 7.17(s,1H), 6.09( m,1H), 3.97(m,5H), 3.77(m,4H), 3.62(m,2H), 3.26(m,2H), 2.55(s,3H), 2.38(s,6H), 1.84(d,3H) MS (ESI +, m / z): 546.2 [M + H] +

[0138] 13: (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 2 was repeated except that 2.0 M ammonia (0.22 ml, 0.45 mmol) was used instead of 2.0 M methylamine in [Step-3] of Example 2, to give 15 mg of the title compound in 13% yield. 1 H-NMR (300MHz, CD3OD): δ7.78(s,1H), 7.52(m,2H), 7.30(m,5H), 6.10(m,1H), 4.57( s,2H), 3.98(s,3H), 3.76(m,4H), 3.62(m,2H), 3.26(m,2H), 2.56(s,3H), 1.82(d,3H) MS (ESI +, m / z): 518.2 [M + H] +

[0139] Example 14: (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 2 was repeated, except that 2-(hydroxymethyl)phenylboronic acid (0.14 ml, 0.92 mmol) was used instead of (2-formylphenyl)boronic acid in [Step-2] of Example 2, to obtain 88 mg of the title compound in 20% yield. 1 H-NMR (300MHz, CD3OD): δ7.76(s,1H), 7.51(m,2H), 7.31(m,5H), 6.10(m,1H), 4.57( s,2H), 3.98(s,3H), 3.76(m,4H), 3.60(m,2H), 3.27(m,2H), 2.55(s,3H), 1.24(d,3H) MS (ESI +, m / z): 519.2 [M + H]+

[0140] Example 15: (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (33 mg, 0.16 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of Example 1 above, to obtain 20 mg of the title compound in 27% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.38(d,1H), 7.85(s,2H), 7.78(d,1H), 7.60(d,2H), 7.41(s,1H) , 5.74(m,1H), 3.96(s,3H), 3.65(m,4H), 3.49(m,2H), 3.12(m,2H), 2.37(s,3H), 1.67(m,3H). MS (ESI+, m / z): 475.2 [M+H] +

[0141] Example 16: (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-4-methyl-5-(trifluoromethyl)aniline hydrochloride (83 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of Example 1 above, to obtain 15 mg of the title compound in a 13% yield. 1H-NMR (300MHz, DMSO-d6): δ8.36(d,1H), 7.91(s,1H), 7.39(s,1H), 6.92(d,2H), 6.79(s,1H), 5.68( m,1H), 5.25(s,2H), 3.96(s,3H), 3.65(m,4H), 3.51(m,2H), 3.12(m,2H), 2.38(d,6H), 1.55(m,3H). MS (ESI +, m / z): 504.2 [M + H] +

[0142] Example 17: (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (46 mg, 0.24 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 24 mg of the title compound in 25% yield. 1 H-NMR (300MHz, CD3OD): δ8.00(s,1H), 7.53(s,1H), 6.58(s,1H), 6.44(m,1H), 6.31(m,1H), 5.73(m,1H), 4.04(s,3H), 3.76(m,4H), 3.61(m,2H), 3.27(m,2H), 2.61(s,3H), 1.69(d,3H) MS (ESI+, m / z): 440.2 [M+H] +

[0143] Example 18: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone [ka] The process of Example 1 was repeated except that thiomorpholine 1,1-dioxide (30 mg, 0.21 mmol) was used instead of morpholine in Step 8 of Example 1, to give 23 mg of the title compound in 30% yield. 1 H-NMR (300MHz, CD3OD): δ7.85(s,1H), 7.58(s,1H), 7.01(m,2H), 6.83(s,1H), 5.67(m,1H), 4.26 (m,2H), 4.03(s,3H), 3.68(m,2H), 3.24(m,2H), 3.13(m,2H), 2.50(s,3H), 1.67(d,J=6.9Hz,3H). MS (ESI +, m / z): 538.1 [M + H] +

[0144] Example 19: (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-2-methoxyaniline hydrochloride (49 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of Example 1 above, to obtain 30 mg of the title compound in 31% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.24(m,1H), 7.92(s,1H), 7.38(s,1H), 6.78(m,1H), 6.67(m,1H), 6.57(m,1H), 5.92( m,1H), 4.92(m,2H), 3.97(s,3H), 3.90(d,3H), 3.65(m,4H), 3.51(m,2H), 3.13(m,2H), 2.34(s,3H), 1.52(m,3H). MS (ESI +, m / z): 452.2 [M + H] +

[0145] Example 20: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone [ka] The process of Example 1 was repeated except that thiazolidine (0.06 mL, 0.70 mmol) was used instead of morpholine in [Step-8] of Example 1, to give 18 mg of the title compound in 56% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.31(d,1H), 7.88(s,1H), 7.44(s,1H), 6.90(d,2H), 6.72(s,1H), 5.63(m,3H), 4.64( s,1H), 4.22(s,1H), 3.95(s,3H), 3.86(m,1H), 3.45(m,1H), 3.12(m,1H), 2.99(m,1H), 2.39(s,3H), 1.60(d,3H). MS (ESI +, m / z): 492.2 [M + H] +

[0146] Example 21: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (45 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of Example 1 above, to obtain 15 mg of the title compound in 16% yield. 1H-NMR (300MHz, DMSO-d6): δ8.20(m,1H), 7.87(s,1H), 7.39(s,1H), 6.63(m,2H), 6.48(m,1H), 5.60(m,1H) , 4.92(m,2H), 3.94(d,3H), 3.65(s, 4H), 3.54(m,2H), 3.12(m,2H), 2.40(d,3H), 2.20(d,3H), 1.55(m,3H). MS (ESI+, m / z): 436.2 [M+H] +

[0147] Example 22: (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile [ka] The process of Example 1 was repeated except that (R)-3-amino-5-(1-aminoethyl)benzonitrile hydrochloride (65 mg, 0.33 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 6 mg of the title compound in 6% yield. 1 H-NMR (300MHz, CD3OD): δ7.80(s,1H), 7.49(s,1H), 7.02(m,2H), 6.80(s,1H), 5.58( m,1H), 4.01(s,3H), 3.76(m,4H), 3.61(m,2H), 3.27(m,2H), 2.47(s,3H), 1.64(d,3H) MS (ESI+, m / z): 447.2 [M+H] +

[0148] Example 23: (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-1-(2,3-dihydro-1H-inden-4-yl)ethan-1-amine (45 mg, 0.27 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 35 mg of the title compound in 31% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.29(m,1H), 7.86(s,1H), 7.37(s,1H), 7.27(m,1H), 7.09(s,1H), 5.63(m,1H) , 3.95(s,3H), 3.64(m,4H), 3.48(m,2H), 3.32(m,2H), 2.95(m,2H), 2.36(s,3H), 2.09(m,2H), 1.58(m,3H) MS (ESI+, m / z): 447.2 [M+H] +

[0149] Example 24: (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-cyclopropylaniline hydrochloride (57 mg, 0.27 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 23 mg of the title compound in 20% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.18(d,1H), 7.86(s,1H), 7.38(s,1H), 6.41(s,2H), 6.10(s,1H), 5.55(m,1H), 4.89(s,2H), 3.95 (s,3H), 3.65(m,4H), 3.50(m,2H), 3.38(m,2H), 3.11(s,2H), 2.39(s,3H), 1.83(m,1H), 1.53(m,3H), 0.83(m,2H), 0.55(m,2H) MS (ESI+, m / z): 462.2 [M+H] +

[0150] Example 25: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-4-fluoro-5-trifluoromethyl)aniline hydrochloride (62 mg, 0.24 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 40 mg of the title compound in 36% yield. 1 H-NMR (300MHz, CD3OD): δ7.84(m,1H), 7.47(s,1H), 6.92(m,1H), 6.77(m,1H), 5.72(m,1H) , 4.00(s,3H), 3.78(m,4H), 3.57(m,2H), 3.22(m,2H), 2.39(m,3H), 1.64(d,J=7.4Hz,3H). MS (ESI +, m / z): 508.1 [M + H] +

[0151] Example 26: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (58 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of Example 1 above, to obtain 33 mg of the title compound in a 31% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.30(m,1H), 7.92(s,1H), 7.41(s,1H), 7.09(m,1H), 6.79(d,1H), 6.63(m,1H) , 5.78(m,1H), 5.20(s,2H), 3.97(s,3H), 3.66(s,4H), 3.54(m,2H), 3.13(m,2H), 2.35(s,3H), 1.60(m,3H). MS (ESI+, m / z): 490.2 [M+H] +

[0152] Example 27: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.11 g, 4.6 mmol) was used instead of methyl iodide in Step 4 of Example 1, to obtain 25 mg of the title compound in 18% yield. 1 H-NMR (300MHz, CD3OD): δ7.79(m,1H), 7.58(s,1H), 7.52(s,1H), 7.01(m,1H), 6.83(s,1H), 5.67(m,1H), 5.25 (m,1H), 3.94(m,4H), 3.81(m,4H), 3.62(m,2H), 3.34(m,2H), 2.49(s,3H), 2.38(m,2H), 1.68(d,J=5.4Hz,3H). MS (ESI +, m / z): 546.2 [M + H] +

[0153] Example 28: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(furan-3-yl)aniline hydrochloride (62 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 10 mg of the title compound in 9% yield. 1 H-NMR (300MHz, CD3OD): δ8.04(s,1H), 7.80(s,1H), 7.51(m,2H), 6.97(s,1H), 6.83(s,1H), 6.74( m,2H), 5.80(m,1H), 4.04(s,3H), 3.78(m,4H), 3.61(m,2H), 3.27(m,2H), 2.64(s,3H), 1.75(d,3H) MS (ESI +, m / z): 488.2 [M + H] +

[0154] Example 29: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)aniline hydrochloride (58 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1 above, to obtain 10 mg of the title compound in 10% yield. 1 H-NMR (300MHz, CD3OD): δ7.82(s,1H), 7.49(s,1H), 6.91(s,2H), 6.58(s,1H), 6.39(m,1H), 5.68(m,1H), 4.00(s,3H), 3.76(m,4H), 3.60(m,2H), 3.27(m,2H), 2.49(s,3H), 1.67(d,3H) MS (ESI+, m / z): 472.2 [M+H] +

[0155] Example 30: (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(thiazol-5-yl)aniline hydrochloride (67 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1, to obtain 4 mg of the title compound in 4% yield. 1 H-NMR (300MHz, CD3OD): δ8.89(s,1H), 8.06(d,1H), 7.81(s,1H), 7.49(s,1H), 7.06(s,1H), 6.87(s,1H), 6.84(m,1H), 5.65(m,1H), 4.00(s,3H), 3.78(m,4H), 3.61(m,2H), 3.27(m,2H), 2.48(s,3H), 1.69(d,3H) MS (ESI +, m / z): 505.2 [M + H] +

[0156] Example 31: (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone [ka]

[0157] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (50 mg, 0.10 mmol) obtained in Example 1 [Step-10] was dissolved in 1 mL of dichloromethane. To the reaction solution were added acetaldehyde (5.4 mg, 0.12 mmol) and 1.0 M titanium tetrachloride dichloromethane solution (0.01 mL, 0.01 mmol). Sodium cyanobromine hydride (26 mg, 0.41 mmol) was added, and the mixture was stirred at room temperature overnight. Upon completion of the reaction, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain 16 mg of the title compound in 31% yield. 1 H-NMR (300MHz, CD3OD): δ7.82(d,1H), 7.51(s,1H), 6.98(d,2H), 6.71(s,1H), 5.68(m,1H), 4.02(s,3H) , 3.77(m,4H), 3.63(m,2H), 3.35(m,2H), 3.28(m,2H), 2.49(s,3H), 1.68(d,J=6.9Hz,3H), 1.25(m,3H). MS (ESI +, m / z): 518.2 [M + H] +

[0158] Example 32: Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that 2-methoxyethyl 4-methylbenzenesulfonate (3.2 g, 14.11 mmol) was used instead of methyl iodide in [Step-4] of Example 1, to obtain 7 mg of the title compound in a 6% yield. 1H-NMR (300MHz, DMSO-d6): δ8.31(m,1H), 7.86(s,1H), 7.41(s,1H), 6.89(m,2H), 6.71(s,1H), 5. 57(m,3H), 4.28(m,2H), 3.94-3.50(m,8H), 3.37(m,3H), 3.16(m,2H), 2.39(s,3H), 1.59(m,3H). MS (ESI +, m / z): 534.2 [M + H] +

[0159] Example 33: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 1 was repeated except that fluoroacetonitrile (7.1 mL, 125 mmol) was used instead of acetonitrile in Step 7 of Example 1, to give 32 mg of the title compound in 34% yield. 1 H-NMR (300MHz, CD3OD): δ7.92(s,1H), 7.68(s,1H), 7.00(m,2H), 6.83(s,1H), 5.68(m,1H), 5.51 (m,1H), 5.39(m,1H), 4.01(s,3H), 3.79(m,4H), 3.63(m,2H), 3.23(m,2H), 1.69(d,J=7.2Hz,3H). MS (ESI+, m / z): 508.2 [M+H] +

[0160] Example 34: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine [Step 1] Preparation of methyl 2-bromo-5-methoxy-methylbenzoate [ka] Methyl 3-methoxy-4-methylbenzoate (5 g, 27.74 mmol) was mixed with 40 mL of acetic acid and 40 mL of water, and then bromine (1.5 mL, 30.52 mmol) was added dropwise. After the addition was complete, the mixture was refluxed and stirred at 60°C for 1 hour. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. The aqueous solution was extracted three times with a hexane / ether (8:3) solution. The organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to give 6.92 g of the title compound in 96% yield. 1 H-NMR (300MHz, CDCl3): δ7.39(s,1H), 7.26(s,1H), 3.92(s,3H), 3.84(s,3H), 2.21(s,3H).

[0161] [Step-2] Preparation of methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate [ka] Methyl 2-bromo-5-methoxymethylbenzoate (6.92 g, 26.70 mmol) obtained in Step 1 above, N-bromosuccinimide (4.28 g, 24.60 mmol), and azobisisobutyronitrile (853 mg, 5.19 mmol) were dissolved in 130 mL of chloroform and refluxed at 70 °C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. The mixture was extracted three times with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 5.98 g of the title compound in 66% yield. 1 H-NMR (300MHz, CDCl3): δ7.59(s,1H), 7.30(s,1H), 4.45(s,2H), 3.93(s,3H), 3.91(s,3H).

[0162] [Step-3] Preparation of methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate [ka] Methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate (1.2 g, 3.55 mmol) obtained in Step 2 above, morpholine (0.34 mL, 3.90 mmol), and potassium carbonate (981 mg, 7.10 mmol) were dissolved in 20 mL of acetonitrile and stirred at room temperature for 18 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and aqueous sodium bicarbonate solution was added dropwise. The mixture was extracted three times with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 1.0 g of the title compound in 82% yield. 1 H-NMR (300MHz, CDCl3): δ7.68(s,1H), 7.28(s,1H), 3.93(s,3H), 3.84(s,3H), 3.73(m,4H), 3.51(m,2H), 2.49(m,4H).

[0163] [Step-4] Preparation of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinomethyl)benzoate [ka] Methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate (1.0 g, 2.90 mmol), tert-butyl carbamate (566 mg, 3.19 mmol), xanthophos (336 mg, 0.58 mmol), Pd2(dba)3dba (266 mg, 0.29 mmol), and cesium carbonate (2.83 g, 8.71 mmol) were dissolved in 25 mL of 1,4-dioxane and stirred at 110 °C for 2 h. Upon completion of the reaction, the mixture was cooled to room temperature, filtered through a Celite-filled filter, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 953 mg of the title compound in 86% yield. 1H-NMR (300MHz, CDCl3): δ8.39(s,1H), 7.41(s,1H), 3.91(s,3H), 3.81(s,3H), 3.73(m,4H), 3.56(s,2H), 2.51(m,4H), 1.52(s,9H).

[0164] [Step-5] Preparation of 6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-ol [ka] Methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinomethyl)benzoate (950 mg, 2.49 mmol) obtained in Step 4 above was dissolved in 10 mL of acetonitrile, and 10 mL of a 4N solution of hydrogen chloride in dioxane was added dropwise. The mixture was refluxed and stirred at 80°C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding an aqueous solution of sodium bicarbonate dropwise. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to give 680 mg of the title compound in 94% yield. 1 H-NMR (300MHz, CD3OD): δ7.70(s,1H), 7.59(s,1H), 3.95(s,3H), 3.73(m,4H), 3.67(s,2H), 2.55(m,4H), 2.43(s,3H).

[0165] [Step-6] Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine [ka] 6-Methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-ol (100 mg, 0.34 mmol) obtained in Step 5 above, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (125 mg, 0.51 mmol), PyBOP (269 mg, 0.51 mmol), and DBU (0.13 mL, 0.86 mmol) were dissolved in 3 mL of acetonitrile and stirred at 80 °C for 5 h. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to give 14 mg of the title compound in 8% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.11(d,1H), 7.71(s,1H), 7.57(s,1H), 6.85(m,2H), 6.69(s,1H) , 5.57(m,3H), 3.92(s,3H), 3.61(m,4H), 3.57(s,2H), 2.44(m,4H), 2.36(s,3H), 1.56(d,3H) MS (ESI +, m / z): 476.2 [M + H] +

[0166] Example 35: (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine [ka] The process of Example 34 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (125 mg, 0.51 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 6 of Example 34, to obtain 9 mg of the title compound in 5% yield. 1H-NMR (300MHz, DMSO-d6): δ8.11(d,1H), 7.76(s,1H), 7.55(s,1H), 7.06(t,1H), 6.74(m,1H), 6.58(m,1H) , 5.72(m,3H), 5.16(s,2H), 3.94(s,3H), 3.60(m,4H), 3.56(s,2H), 2.42(m,4H), 2.31(s,3H), 1.55(d,3H) MS (ESI +, m / z): 476.2 [M + H] +

[0167] Example 36: (R)—N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine [Step 1] Preparation of methyl 4-hydroxy-5-methoxy-2-nitrobenzoate [ka] Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (11.7 g, 36.9 mmol) was dissolved in 250 mL of methanol, and Pd / C (1.2 g, 10 wt%) was added. The reaction solution was stirred under hydrogen gas at 50 °C for 20 hours. Upon completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give the title compound 7g in 96% yield. 1 H-NMR (300MHz, CD3OD): δ7.29(s,1H), 6.24(s,1H), 6.84(m,1H), 4.87(bs,2H), 3.91(s,3H), 3.81(s,3H).

[0168] [Step-2] Preparation of 7-hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one [ka] Methyl 4-hydroxy-5-methoxy-2-mitrobenzoate (7.0 g, 35.5 mmol) obtained in Step 1 above was dissolved in 4N hydrogen chloride in dioxane (71 mL, 284 mmol) and acetonitrile (20 mL, 355 mmol), and the mixture was refluxed and stirred at 70 °C for 15 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature, and 30 mL of dichloromethane was added. The mixture was stirred for 0.5 hours to obtain a solid product. The resulting solid was filtered under reduced pressure and dried in an oven dryer at 55 °C to obtain 9 g of the title compound in 82% yield. 1 H-NMR (300MHz, DMSO-d6): δ11.2(s,1H), 9.38(s,1H), 8.24(s,1H), 7.49(s,1H), 6.86(s,1H), 3.85(s,3H), 3.79(s,3H).

[0169] [Step-3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(1H)-one [ka] 7-Hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one (1.8 g, 8.7 mmol) obtained in Step 2 above was dissolved in 20 mL of DMF, and tetrahydro-2H-pyran-4-yl methanesulfonate (1.7 g, 9.5 mmol) and cesium carbonate (3.4 g, 10.4 mmol) were added. The mixture was stirred at 100°C for 15 hours. Upon completion of the reaction, water was added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 10 mL of acetone was added and stirred. The precipitated crystals were filtered to obtain 250 mg of the title compound in 10% yield. 1 H-NMR (300MHz, CD3OD): δ7.84(s,1H), 7.58(s,1H), 4.77(m,1H), 4.13(m,2H), 3.96(s,3H), 3.64(m,2H), 2.44(s,3H), 2.22(m,2H), 2.09(m,2H).

[0170] [Step-4] Preparation of 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline [ka] 6-Methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(1H)-one (250 mg, 0.86 mmol) obtained in Step 3 above was dissolved in 14 mL of phosphoryl chloride and refluxed at 110° C. for 2 hours. Upon completion of the reaction, the solution was cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The solution was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solution was used in the next step without further purification. [Step-5] Preparation of (R)-N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine [ka] 4-Chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (100 mg, 0.33 mmol) prepared in Step 4 above was dissolved in 1 mL of DMF, and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (92 mg, 0.36 mmol) and DIPEA (0.17 mL, 0.97 mmol) were added. The mixture was stirred at 100 °C for 13 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to give 21 mg of the title compound in 13% yield. 1 H-NMR (300MHz, CD3OD): δ7.67(s,1H), 7.06(s,1H), 6.99(m,2H), 6.82(s,1H), 5.64(m,1H), 4.74(m,1H), 4.12(m,5H), 3.66(m,2H), 2.46(s,3H), 2.16(m,2H), 1.86(m,2H), 1.67(d,3H). MS (ESI +, m / z): 477.2 [M + H] +

[0171] Example 37: (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine [ka] The process of Example 36 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline (69 mg, 0.28 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 5 of Example 36, to obtain 5.7 mg of the title compound in a yield of 4.6%. 1 H-NMR (300MHz, CD3OD): δ7.73(s,1H), 7.09(s,1H), 6.79(m,3H), 5.81(m,1H), 4.59(m ,1H), 3.99(m,5H), 3.66(m,2H), 2.42(s,3H), 2.17(m,2H), 1.73(m,2H), 1.62(d,3H). MS (ESI +, m / z): 477.2 [M + H] +

[0172] Example 38: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine [ka] The process of Example 36 was repeated except that (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (752 mg, 2.78 mmol) was used instead of tetrahydro-2H-pyran-4-yl methanesulfonate in Step 3 of Example 36, to give 15 mg of the title compound in 3.5% yield. 1H-NMR (300MHz, CD3OD): δ7.46(s,1H), 7.00(s,3H), 6.83(s,1H), 5.67(q, 1H), 4.08~4.1 0(m,7H), 3.73(m,2H), 3.50(t,2H), 2.54(s,3H), 1.89(m,2H), 1.68(d,3H), 1.57(m,2H). MS (ESI+, m / z): 491.2 [M+H] +

[0173] Example 39: (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine [ka] The process of Example 36 was repeated except that oxetan-3-ylmethyl 4-methylbenzenesulfonate (530 mg, 2.17 mmol) was used instead of tetrahydro-2H-pyran-4-ylmethanesulfonate in Step 3 of Example 36, to give 20 mg of the title compound in 15% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.00(d,1H), 7.71(s,1H), 7.10(s,1H), 6.89(d,2H), 6.70(s,1H), 5.59( m,3H), 4.76(m,2H), 4.47(m,2H), 4.34(m,2H), 3.90(s,3H), 3.50(m,1H), 2.36(s,3H), 1.57(d,3H). MS (ESI+, m / z): 463.2 [M+H] +

[0174] Example 40: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid [ka] 2-Bromoterephthalic acid (75 g, 306.12 mmol) was dissolved in 490 mL of sulfuric acid, and then 98 mL of nitric acid was slowly added dropwise at 0°C. After the addition was complete, the mixture was refluxed and stirred at room temperature for 17 hours. Upon completion of the reaction, the reaction solution was slowly added dropwise to ice water and stirred at room temperature for 1 hour. After stirring, the mixture was filtered under reduced pressure, and the resulting solid was washed with distilled water to obtain 61 g of the title compound in 69% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.34(s,1H), 8.17(s,1H).

[0175] [Step 2] Preparation of dimethyl 2-bromo-5-nitroterephthalate [ka] 2-Bromo-5-nitroterephthalic acid (61 g, 210.32 mmol) obtained in Step 1 above was dissolved in 2.2 L of methanol, and then 240 mL of sulfuric acid was slowly added dropwise at 0°C. After the addition was complete, the mixture was refluxed and stirred at 90°C for 17 hours. Upon completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. 600 mL of distilled water was added dropwise at 0°C and stirred at room temperature for 0.5 hours. After stirring, the mixture was filtered under reduced pressure to obtain 61 g of the title compound in 91% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.47(s,1H), 8.28(s,1H), 3.93-3.89(m,6H).

[0176] [Step 3] Preparation of dimethyl 2-(methylamino)-5-nitroterephthalate [ka] Dimethyl 2-bromo-5-nitroterephthalate (60 g, 188.63 mmol) prepared in Step 2 above, methylamine hydrochloride (63.6 g, 941.94 mmol), and DIPEA (492 mL, 2829.48 mmol) were dissolved in 900 mL of DMF and refluxed at 100°C for 1 hour. Upon completion of the reaction, the solution was cooled to 0°C, and 1.8 L of distilled water was added dropwise. The mixture was then stirred at room temperature for 0.5 hours. After stirring, the mixture was filtered under reduced pressure to obtain 48.6 g of the title compound in 96% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.59(s,2H), 6.95(s,1H), 3.88(s,3H), 3.86(s,3H), 3.01-2.99(d,3H).

[0177] [Step 4] Preparation of dimethyl 2-amino-5-(methylamino)terephthalate [ka] Dimethyl 2-(methylamino)-5-nitroterephthalate (45.5 g, 169.63 mmol) obtained in Step 3 above and zinc dust (39.4 g, 593.71 mmol) were dissolved in 460 mL of dioxane:distilled water (4:1) and refluxed at room temperature for 0.5 hours. After stirring, the reaction solution was cooled to 0°C, and ammonium chloride (45.4 g, 848.76 mmol) was slowly added dropwise. After the addition was complete, the mixture was refluxed at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. The resulting organic layer was extracted three times with ethyl acetate after adding dioxane (1:1 vol / vol). The resulting organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:8 (v / v) to 1:4 (v / v)) to obtain 31 g of the title compound in 77% yield. 1 H-NMR (300MHz, DMSO-d6): δ7.39(s,1H), 7.02(s,1H), 6.55(m,1H), 5.88(s,2H), 3.83-3.81(m,6H), 2.78-2.76(d,3H).

[0178] [Step-5] Preparation of methyl 4-hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate [ka] Dimethyl 2-amino-5-(methylamino)terephthalate (31 g, 130.12 mmol) obtained in Step 4 above and acetonitrile (68 mL, 1301.20 mmol) were dissolved in 260 mL of 4N hydrochloric acid dissolved in dioxane, and the mixture was refluxed and stirred at 90°C for 3 hours using a sealed tube. Upon completion of the reaction, the reaction solution was cooled to room temperature, filtered, and washed with hexane. The filtered solid was neutralized with aqueous sodium bicarbonate, filtered under reduced pressure, and washed with distilled water to obtain 30 g of the title compound in 93.2% yield. 1 H-NMR (300MHz, DMSO-d6): δ12.03(m,1H), 8.02(s,1H), 7.41(m,1H), 7.16(s,1H), 3.87(s,3H), 2.91(d,3H), 2.28(s,3H).

[0179] [Step-6] Preparation of methyl 4-chloro-2-methyl-6-(methylamino)quinazoline-7-carboxylate [ka] Methyl 4-hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate (6.1 g, 24.69 mmol) obtained in Step 5 above was dissolved in 150 mL of phosphoryl chloride and stirred at reflux at 120°C for 3 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane and neutralized with aqueous sodium bicarbonate at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:ethyl acetate = 45:55 (v / v)) to give 1.6 g of the title compound in 24% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.36(s,1H), 7.57(m,1H), 6.92(s,1H), 3.93(s,3H), 2.94(d,3H), 2.66(s,3H).

[0180] [Step 7] Preparation of methyl (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylate [ka] Methyl 4-chloro-2-methyl-6-(methylamino)quinazoline-7-carboxylate (600 mg, 2.26 mmol) prepared in Step 6 above, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (705 mg, 2.93 mmol) synthesized by the method proposed in WO2018115380, and DIPEA (1.21 mL, 6.78 mmol) were dissolved in 30 mL of DMF and refluxed at 90 °C for 13 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to give 280 mg of the title compound in 29% yield. 1 H-NMR (300MHz, CDCl3): δ8.46(s,1H), 7.12(s,1H), 6.94(s,1H), 6.83(s,1H), 6.47(s,1H), 5.62(m,1H), 3.93(s,3H), 2.93(s,3H), 2.55(s,3H).

[0181] [Step 8] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylate (280 mg, 0.64 mmol) obtained in Step 7 above was dissolved in 20 mL of tetrahydrofuran:methanol:water (2:1:1). Sodium hydroxide (129 mg, 3.23 mmol) was added and the mixture was refluxed at room temperature for 2 hours. Upon completion of the reaction, the mixture was titrated to pH 5-6 by dropwise addition of 2N aqueous HCl and then washed with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylic acid without further purification. The title compound was dissolved in 5 mL of DMF with morpholine (0.62 mL, 0.72 mmol), HATU (272 mg, 0.18 mmol), and DIPEA (0.26 mL, 1.43 mmol). The mixture was refluxed and stirred at room temperature for 2.5 hours. Upon completion of the reaction, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give 30 mg of the title compound in 20% yield. 1 H-NMR (300MHz, CD3OD): δ7.38(s,1H), 7.28(s,1H), 6.99(m,2H), 6.82(s,1H) , 5.67(m,1H), 3.73(m,8H), 2.96(s,3H), 2.46(s,3H), 1.67(d,J=7.2Hz,3H). MS (ESI +, m / z): 489.2 [M + H] +

[0182] Example 41: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that dimethylamine hydrochloride (2.3 g, 28 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40, to give 40 mg of the title compound in 12% yield. 1 H-NMR (300MHz, DMSO-d6): δ7.77(d,1H), 7.38(s,1H), 6.90(d,2H), 6.74(s,1H) , 5.68(m,3H), 3.77(m,6H), 3.11(m,2H), 2.87(d,6H), 2.47(s,3H), 1.63(m,3H). MS (ESI +, m / z): 503.2 [M + H] +

[0183] Example 42: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that pyrrolidine (2.0 g, 28 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40, to give 60 mg of the title compound in 19% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.17(d,1H), 7.34(m,2H), 6.90(d,2H), 6.70(s,1H) , 5.65(m,3H), 3.76(m,6H), 3.28(m,6H), 2.35(d,3H), 1.98(m,4H), 1.58(m,3H). MS (ESI+, m / z): 529.3 [M+H] +

[0184] Example 43: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 40 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 40, to obtain 24 mg of the title compound in 38% yield. 1 H-NMR (300MHz, CD3OD): δ7.38(s,1H), 7.32(s,1H), 7.09(m,2H), 5.78(m,1H), 3.67(m,8H), 2.98(s,3H), 2.42(s,3H), 1.67(d,J=7.2Hz,3H). MS (ESI +, m / z): 489.2 [M + H] +

[0185] Example 44: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40 to give 12 mg of the title compound in 11% yield. 1 H-NMR (300MHz, CD3OD): δ7.39(m,2H), 6.99(m,1H), 6.83(s,1H), 5.65(m,1H) ), 3.76(m,8H), 3.68(m,4H), 3.66(s,3H), 2.52(s,3H), 1.66(d,J=6.9Hz,3H) MS (ESI +, m / z): 533.2 [M + H] +

[0186] Example 45: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that cyclopentanamine (4.7 g, 47.2 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40, to give 22 mg of the title compound in 6% yield. 1 H-NMR (300MHz, CD3OD): δ7.44(s,1H), 7.38(s,1H), 6.99(m,2H), 6.84(m,1H), 5.73(m ,1H), 4.08(m,1H), 3.67(m,8H), 2.52(s,3H), 1.81(m,4H), 1.73(m,3H), 1.53(m,4H). MS (ESI +, m / z): 543.2 [M + H] +

[0187] Example 46: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that 2.0 M ethylamine (23 mL, 47 mmol) dissolved in tetrahydrofuran was used instead of methylamine hydrochloride in Step 3 of Example 40, to give 120 mg of the title compound in 53% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.74(s,1H), 7.37(d,2H), 6.89(d,2H), 6.73(s,1H) , 5.76(m,4H), 3.65(m,6H), 3.33(m,4H), 2.43(s,3H), 1.62(d,3H), 1.26(m,3H). MS (ESI +, m / z): 503.2 [M + H]+

[0188] Example 47: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The procedure of Example 40 was repeated except that isopropylamine (3.86 mL, 47.1 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40 to give 3 mg of the title compound in 1% yield. 1 H-NMR (300MHz, CD3OD): δ7.36(m,2H), 6.98(m,2H), 6.80(s,1H), 5.64(m,1H), 3.92(m,1H), 3.69(m,8H), 2.42(s,3H), 1.64(d,3H), 1.27(m,6H). MS (ESI +, m / z): 517.2 [M + H] +

[0189] Example 48: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 40 was repeated except that 4-aminotetrahydropyran hydrochloride (3.89 g, 28.29 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 40, to obtain 130 mg of the title compound in 56% yield. 1H-NMR (300MHz, DMSO-d6): δ7.42(s,1H), 7.34(s,1H), 6.88(s,1H), 6.85(s,1H), 6.42(s,1H), 5.68(p,1H), 5.57(b r,2H), 5.15(d,1H), 3.90(d,2H), 3.82-3.48(br,10H), 2.41(s,3H), 1.92(d,2H), 1.62(d,3H), 1.57-1.48(m,2H). MS (ESI +, m / z): 559.2 [M + H] +

[0190] Example 49: (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-Dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine [Step 1] Preparation of ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate [ka] Methyl 2-amino-4-methylbenzoate (6.2 g, 34.5 mmol), di-tert-butyl dicarbonate (20 mL, 86.2 mmol), triethylamine (12 mL, 86.2 mmol), and 4-dimethylaminopyridine (4.2 g, 34.5 mmol) were dissolved in 100 mL of tetrahydrofuran and refluxed at room temperature for 15 hours. Upon completion of the reaction, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 5:1 (v / v)) to give 4.7 g of the title compound in 49% yield. 1 H-NMR (300MHz, CDCl3): δ10.35(s,1H), 8.30(s,1H), 7.93(d,1H), 6.84(m,1H), 4.41(m,2H), 2.40(s,3H), 1.55(s,9H), 1.44(m,3H).

[0191] [Step-2] Preparation of ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate [ka] Ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate (4.7 g, 16.8 mmol) prepared in Step 1 above, N-bromosuccinimide (3.0 g, 16.8 mmol), and azobisisobutyronitrile (0.55 g, 3.3 mmol) were dissolved in 100 mL of chloroform and refluxed at 70° C. for 1.5 hours. Upon completion of the reaction, the solution was cooled to room temperature and concentrated under reduced pressure to obtain 4.3 g of the title compound, which was used in the next reaction without further purification. [Step-3] Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate [ka] Ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate (4.3 g, 11.9 mmol), morpholine (2.0 mL, 23.8 mmol), and potassium carbonate (6.6 g, 47.6 mmol) prepared in Step 2 above were dissolved in 40 mL of acetonitrile and refluxed at room temperature for 1 hour. After the reaction was completed, water was added dropwise, and the resulting mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate = 5:1 (v / v)) to give 2.1 g of the title compound in 34% yield. 1 H-NMR (300MHz, CDCl3): δ10.34(s,1H), 8.39(d,1H), 8.00(d,1H), 7.08(m,1H), 4.42(m,2H), 3.75(m,4H), 3.54(m,2H), 2.49(m,4H), 1.55(s,9H), 1.45(m,3H).

[0192] [Step 4] Preparation of 2-methyl-7-(morpholinomethyl)quinazolin-4-ol [ka] Ethyl 2-((tert-butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate (2.1 g, 5.73 mmol) prepared in Step 3 above and acetonitrile (21 mL, 402.5 mmol) were dissolved in 21 mL of 4N hydrochloric acid dissolved in dioxane, and the mixture was refluxed and stirred at 90°C for 3 hours using a sealed tube. Upon completion of the reaction, the reaction solution was cooled to room temperature, filtered, and washed with hexane. The filtered solid was neutralized with aqueous sodium bicarbonate, filtered under reduced pressure, and washed with distilled water to obtain 1.2 g of the title compound in 81% yield. 1 H-NMR (300MHz, DMSO-d6): δ12.17(m,1H), 8.04(d,1H), 7.49(s,1H), 7.42(m,1H), 3.61(m,6H), 2.52(m,4H), 2.39(m,3H).

[0193] [Step-5] Preparation of 2-methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol [ka] 2-Methyl-7-(morpholinomethyl)quinazolin-4-ol (1.2 g, 4.62 mmol) obtained in Step 4 above was dissolved in 12 mL of sulfuric acid, and 2.4 mL of nitric acid was slowly added dropwise at 0°C. The mixture was refluxed and stirred at 70°C for 3 hours. Upon completion of the reaction, the reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane and neutralized with aqueous sodium hydroxide at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure to obtain 1.2 g of the title compound in 85% yield. 1 H-NMR (300MHz, DMSO-d6): δ12.57(m,1H), 8.49(s,1H), 7.79(s,1H), 3.86(s,2H), 3.55(m,4H), 2.52(m,3H), 2.39(m,4H).

[0194] [Step-6] Preparation of 6-amino-2-methyl-7-(morpholinomethyl)quinazolin-4-ol [ka] 2-Methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol (450 mg, 1.47 mmol) obtained in Step 5 above and zinc dust (340 mg, 5.14 mmol) were dissolved in 5 mL of dioxane:distilled water (4:1) and refluxed at room temperature for 0.5 hours. After stirring, the reaction solution was cooled to 0°C and ammonium chloride (400 mg, 7.35 mmol) was slowly added dropwise. After the addition was complete, the mixture was refluxed at room temperature for 2 hours. Upon completion of the reaction, the reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. Distilled water was added to the resulting organic layer (1:1 (v / v)) and extracted three times with ethyl acetate. The resulting organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol=10:1 (v / v)) to give 330 mg of the title compound in 81% yield. 1 H-NMR (300MHz, DMSO-d6): δ11.76(m,1H), 7.26(d,2H), 5.62(s,2H), 3.60(m,6H), 2.38(m,4H), 2.26(s,3H).

[0195] [Step-7] Preparation of 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-ol [ka] 6-Amino-2-methyl-7-(morpholinomethyl)quinazolin-4-ol (155 mg, 0.56 mmol) obtained in Step 6 above, methyl iodide (70 mg, 0.50 mmol), and calcium carbonate (84 mg, 0.84 mmol) were dissolved in 2 mL of dimethylformamide and refluxed at 50°C for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 13:1 (v / v)) to give 30 mg of the title compound in 18% yield. 1H-NMR (300MHz, CDCl3): δ9.75(s,1H), 7.38(s,1H), 7.27(s,1H), 6.41(d,1H), 3.73(m,6H), 2.98(d,3H), 2.50(s,3H), 2.47(m,4H).

[0196] [Step-8] Preparation of 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate [ka] 2-Methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-ol (30 mg, 0.10 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (48 mg, 0.12 mmol), 4-dimethylaminopyridine (3 mg, 0.01 mmol), and triethylamine (0.04 mL, 0.30 mmol) were dissolved in 2 mL of dichloromethane and refluxed at room temperature for 18 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 25 mg of the title compound in 43% yield.

[0197] [Step-9] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 Preparation of ,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine [ka] 2-Methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (25 mg, 0.04 mmol) prepared in Step 8 above, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (15 mg, 0.05 mmol), and triethylamine (0.025 mL, 0.18 mmol) were dissolved in 2 mL of DMF and refluxed at 90 °C for 22 hours. Upon completion of the reaction, water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to give 3 mg of the title compound in 14% yield. 1 H-NMR (300MHz, CDCl3): δ7.52(s,1H), 7.11(s,1H), 7.00(m,1H), 6.82(s,1H), 6.49(m,2H), 5.71(m,1H), 3.89(s,2H), 3.71(m,6H), 2.97(s,3H), 2.59(s,3H), 2.44(m,4H), 1.71(d,3H). MS (ESI+, m / z): 475.2 [M+H] +

[0198] Example 50: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 23 mg of the title compound in 15% yield. 1H-NMR (300MHz, CD3OD): δ7.38(s,1H), 7.32(s,1H), 7.09(m,2H), 6.95(m,1H), 6.81 (m,1H), 5.75(m,1H), 3.68(m,8H), 2.98(s,3H), 2.41(s,3H), 1.68(d,J=6.9Hz,3H). MS (ESI +, m / z): 507.2 [M + H] +

[0199] Example 51: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)aniline hydrochloride (270 mg, 1.20 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 70 mg of the title compound in a 41% yield. 1 H-NMR (300MHz, DMSO-d6): δ9.15(d,1H), 7.34(d,2H), 7.03-6.66(m,3H), 6.62(s,1H), 5.81(d,1H) , 5.73(m,1H), 5.45(d,2H), 3.68-3.51(m,6H), 3.32(s,2H), 2.88(d,3H), 2.48(s,3H), 1.62(d,3H). MS (ESI +, m / z): 471.2 [M + H] +

[0200] Example 52: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that 2.0 M ethylamine (23 mL, 47 mmol) dissolved in tetrahydrofuran was used instead of methylamine hydrochloride in the above Example 49 [Step-3], and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (230 mg, 0.96 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], to obtain 55 mg of the title compound in a 41% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.53(s,1H), 7.41(d,2H), 7.27-6.90(m,1H), 6.76(d,1H), 6.63(m,1H), 5. 81(m,1H), 5.36(s,1H), 5.27(d,2H), 3.64(s,6H), 3.32(m,4H), 2.37(s,3H), 1.60(d,3H), 1.28(m,3H). MS (ESI +, m / z): 503.2 [M + H] +

[0201] Example 53: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone [ka] The procedure of Example 49 was repeated except that thiazolidine (24 mg, 0.26 mmol) was used instead of morpholine in Step-8 of Example 49 to give 16 mg of the title compound in 14% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.10(d,1H), 7.36(s,1H), 7.22(s,1H), 6.90(d,2H), 6.70(s,1H), 5. 61-5.53(m,4H), 4.55(m,2H), 3.72(m,2H), 3.04(m,2H), 2.87(m,3H), 2.34(s,3H), 1.58(d,3H). MS (ESI+, m / z): 491.2 [M+H] +

[0202] Example 54: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(furan-3-yl)aniline hydrochloride (233 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 15 mg of the title compound in 32% yield. 1 H-NMR (300MHz, CD3OD): δ7.80(s,1H), 7.52(s,1H), 7.38(s,1H), 7.29(s,1H), 7.01(s,1H), 6.77(s,1H) , 6.75(s,1H), 6.72(s,1H), 5.67(m,1H), 3.66(m,8H), 2.96(s,3H), 2.46(s,3H), 1.67(d,J=7.2Hz,3H). MS (ESI +, m / z): 487.2 [M + H] +

[0203] Example 55: (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that isopropylamine (2.7 mL, 31.4 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 49, and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (224 mg, 0.92 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 20 mg of the title compound in a yield of 23%. 1 H-NMR (300MHz, DMSO-d6): δ8.03(d,1H), 7.40(s,1H), 7.27(s,1H), 7.07(t,1H), 6.73(m,1H), 6.58(m,1H) , 5.71(m,1H), 5.17(s,2H), 4.80(m,1H), 3.94(m,1H), 3.72(m,8H), 2.28(s,3H), 1.55(d,3H), 1.23(m,6H). MS (ESI +, m / z): 517.2 [M + H] +

[0204] Example 56: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 49, and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 35 mg of the title compound in a 30% yield. 1H-NMR (300MHz, DMSO-d6): δ8.06(d,1H), 7.40(s,1H), 7.30(s,1H), 7.07(t,1H), 6.74(m,1H), 6.59( m,1H), 5.72(m,1H), 5.21(m,3H), 3.60(m,8H), 3.42(m,4H), 3.31(s,3H), 2.29(s,3H), 1.55(d,3H). MS (ESI +, m / z): 533.2 [M + H] +

[0205] Example 57: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone [ka] The procedure of Example 49 was repeated except that 1-methylpiperazine (0.03 mL, 0.25 mmol) was used instead of morpholine in Step 8 of Example 49 to give 20 mg of the title compound in 16% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.32(s,1H), 7.26(d,2H), 6.90(d,2H), 6.71(s,1H) , 5.64-5.46(m,4H), 3.74(m,4H), 2.87(d,3H), 2.38-2.26(m,10H), 1.60(d,3H). MS (ESI+, m / z): 502.2 [M+H] +

[0206] Example 58: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone [ka] The procedure of Example 49 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in Step 8 of Example 49 to give 38 mg of the title compound in 31% yield. 1 H-NMR (300MHz, DMSO-d6): δ9.12(m,1H), 7.36(d,2H), 6.90(d,2H), 6.74(s,1H) , 5.88-5.60(m,4H), 3.80-3.45(m,8H), 2.92(m,5H), 2.48(s,3H), 1.60(d,3H). MS (ESI +, m / z): 515.2 [M + H] +

[0207] Example 59: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone [ka] The procedure of Example 49 was repeated except that thiomorpholino 1,1-dioxide (35 mg, 0.26 mmol) was used instead of morpholine in Step 8 of Example 49 to give 5 mg of the title compound in 4% yield. 1 H-NMR (300MHz, CD3OD): δ7.42(s,1H), 7.27(s,1H), 6.99(m,2H), 6.80(m,1H), 5.64(m,1H), 3.22(m,8H), 2.94(s,3H), 2.44(s,3H), 1.65(d,3H). MS (ESI +, m / z): 537.2 [M + H] +

[0208] Example 60: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone [ka] The procedure of Example 49 was repeated except that thiomorpholine (0.03 mL, 0.26 mmol) was used instead of morpholine in Step-8 of Example 49 to give 22 mg of the title compound in 18% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.07(d,1H), 7.25(s,1H), 7.19(s,1H), 6.90(d,2H), 6.70(s,1H), 5.60-5.53(m,3 H), 5.36(m,1H), 3.89(m,2H), 3.50(m,2H), 2.85(m,3H), 2.73(m,2H), 2.53(m,2H), 2.34(s,3H), 1.55(d,3H). MS (ESI +, m / z): 505.2 [M + H] +

[0209] Example 61: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone [ka] The procedure of Example 49 was repeated except that piperazine (100 mg, 0.50 mmol) was used instead of morpholine in Step 8 of Example 49 to give 30 mg of the title compound in 13% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.06(d,1H), 7.21(d,2H), 6.90(d,2H), 6.70(s,1H), 5.64-5.33( m,4H), 3.61(m,2H), 3.18(m,2H), 2.86(d,3H), 2.78-2.55(m,4H), 2.34(s,3H), 1.58(d,3H). MS (ESI +, m / z): 488.2 [M + H] +

[0210] Example 62: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone [ka] The procedure of Example 49 was repeated except that azetidine hydrochloride (24 mg, 0.26 mmol) was used instead of morpholine in Step 8 of Example 49 to give 12 mg of the title compound in 11% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.16(m,1H), 7.42(s,1H), 7.20(s,1H), 6.88(m,2H), 6.69(s,1H), 6.35 (m,1H), 5.56(m,3H), 4.12(m,2H), 4.04(m,2H)2.87(m,3H), 2.34(s,3H), 2.22(m,2H), 1.56(d,3H). MS (ESI +, m / z): 459.2 [M + H] +

[0211] Example 63: (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (230 mg, 0.96 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], and hexahydro-1H-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 40 mg of the title compound in a 32% yield. 1H-NMR (300MHz, DMSO-d6): δ9.56(m,1H), 7.44(d,2H), 7.27-6.91(m,1H), 6.80(d,1H), 6. 67(m,1H), 6.06-5.32(m,4H), 3.80-3.43(m,8H), 2.91(m,5H), 2.50(s,3H), 1.65(d,3H). MS (ESI +, m / z): 515.2 [M + H] +

[0212] Example 64: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 49 [Step-7] and thiomorpholino 1,1-dioxide (35 mg, 0.26 mmol) was used instead of morpholine in [Step-8], to obtain 8 mg of the title compound in a 6% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.09(m,1H), 7.41(s,1H), 7.26(t,1H), 6.75(m,2H), 6.59(m,1H), 5.72(m,1H) , 5.19(m,2H), 4.07(m,2H), 3.58(m,2H), 3.31(m,2H), 3.19(m,2H), 2.87(m,3H), 2.29(s,3H), 1.55(d,3H). MS (ESI +, m / z): 537.2 [M + H] +

[0213] Example 65: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone [ka] The process of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (165 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 3.5 mg of the title compound in 10% yield. 1 H-NMR (300MHz, CD3OD): δ7.37(s,1H), 7.28(s,1H), 6.66(m,2H), 6.47(s,1H), 5.65(m,1H), 3.98(m,8H), 2.96(s,3H), 2.48(s,3H), 2.24(s,3H), 1.66(s,3H). MS (ESI+, m / z): 435.2 [M+H] +

[0214] Example 66: (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone [ka] The process of Example 49 was repeated except that 2-methoxyethylamine (4.1 mL, 47.15 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (190 mg, 0.76 mmol) was used in the above Example 49 [Step-7], and hexahydro-1H-furo[3,4-c]pyrrole (22 mg, 0.18 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 40 mg of the title compound in 36% yield. 1 H-NMR (300MHz, DMSO-d6): δ8.63(m,1H), 7.46(d,2H), 7.09-6.91(m,1H), 6.76(d,1H), 6. 63(m,1H), 5.78-5.24(m,4H), 4.11-3.32(m,15H), 2.91(m,2H), 2.37(s,3H), 1.60(d,3H). MS (ESI +, m / z): 559.2 [M + H] +

[0215] Example 67: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone [ka] The process of Example 49 was repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 49, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) in Step 7, and thiomorpholino 1,1-dioxide (29 mg, 0.21 mmol) was used instead of morpholine in Step 8. 2 mg of the title compound was obtained in a 2% yield. 1 H-NMR (300MHz, CD3OD): δ7.40(s,1H), 7.38(s,1H), 6.88(t,1H), 6.85(m,1H), 6.77(m,1H), 5.77(m,1H), 4.59(m,4H), 3.69(m,6H), 3.48(m,2H), 3.42(s,3H), 2.39(s,3H), 1.65(d,3H). MS (ESI +, m / z): 581.2 [M + H] +

[0216] Example 68: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone [ka] The process of Example 49 was repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 49, and thiomorpholino 1,1-dioxide (55 mg, 0.40 mmol) was used instead of morpholine in Step 8 of Example 49, to give 18 mg of the title compound in 8% yield. 1H-NMR (300MHz, DMSO-d6): δ8.07(m,1H), 7.42(s,1H), 7.32(s,1H), 6.87(m,2H), 6.69(s,1H) , 5.56(m,3H), 5.31(m,1H), 3.59(m,2H), 3.41(m,4H), 3.29(m,9H), 2.33(s,3H), 1.55(d,3H). MS (ESI +, m / z): 581.2 [M + H] +

[0217] Example 69: (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 -(Tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine [Step 1] Preparation of methyl 5-methoxy-2-nitro-4((tetrahydro-2H-pyran-4-yl)amino)benzoate [ka] Methyl bromo-5-methoxy-2-nitrobenzoate (800 mg, 2.75 mmol), 4-aminotetrahydropyran hydrochloride (455 mg, 3.30 mmol), Pd(OAc) (43 mg, 0.19 mmol), (±)BINAP (120 mg, 0.19 mmol), and cesium carbonate (3.14 g, 9.64 mmol) were dissolved in 16 mL of 1,4-dioxane and stirred at 100 °C for 24 h. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to give the title compound (970 mg) in 91% yield. 1 H-NMR (300MHz, CDCl3): δ7.07(s,1H), 6.89(s,1H), 4.69(m,1H), 4.01(m,2H), 3.95(s,3H), 3.85(s,3H), 3.54(m,2H), 2.03(m,2H), 1.54(m,2H).

[0218] [Step-2] Preparation of methyl 2-amino-5-methoxy-4((tetrahydro-2H-pyran-4-yl)amino)benzoate [ka] Methyl 5-methoxy-2-nitro-4((tetrahydro-2H-pyran-4-yl)amino)benzoate (970 mg, 3.12 mmol) obtained in Step 1 above and iron (715 mg, 10.94 mmol) were dissolved in 10 mL of 1,4-dioxane:distilled water (4:1) and cooled to 0 °C. Ammonium chloride (836 mg, 15.62 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. Upon completion of the reaction, the reaction mixture was filtered through a filter filled with Celite and washed with dichloromethane. Water was added dropwise to the filtrate, which was then extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to give 850 mg of the title compound in 97% yield. 1 H-NMR (300MHz, CDCl3): δ6.88(s,1H), 5.53(s,1H), 5.24(s,2H), 3.35(m,1H), 3.72(m,2H), 3.54(m,6H), 3.26(m,2H), 1.74(m,2H), 1.26(m,2H).

[0219] [Step-3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol [ka] Methyl 2-amino-5-methoxy-4((tetrahydro-2H-pyran-4-yl)amino)benzoate (850 mg, 3.03 mmol) obtained in Step 2 above was dissolved in 3 mL of acetonitrile, and 6 mL of a 4N solution of hydrochloric acid in dioxane was added dropwise. The mixture was refluxed and stirred at 80°C for 2 hours. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding an aqueous solution of sodium bicarbonate dropwise. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to obtain 830 mg of the title compound in 95% yield. 1H-NMR (300MHz, DMSO-d6): δ7.23(s,1H), 6.62(s,1H), 5.52(m,1H), 3.85(m,5H), 3.63(m,1H), 3.49(m,1H), 2.25(s,3H), 1.89(m,2H), 1.54(m,2H).

[0220] [Step-4] Preparation of 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinazolin-7-amine [ka] 6-Methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol (200 mg, 0.69 mmol) obtained in Step 3 above was dissolved in 2 mL of phosphoryl chloride and refluxed at 100°C for 1 hour. Upon completion of the reaction, the mixture was cooled to room temperature and neutralized by adding aqueous sodium bicarbonate solution dropwise. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was used for the next step without further purification.

[0221] [Step-5] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 Preparation of 2H-(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine [ka] 4-Chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinazolin-7-amine (130 mg, 0.42 mmol) prepared in Step 4 above was dissolved in 2 mL of DMF, and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline (163 mg, 0.67 mmol) and DIPEA (0.23 mL, 1.26 mmol) were added. The mixture was stirred at 90 °C for 13 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, and the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to give 2 mg of the title compound in 1% yield. 11H-NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 6.96 (m, 2H), 6.80 (m, 1H), 6.61 (s, 1H), 5.63 (m, 1H), 3.98 (m, 5H), 3.68 (m, 1H), 3.58 (m, 2H), 2.44 (s, 3H), 2.04 (m, 2H), 1.67 (m, 5H). MS (ESI+, m / z): 476.2 [M+H] +

[0222]

Table 1

[0224] Briefly, glutathione S-transferase (GST)-labeled KRAS G12C protein (amino acid residues 2–169), streptavidin-tagged SOS1 protein (catalytic domain, amino acid residues 564–1049), anti-GST antibody (#61GSTKLA, purchased from CISBIO), and nucleic acid (#NU-820-647P1, purchased from Jena Bioscience) were mixed with the compounds in a buffer solution consisting of 10 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, and 1 mM dithiothreitol (DTT). The mixture was then added to a 384-well plate and incubated at room temperature. FRET signals were then measured using a Perkin Elmer Envision microplate reader. The excitation signal was measured at 320 nm, and the emission signal was measured at 615 / 665 nm. The fluorescence measurement value when SOS1 protein was not included was calculated as the background signal value, and was completely excluded from the measured HTRF values. The fluorescence measurement value when the synthesized compound was not included was measured as the non-inhibitory value (control value), and this value was selected as the 100% reference point. The fluorescence of the compounds of the examples was measured at concentrations of 1.6, 8, 40, 200, and 1,000 nM (5 points, 5-fold), and the 50% activity inhibition value (IC 50 ) was calculated using GraphPad Prism. The results, which show the KRAS G12C-SOS1 binding inhibitory ability of the compounds of the examples, are shown in Table 2 below.

[0225] I C 50 Values ​​below 50 nM are indicated as +++, values ​​above 50 nM up to 100 nM as ++, and values ​​above 100 nM as +.

[0226] [Table 2]

Claims

1. A compound selected from the group consisting of compounds of the following chemical formula 1, pharmaceutically acceptable salts, optical isomers, partial stereoisomers, hydrates and solvates thereof: [Chemical formula 1] 【Chemical 1】 In the above chemical formula 1, R １ is hydrogen or C １－４ is alkyl; R ２ is C １－４ Alkyl, haloC １－４ Alkyl, C ２－６ Alkenyl or C ２－６ is alkynyl; R ３ is R ３ａ or 【Chemistry 2】 can be; Each R ３ａ are each independently a halogen, hydroxy, cyano, amino, amine, nitro, oxo (=O), C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, HaloC １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy, hydroxy-C １－４ Alkyl, —CF ２ H, -(CH ２ ) ｒ —NH(CO)—R ａ or -(CH ２ ) ｒ -NR ａ R ｂ and R ａ and R ｂ are each independently hydrogen, C １－６ Alkyl, haloC １－６ Alkyl, hydroxy-C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, —CF ２ H and C ３－８ carbocyclyl; r is an integer from 0 to 1; m is an integer from 0 to 5; L ２ is a direct bond, —O—(CH ２ ) ｐ or -CH=CH-(CH ２ ) ｑ and p is an integer from 0 to 3; q is an integer from 0 to 2; 【Chemistry 3】 is phenyl, thiophenyl, or indanyl; 【Chemistry 4】 is C ６－１０ Aryl, C ４－１０ Heteroaryl, C ３－１０ Carbocyclyl, C ２－１０ Heterocyclyl or C ９－１２ bicyclic heterocyclyl, wherein 【Chemistry 5】 C ６－１０ Aryl, C ４－１０ Heteroaryl, C ３－１０ Carbocyclyl, C ２－１０ Heterocyclyl or C ９－１２ A bicyclic heterocyclyl is unsubstituted or has one or more R ３ａ may be substituted with; X １ is -O(R ４ ) or -N(R ５ ) (R ６ ) and R ４ is hydrogen, C １－６ Alkyl, hydroxy C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl, C ２－９ Heterocyclyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ８－１６ Spirocarbocyclyl, C ６－１４ Heterospirocarbocyclyl, C ８－１６ Fused carbocyclyl, C ６－１４ Fused heterocyclyl, C ８－１６ Bridged carbocyclyl or C ６－１４ and bridged heterocyclyls, which include halogen, hydroxy, nitro, oxo (=O), cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, —S(O)—C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR ｃ R ｄ , -C(O)OR ｃ , -OR ｃ or -NR ｃ R ｄ may be substituted or unsubstituted with, where R ｃ and R ｄ are each independently hydrogen or C １－６ is alkyl; R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, hydroxy C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl, C ２－９ Heterocyclyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ８－１６ Spirocarbocyclyl, C ６－１４ Heterospirocarbocyclyl, C ８－１６ Fused carbocyclyl, C ６－１４ Fused heterocyclyl, C ８－１６ Bridged carbocyclyl or C ６－１４ bridged heterocyclyl, wherein said C １－６ Alkyl, hydroxy C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl, C ２－９ Heterocyclyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ８－１６ Spirocarbocyclyl, C ６－１４ Heterospirocarbocyclyl, C ８－１６ Fused carbocyclyl, C ６－１４ Fused heterocyclyl, C ８－１６ Bridged carbocyclyl or C ６－１４ The bridged heterocyclyl may be unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, —S(O)—C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR ｅ R ｆ , -C(O)OR ｅ , -OR ｅ and -NR ｅ R ｆ wherein R ｅ and R ｆ are each independently hydrogen or C １－６ is alkyl, Alternatively, the -N(R ５ ) (R ６ ) is R ５ and R ６ are connected to each other to form -N(R ５ ) (R ６ C forming a ring together with the nitrogen atom in ２－９ Heterocyclyl, C ６－１４ Heterospirocarbocyclyl, C ６－１４ Fused heterocyclyl, C ６－１４ Bridged heterocyclyl or C ４－１０ heteroaryl, wherein the C ２－９ Heterocyclyl, C ６－１４ Heterospirocarbocyclyl, C ６－１４ Fused heterocyclyl, C ６－１４ Bridged heterocyclyl or C ４－１０ Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy, —S(O)—C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR ｇ R ｈ , -C(O)OR ｇ , -OR ｇ and -NR ｇ R ｈ wherein R ｇ and R ｈ are each independently hydrogen, C １－６ Alkyl, hydroxy-C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, HaloC １－６ Alkoxy or C ３－８ is carbocyclyl; L １ is a direct bond, —C(O)—, —O—, or —NH—; n is an integer from 0 to 2; 【Chemistry 6】 is C ３－１０ Carbocyclyl, C ２－９ Heterocyclyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ６－１４ Heterospirocarbocyclyl, C ６－１４ Fused heterocyclyl or C ６－１４ bridged heterocyclyl, wherein said C ３－１０ Carbocyclyl, C ２－９ Heterocyclyl, C ６－１０ Aryl, C ４－１０ Heteroaryl, C ６－１４ Heterospirocarbocyclyl, C ６－１４ Fused heterocyclyl or C ６－１４ The bridged heterocyclyl may be unsubstituted or may be substituted with halogen, hydroxy, nitro, oxo (=O), haloC １－６ Alkyl, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, —S(O)—C １－４ Alkyl, —S(O) ２ -C １－４ Alkyl, —C(O)—NR ｉ R ｊ , -C(O)OR ｉ , -OR ｉ and -NR ｉ R ｊ wherein R ｉ and R ｊ are each independently hydrogen or C １－６ is alkyl, Here, L １ When is a direct bond, X １ is -O(R ４ ) or —NH—, L １ When is -O-, 【Chemistry 7】 is tetrahydro-2H-pyran-4-yl or oxetan-3-ylmethoxy. 【Request 2】 【Chemical 8】 is C ６－１０ Aryl or C ４－１０ The compound of claim 1 which is heteroaryl.

3. R ３ａ are each independently halogen, hydroxy, cyano, amino, amine, nitro, C １－６ Alkyl, haloC １－６ Alkyl, Amino C １－６ Alkyl, C １－６ Alkoxy, —CF ２ H, C ６－１０ Aryl, C ３－６ Cyclyl, -(CH ２ ) ｒ -C ２－６ Heterocyclyl, -(CH ２ ) ｒ —NH(CO)—R ａ or -(CH ２ ) ｒ -NR ａ R ｂ where R ａ and R ｂ are each independently hydrogen, C １－６ Alkyl, —CF ３ or -CF ２ 2. The compound of claim 1, wherein R is H.

4. R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl or C ２－９ is heterocyclyl; R ５ and R ６ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl or C ２－９ heterocyclyl, or the —N(R ５ ) (R ６ ) is C ２－９ The compound of claim 1 which is heterocyclyl.

5. The compound represented by the above chemical formula 1 is the compound according to claim 1 represented by the following chemical formula 2: [Chemical formula 2] 【Chemistry 9】 In the above chemical formula 2, L １ is a direct bond, —C(O)—, —O—, or —NH—; n is an integer from 0 to 2; Z １ , Z ２ are each independently hydrogen, —F, or —CF ２ H, -CF ３ , -CH ３ or -NH ２ At this time, Z １ , Z ２ are both hydrogen; R ４ａ is hydrogen, C １－６ Alkyl, C ３－１０ Carbocyclyl or C ２－９ is heterocyclyl; 【Chemistry 10】 is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl is unsubstituted or is selected from the group consisting of halogen, —CH ３ may be substituted with one or more functional groups selected from the group consisting of:

6. The compound represented by the above Chemical Formula 1 is the compound according to claim 1 represented by the following Chemical Formula 3: [Chemical formula 3] 【Chemistry 11】 In the above chemical formula 3, L ３ is —C(O)—; n is an integer from 0 to 2; Z １ , Z ２ are each independently hydrogen, —F, or —CF ２ H, -CF ３ , -CH ３ or -NH ２ At this time, Z １ , Z ２ are both hydrogen; R ５ａ and R ５ｂ are each independently hydrogen, C １－６ Alkyl, C １－６ Alkoxy, C ３－１０ Carbocyclyl or C ２－９ is heterocyclyl, Alternatively, the -N(R ５ａ ) (R ５ｂ ) is R ５ａ and R ５ｂ are connected to each other to form -N(R ５ａ ) (R ５ｂ C forming a ring together with the nitrogen atom in ２－９ is heterocyclyl; 【Chemistry 12】 is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl is unsubstituted or is selected from the group consisting of halogen, —CH ３ may be substituted with one or more functional groups selected from the group consisting of:

7. The compound represented by the above chemical formula 2 is the compound according to claim 5 represented by the following chemical formula 4: [Chemical formula 4] 【Chemistry 13】 In the above chemical formula 4, L ４ is a direct bond or —C(O)—; n is an integer from 0 to 2; Z １ , Z ２ are each independently hydrogen, —F, or —CF ２ H, -CF ３ , -CH ３ or -NH ２ At this time, Z １ , Z ２ are both hydrogen; 【Chemistry 14】 is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, or tetrahydropyranyl, wherein said morpholinyl, piperazinyl, thiazolidinyl, or tetrahydropyranyl is unsubstituted or is selected from the group consisting of halogen and -CH ３ may be substituted with one or more functional groups selected from the group consisting of:

8. The compound represented by the above chemical formula 3 is the compound according to claim 6 represented by the following chemical formula 5: [Chemical formula 5] 【Chemistry 15】 In the above chemical formula 5, L ５ is —C(O)—; n is an integer from 0 to 2; Z １ , Z ２ are each independently hydrogen, —F, or —CF ２ H, -CF ３ , -CH ３ or -NH ２ At this time, Z １ , Z ２ are both hydrogen; 【Chemistry 16】 is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or is substituted with halogen or —CH ３ may be substituted with one or more functional groups selected from the group consisting of:

9. The compound of claim 1, wherein the compound of formula 1 is selected from the group consisting of the following compounds: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone; (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone; (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl))amino)ethyl)-5-(trifluoromethyl)phenylacetamide; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone; (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone; (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl))ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl))ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(fluorophenyl))ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile; (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone; Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine; (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine; (R)—N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)—N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine; (R)—N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone; (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N ６ , 2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; and (R)-N ４ -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N ７ -(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine.

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

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is used for treating cancer or tumors that can be treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

12. A pharmaceutical formulation comprising the pharmaceutical composition of claim 10.

13. 13. The pharmaceutical preparation according to claim 12, characterized in that the pharmaceutical preparation is in the form of a tablet, pill, powder, capsule, syrup or emulsion.

14. The pharmaceutical formulation according to claim 12, further comprising one or more selected from the group consisting of pharmaceutically acceptable carriers, strengthening agents, and excipients.

15. A method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in a subject or cell, comprising administering to the subject (other than a human) a pharmaceutically effective amount of a compound described in any one of claims 1 to 9.

16. 10. A method of inhibiting tyrosine kinase in a subject or cell (other than a human) comprising administering to the subject a pharmaceutically effective amount of a compound according to any one of claims 1 to 9.

17. 10. A method of preventing or treating cancer in a subject (non-human) comprising administering to the subject a pharmaceutically effective amount of a compound of any one of claims 1 to 9.

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