Novel quinazoline derivatives as SOS1 inhibitors and use thereof

Abstract

The present invention relates to a novel quinazoline derivative compound as a SOS1 inhibitor and to uses thereof. More particularly, the present invention relates to a novel quinazoline derivative compound having inhibitory activity on SOS1 binding to RAS family proteins and / or RAC1, to pharmacologically acceptable salts thereof, and to pharmaceutical compositions comprising such compounds.

Description

[Technical Field]

[0001] Field of Invention

[0002] This invention relates to a novel quinazoline-derived compound and its use as an SOS1 inhibitor, and more specifically, to a novel quinazoline-derived compound having activity of inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound. [Previous Technology]

[0003] Background of the Invention

[0004] Rat sarcoma virus (RAS) is a family of proteins found in 20% to 30% of human cancers and has been identified as the Kirstin RAS oncogene homolog (KRAS), the neuroblastoma RAS oncogene homolog (NRAS), and the Harvey rat sarcoma virus oncogene (HRAS). RAS regulates cell proliferation via the RAF / MEK / ERK pathway, which induces activation of mitogen-activated protein kinase (MAPK), and the PI3K / Akt / mTOR pathway, which involves phosphatidylinositol 3-kinase (PI3K). Cancer-associated mutations in RAS family proteins inhibit intrinsic GAP-induced GTPase activity, thereby increasing the number of GTP-binding / active RAS family proteins.

[0005] On the other hand, RAS proteins act as molecular switches, and GTP and GDP exist in the cell in active (GTP-bound) and inactive (GDP-bound) states. RAS bound to activating GTP recruits other proteins by binding to the homologous RAS binding domain (RBD) to activate effector proteins, and subsequently generates downstream signals for various functions. The active state of RAS is regulated by guanine nucleotide exchange factor (GEF) and GTPase activating protein (GAP). Binding to GTPase activating protein (GAP) such as NF1 increases the GTPase activity of RAS family proteins.

[0006] The binding of guanine nucleotide exchange factors (GEFs), such as Son of Sevenless 1 (SOS1), promotes the release of GDP from RAS family proteins, thereby allowing RAS family proteins to bind and activate GTP. The Son of Sevenless (SOS) protein exists in two isoforms, SOS1 and SOS2, with only SOS1 being phosphorylated by ERK. Growth factor-induced phosphorylation of SOS1 is primarily mediated by ERK, which phosphorylates at least four serine residues in the C-terminal region of SOS1. This indicates that SOS1 plays an important role in the negative feedback regulation of the KRAS pathway.

[0007] The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multi-regional protein, including the Dbl homology region (DH), followed by two tandem N-terminal histone regions (HD), a plextrin homology region (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology region, and a C-terminal proline-rich region (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 a synergistic site that binds to GTP-bound RAS family proteins, leading to a further increase in SOS1's catalytic GEF function. The selective pharmacological inhibition of SOS1 binding to the catalytic sites of RAS family proteins is expected to prevent SOS1-mediated RAS family protein activation via GTP binding.

[0008] It is anticipated that these SOS1 inhibitor compounds will thus inhibit signal transduction (i.e., ERK phosphorylation) downstream of RAS family proteins in cells. Therefore, novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site (confirmed by crystallography) and simultaneously prevent the binding and activation of RAS family proteins are being developed. Specifically, substances that significantly inhibit the interaction between SOS1 and RAS family proteins, especially KRAS (low IC50 value) in RAS family proteins, thereby inducing a significant reduction in ERK phosphorylation in KRAS-mutant cancer cell lines are being developed.

[0009] The inventors have discovered that novel quinazoline-derived compounds, as SOS1 inhibitors, have the activity of inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, thereby completing the present invention. [Summary of the Invention]

[0010] Invention Summary and Technical Solution

[0011] One objective of the present invention is to provide a novel quinazoline-derived compound that effectively inhibits the binding of SOS1 to RAS family proteins and / or RAC1.

[0012] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound. Technical Solution

[0013] According to one embodiment of the present invention, a compound is provided selected from the following compounds of Formula 1 and pharmaceutically acceptable salts, optical isomers, non-mirror image isomers, hydrates and solvates of compounds of Formula 1: [Formula 1] In Formula 1, R1 is hydrogen or C1-4 alkyl; R2 is hydrogen, C1-4 alkyl, halogroup C1-4 alkyl, C2-6 alkenyl or C2-6 alkynyl; R3 is R3a or -L2-; R3a is independently selected from any of the following: halogen, hydroxyl, cyano, amino, amine, nitro, oxy(=O), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, amino-C1-6 alkyl, C1-6 alkoxy, hydroxy-C1-4 alkyl, -CF2H, -(CH2)r-NH(CO)-Ra, -(CH2)r-NRaRb, and Ra and Rb are independently selected from any of the following groups: hydrogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -CF2H, and C3-8 carbocyclic; r is an integer in the range of 0 to 1; m is an integer in the range of 0 to 5; L2 is a direct bond, -O-(CH2)p or -CH=CH-(CH2)q; p is an integer in the range of 0 to 3; q is an integer in the range of 0 to 2; and each is independently a C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic, or C9-12 bicyclic heterocyclic, wherein the C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic, or C9-12 bicyclic heterocyclic is unsubstituted or substituted with one or more R3a; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic, and is unsubstituted or halogenated. The following groups are substituted with hydroxyl, nitro, lateral oxy (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRcRd, -C(O)ORc, -ORc or -NRcRd, wherein Rc and Rd are each independently hydrogen or C1-6 alkyl.R5 and R6 are each hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 crosslinked carbocyclic, or C6-14 bridged heterocyclic, wherein C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6- 10 aryl, C4-10 heteroaryl, C8-16 spirocyclocyclic, C6-14 heterospirocyclocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic are unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen, hydroxyl, nitro, oxy(=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRe Rf, -C(O)ORe, -ORe, and -NReRf, wherein Re and Rf are each independently hydrogen or C1-6 alkyl, and or, -N(R5)(R6) are C2-9 heterocyclic, C6-14 heterospirocyclic, C6-14 fused heterocyclic, C6-14 bridged heterocyclic, or C4-10 heteroaryl, wherein in each of them R5 and R6 are linked to each other and bonded to a nitrogen atom to form a ring, wherein the C2-9 heterocyclic, C6-14 heterospirocyclic, C6-14 fused heterocyclic, C6-14 bridged heterocyclic, or C4-10 heteroaryl are unsubstituted or selected from one or more of the following compositions. Functional group substitutions: halogen, hydroxyl, nitro, lateral oxygen (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRgRh, -C(O)ORg, -ORg, and -NRgRh, wherein Rg and Rh are each independently hydrogen, C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, or C3-8 carbocyclic; L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer in the range of 0 to 2;And C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic, wherein the C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic are unsubstituted or have been selected from one or more... The functional groups are substituted by: halogen, hydroxyl, nitro, oxy(=O), halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRiRj, -C(O)ORi, -ORi, and -NRiRj, wherein Ri and Rj are each independently hydrogen or C1-6 alkyl.

[0014] According to another embodiment of the present invention, a pharmaceutical composition and pharmaceutical preparation are provided for the prevention or treatment of various diseases related to the inhibition of the binding of SOS1 to RAS family proteins and / or RAC1, the composition and preparation comprising a therapeutically effective amount of the compounds described above.

[0015] According to another embodiment of the present invention, a method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in an individual or cell is provided, the method comprising administering to the individual a pharmaceutically effective amount of a compound.

[0016] According to yet another embodiment of the present invention, a method for inhibiting tyrosine kinase in an individual or cell is provided, the method comprising administering to the individual a pharmaceutically effective amount of a compound.

[0017] According to yet another embodiment of the present invention, a method for preventing or treating cancer in an individual is provided, the method comprising administering to the individual a pharmaceutically effective amount of a compound.

[0018] According to yet another embodiment of the present invention, the use of the compounds or pharmaceutically acceptable salts described above is provided for the prevention or treatment of cancer or tumors. Beneficial effects

[0019] The quinazoline derivative compound of chemical formula 1 in this invention has excellent ability to inhibit the binding of SOS1 to RAS family proteins and / or RAC1, has anticancer activity against cancers associated with cell proliferation attributable to abnormal SOS1 activity, and can be effectively used as a therapeutic agent.

Implementation Method

[0020] Detailed Description of Preferred Embodiments

[0021] Unless otherwise defined, all technical terms used in this invention have the meanings commonly understood by those skilled in the art. Furthermore, although preferred methods and samples are described herein, similar or equivalent methods are also within the scope of this invention. Additionally, even if not explicitly stated, numerical values ​​described herein are to include the meaning of "about". All disclosures herein are incorporated by reference in their entirety.

[0022] In chemical formula 1, residues listed as R1 to R6 are used as commonly understood by those skilled in the art.

[0023] In this invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine, or iodine. Specifically, the term "halogen" may refer to fluorine or chlorine, but is not limited thereto.

[0024] As used herein, unless otherwise specified, the term "alkyl" means a saturated straight-chain or branched monovalent hydrocarbon group.

[0025] In this invention, unless otherwise specified, the term "alkenyl" refers to a monovalent hydrocarbon group containing at least one carbon-carbon double bond, each double bond having a three-dimensional E or Z arrangement.

[0026] Unless otherwise specified, as used herein, the term "alkynyl" means a monovalent group derived from an unsaturated straight-chain or branched hydrocarbon moiety having at least one carbon-carbon linkage.

[0027] These alkyl, alkenyl, and alkynyl groups can be straight (i.e., straight-chain) or branched. As defined, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, or 6, or 1, 2, 3, or 4. Examples of alkyl groups include: methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, secondary butyl, isobutyl, and tertiary butyl; pentyl, including n-pentyl, 1-methylbutyl, isopentyl, neopentyl, and tertiary pentyl; and hexyl, including n-hexyl, 3,3-dimethylbutyl, and isohexyl. Each of the double and triple bonds in an alkenyl and alkynyl group can be present in any position. Examples of alkenyl and alkynyl groups are vinyl, 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 (=propynyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl, or hex-5-ynyl. However, each of the alkyl, alkenyl, and alkynyl groups can be substituted at any position, provided that the compound is sufficiently stable and suitable for the intended purpose, such as use as a pharmaceutical substance.

[0028] In this invention, unless otherwise specified, the term "carbocyclic" refers to a substituted or unsubstituted cycloalkyl group and may refer to a monocyclic or bicyclic aliphatic group. Preferably, examples of carbocyclic groups include, but are not limited to, aryl, carbocyclic, spirocyclic, fused carbocyclic, and bridged carbocyclic groups. More preferably, examples of -1-carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantane-1-yl, decahydronaphthyl, cyclohexyl-side-oxy-side-oxy-cyclohexyl, dicyclohexyl-side-oxy-side-oxy-cyclohexyl, thiocyclohexyl, 2-cyclohexyl-side-oxy-bicyclo[2.2.1]hept-1-enyl or all possible isomers thereof, but are not limited thereto.

[0029] In this invention, the term "heterocyclic group" refers to a monocyclic, bicyclic, or polycyclic alkyl group containing one or more (specifically, 1, 2, 3, or 4) heteroatoms selected from O, N, and S, and may be substituted or unsubstituted. Preferably, examples of heterocyclic groups include, but are not limited to, heteroaryl, heterocyclic, heterospirocyclic, fused heterocyclic, and bridged heterocyclic groups. More preferably, examples of heterocyclic groups include, but are not limited to, piperidinyl, piperidinyl, piperidinyl-1-oxide, piperinyl, thiaperinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, diazabicyclooctyl, diazaspirooctyl, and similar groups. For example, in the case of C2-10 heterocyclic groups, C2-10 represents the number of carbon atoms, meaning the ring size of a 3-membered or larger ring containing one or more heteroatoms.

[0030] In this invention, unless otherwise specified, the term "aryl" refers to an aromatic group, whether substituted or unsubstituted. For example, aryl includes, but is not limited to, phenyl, biphenyl, naphthyl, toluenemethyl, naphthyl, anthracene, and all their isomers.

[0031] In this invention, the term "heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic group containing one or more (specifically, 1, 2, 3, or 4) heteroatoms selected from O, N, and S, and may be substituted or unsubstituted. Preferably, examples of monocyclic heteroaryl groups include, but are not limited to, thiazolyl, acezolyl, thiophene, furanyl, pyrrolyl, imidazolyl, isoacezolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, acezolyl, pyridinyl, pyridinyl, pyridyl, and similar groups. Preferably, examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiopheneyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, purinepyridyl, and similar groups.

[0032] In this invention, the numerical range indicated by the term "to" refers to the range that includes the values ​​described before and after the term "to" as the lower limit and the upper limit, respectively.

[0033] As used herein, the term “binding of SOS1 to RAS family proteins and / or RAC1” refers to the binding of SOS1 to RAS family proteins at the catalytic site of SOS1, and “inhibition of binding activity” refers to the GTP binding form that prevents SOS1-mediated activation of RAS family proteins.

[0034] As used herein, the term "SOS1 inhibitor compound" refers to a compound that inhibits the signal transduction of RAS family proteins to downstream cells, such as by inhibiting ERK phosphorylation. Specifically, "SOS1 inhibitor compound" means a compound that binds to the SOS1 catalytic site, thereby preventing SOS1 from binding to RAS family proteins or preventing the activation of RAS family proteins.

[0035] In this invention, unless otherwise stated, the term "mirror image isomer" refers to various possible stereoisomers and geometric isomers of the compounds according to the invention. Since a compound of Formula 1 according to the invention may have an asymmetric carbon center (absence of carbon), the compound may exist as a mirror image isomer (R or S isomer), a racemic mixture, a non-mirror image isomer, or any mixture thereof. All such isomers and mixtures are within the scope of this invention. Optically active (R)-isomers and (S)-isomers can be analyzed using known techniques or prepared using palmitic synthetic components or palmitic reagents. When the compound contains a double bond, the substituent may be in the E or Z form. When the compound contains a bisubstituted carbocyclic group, the compound may be in the cis or trans form. Additionally, when the compound of Formula 1 includes a bridged ring, the compound may exist as an exo-isomer or an endo-isomer. Furthermore, all tautomers may also be included.

[0036] In this invention, unless otherwise stated, the term "asymmetric carbon atom" refers to the carbon atom in a molecule containing four different atoms, groups of atoms, or functional groups bonded to the carbon atom. In the case of compounds containing such asymmetric carbon atoms, the compound exhibits optical rotation properties or isomerism. Specifically, a compound having the structure of Formula 1 with asymmetric carbon atoms can be a compound having the structure of Formula 1a or Formula 1b. On the other hand, a 1:1 mixture of a pair of mirror-image isomers is called a "racemic" mixture. [Formula 1a]

[0037] In chemical formula 1a, R1 to R3, X1, L1, m, and n are defined in the same manner as in chemical formula 1. [Chemical formula 1b]

[0038] In chemical formula 1b, R1 to R3, X1, L1, m and n are defined in the same manner as in chemical formula 1.

[0039] In a sample, a compound of formula 1, its optical isomers, and its non-mirror image isomers may exist as solvates. The term "solvate" may include molecular complexes, each containing a compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. Complexes in which the solvent molecule is water are called "hydrates".

[0040] In a sample, a compound of formula 1, its optical isomers and non-mirror isomers, and its solvates may be present in pharmaceutically acceptable salt forms.

[0041] In this invention, the term "pharmaceutically acceptable salt" refers to salts that are of low toxicity to humans and do 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 formed from pharmaceutically acceptable free acids and basic compounds of Formula 1, alkali metal salts (such as sodium salts), and alkaline earth metal salts (such as calcium salts); organic base addition salts formed from organic bases and carboxylic acid structures of Formula 1; and amino acid addition salts.

[0042] Preferred salt forms of the compounds according to the present invention include salts of inorganic or organic acids. In this case, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, and similar acids can be used as inorganic acids. Additionally, 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, glutamic acid, and similar acids can be used as organic acids. Organic bases that can be used to prepare organic base addition salts are trimethylolamine, dicyclohexylamine, and similar bases. Amino acids that can be used to prepare amino acid addition salts are natural amino acids, such as alanine and glycine. Those skilled in the art will readily appreciate that other acids or bases besides the inorganic acids, organic acids, organic bases, and amino acids exemplified above can be used.

[0043] Salts can be prepared by conventional methods. For example, salts can be prepared by dissolving a compound of formula 1 in a water-miscible solvent, such as methanol, ethanol, acetone and 1,4-dimethylalkanes; adding a free acid or a free base to the resulting solution; and crystallizing the resulting product.

[0044] The details in the description of a pharmaceutical composition according to one aspect of the present invention are applicable to the prevention or treatment methods according to another aspect of the present invention.

[0045] In this invention, the term "treatment" is used as a concept that includes all meanings of treating, improving, alleviating or managing a disease.

[0046] As used herein, the term “preventing / prevention” means preventing an individual from having a disease, symptom or condition that is susceptible to disease, symptom or condition but has not yet experienced or exhibited any lesion or symptom of the disease.

[0047] As used herein, the terms “individual” or “patient” mean any mammal, such as animals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates; and humans.

[0048] The present invention will be described in more detail below. [Chemical Formula 1] In Chemical Formula 1, R1 is hydrogen or C1-4 alkyl; R2 is hydrogen, C1-4 alkyl, halo-C1-4 alkyl, C2-6 alkenyl or C2-6 ynyl; R3 is R3a or -L2-; R3a is independently a halogen, hydroxyl, cyano, amino, amine, nitro, lateral oxygen (=O), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, amino-C1-6 alkyl, C1-6 alkoxy, hydroxy-C1-4 alkyl, -CF2H, -(CH2)r-NH(CO)-Ra or -(CH2)r-NRaRb, wherein Ra and Rb are independently selected from any of the following groups: hydrogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -CF2H and C3-8 carbocyclic; r is an integer in the range of 0 to 1; m is an integer in the range of 0 to 5; L2 is a direct bond, -O-(CH2)p or -CH=CH-(CH2)q; p is an integer in the range of 0 to 3; q is an integer in the range of 0 to 2; and each is independently a C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic, or C9-12 bicyclic heterocyclic, wherein the C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic, or C9-12 bicyclic heterocyclic is unsubstituted or substituted with one or more R3a; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic, each of which is unsubstituted or untreated. Halogen, hydroxyl, nitro, lateral oxy (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRcRd, -C(O)ORc, -ORc or -NRcRd substitution, wherein Rc and Rd are each independently hydrogen or C1-6 alkyl;R5 and R6 are each hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic, wherein C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, or C6-10 aryl are used. C4-10 heteroaryl, C8-16 spirocyclocyclic, C6-14 heterospirocyclocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic or C6-14 bridged heterocyclic, unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen, hydroxyl, nitro, oxy(=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NReRf, -C(O) ORe, -ORe, and -NReRf, wherein Re and Rf are each independently hydrogen or C1-6 alkyl, or, the -N(R5)(R6) is a C2-9 heterocyclic group, a C6-14 heterospirocyclic group, a C6-14 fused heterocyclic group, a C6-14 bridged heterocyclic group, or a C4-10 heteroaryl group, wherein in each of these, R5 and R6 are linked to each other and bonded to the nitrogen atom contained in the -N(R5)(R6) to form a ring, wherein the C2-9 heterocyclic group, C6-14 heterospirocyclic group, C6-14 fused heterocyclic group, C6-14 bridged heterocyclic group, or C4-10 heteroaryl group is unsubstituted or selected from one or more of the following: The functional group substitutions of the following groups are: halogen, hydroxyl, nitro, oxy- (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRgRh, -C(O)ORg, -ORg, and -NRgRh, wherein Rg and Rh are each independently hydrogen, C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, or C3-8 carbocyclic; L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer in the range of 0 to 2;And C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic, wherein the C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic are unsubstituted or have been selected from one or more... The functional groups are substituted by: halogen, hydroxyl, nitro, oxy(=O), halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRiRj, -C(O)ORi, -ORi, and -NRiRj, wherein Ri and Rj are each independently hydrogen or C1-6 alkyl.

[0049] Preferably, the compound selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their non-mirror image isomers, their hydrates and their solvates, and each is independently C6-10 aryl or C4-10 heteroaryl.

[0050] Preferably, in compounds selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their non-mirror image isomers, their hydrates and their solvates, R3a may each independently be a halogen, hydroxyl, cyano, amino, amine, nitro, C1-6 alkyl, aminoC1-6 alkyl, C1-6 alkoxy, -CF2H, C6-10 aryl, C3-6 cycloyl, -(CH2)r-C2-6 heterocyclic, -(CH2)r-NH(CO)-Ra or -(CH2)r-NRaRb, wherein Ra and Rb may each independently be hydrogen, C1-6 alkyl, -CF3 or -CF2H.

[0051] Preferably, in the compounds selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their hydrates and their solvates, R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic or C2-9 heterocyclic, and R5 and R6 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic or C2-9 heterocyclic, or -N(R5)(R6) is a C2-9 heterocyclic.

[0052] According to another embodiment of the present invention, the compound represented by chemical formula 1 can be represented by chemical formula 2 as follows: [chemical formula 2] In chemical formula 2, L1 is a direct bond, -C(O)-, -O- or -NH-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where Z1 and Z2 are both hydrogen; R4a is hydrogen, C1-6 alkyl, C3-10 carbocyclic or C2-9 heterocyclic; it is arginyl, thioarginyl, dioxythioarginyl, piperyl, thiazodinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetyl or azirone, wherein the arginyl, thioarginyl, dioxythioarginyl, piperyl, thiazodinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetyl or azirone is unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen or -CH3.

[0053] According to another embodiment of the present invention, a compound represented by Chemical Formula 1 may be represented by Chemical Formula 3 as follows: [Chemical Formula 3] In Chemical Formula 3, L3 is a direct bond or -C(O)-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where Z1 and Z2 are both hydrogen; R5a and R5b are each independently hydrogen, C1-6 alkyl, C1 -6 alkoxy, C3-10 carbocyclic, or C2-9 heterocyclic, or -N(R5a)(R5b) is a C2-9 heterocyclic group, wherein R5a and R5b are linked to each other and bonded to the nitrogen atom contained in -N(R5a)(R5b) to form a ring; or α-phylinyl, di-oxythio-α-phylinyl, thio-α-phylinyl, piperyl, thiazolinyl, tetrahydropiperanyl, hexahydro-1H- Furano[3,4-c]pyrrole, oxetane or azirone, wherein the phosphono, dioxythiophosphono, thiophosphono, piperyl, thiazolinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetane or azirone is unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen or -CH3.

[0054] According to yet another embodiment of the present invention, the compound represented by chemical formula 2 may be represented by chemical formula 4 as follows: [chemical formula 4] In chemical formula 4, L4 is a direct bond, -C(O)- or -O-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; and is α-linyl, thio-α-linyl, piperinyl, thiazodinyl or tetrahydropiperanyl, wherein the α-linyl, thio-α-linyl, piperinyl, thiazodinyl or tetrahydropiperanyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH3.

[0055] According to yet another embodiment of the present invention, a compound represented by chemical formula 3 may be represented by chemical formula 5 as follows: [chemical formula 5] In chemical formula 5, L5 is a direct bond or -C(O)-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; is α-linyl, dioxythioα-linyl, thioα-linyl, piperyl, thiazodinyl or hexahydro-1H-furano[3,4-c]pyrrole, wherein the α-linyl, dioxythioα-linyl, thioα-linyl, piperyl, thiazodinyl or hexahydro-1H-furano[3,4-c]pyrrole is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH3.

[0056] In addition, preferred examples of compounds of Formula 1 according to the present invention are as follows, but not limited thereto: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) methyl ketone; (6-methoxy-2-methyl-4-((1-(4-(2-(((methylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)quinazoline-7-yl)(N-pyrinyl) methyl ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)((3R, 5S)-3,5-dimethylpiperazine-1-yl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(thio(N-α-linyl)) ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) ketone; (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-α-linyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(azacyclobutane-1-yl) ketone; (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinoline-8-yl)thiophene-2-yl)ethyl)amino)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(piperazolinyl) ketone; (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(othioline-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-fluoroazacyclobutane-1-yl) ketone; (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(N-othioline) ketone; (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone;(4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(1,1-disideloxythio(N-pyrinyl)) ketone; (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(thiazolinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(𠰌lin-4-carbonyl)quinazoline-4-yl)amino)ethyl)benzonitrile; (R)-(4-((1-(2,3-dihydro-1H-indene-4-yl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone;(R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(thiazoline-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; Methyl(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((N-α-linyl)methyl)quinazoline-4-amine; (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((N-hydroxyl)methyl)quinazoline-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazoline-4-amine; (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazoline-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)methoxy)quinazolin-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxocyclobutane-3-ylmethoxy)quinazolin-4-amine; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazoline-7-yl)(N-pyrrolidone); (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazoline-7-yl)(N-pyrrolidone);(R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)((R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-piperan-4-yl)amino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-((N-pyrinyl)methyl)quinazoline-4,6-diamine; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(thiazolin-3-yl) ketone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazoline-7-(yl)(N-pyrinyl)methyl ketone;(R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazoline-7-yl)(N-hydroxyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(4-methylpiperazolin-1-yl) methyl ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(1,1-dioxythio(N-hydroxyl)) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(thio(N-hydroxyl)) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(piperazolinyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azirmonobutane-1-yl) ketone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxythio(N-hydroxylinyl)) ketone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl) methyl ketone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) methyl ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxythio(N-hydroxyl)) methyl ketone;(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazoline-7-yl)(1,1-disideloxythio(N-hydroxylinyl)) methyl ketone; and (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-piperan-4-yl)quinazoline-4,7-diamine;

[0057] In this invention, the method for preparing the compound of formula 1 is not specifically limited. For example, the compound of formula 1 can be synthesized by the following preparation method of reaction formula 1 or reaction formula 2: [Reaction Formula 1]

[0058] In reaction formula 1, R1, R2, R3, R4, m, and others are the same as defined in chemical formula 1, but are not limited thereto. [Step 1]

[0059] 2-Bromoterephthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5°C to 5°C, and refluxed for 4 to 6 minutes. After mixing the sulfuric acid and nitric acid, the mixture was slowly added dropwise to the reaction product at a temperature ranging from 0°C to 5°C. After the dropwise addition was complete, the solution was refluxed at 95°C to 110°C for 1 to 3 hours. After the reaction was complete, the result was cooled to room temperature and refluxed at room temperature for 11 to 13 hours. Ice water was slowly added dropwise to the reaction product. The reaction product 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 produce the target compound. [Step 2]

[0060] The B (1 equivalent), sodium acetate (2.2 equivalents), sodium hydroxide (3 equivalents), and copper (0.01 equivalents) prepared in [Step 1] were dissolved in distilled water, and the resulting solution was stirred and refluxed under microwave at 110°C to 130°C for 1.5 to 3 hours. After the reaction was complete, the solution was cooled to room temperature, filtered through a filter filled with diatomaceous earth, and washed with water. The aqueous layer obtained through filtration was acidified with 6N hydrochloric acid until the pH became 1-2. The acidified aqueous solution was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the target compound. [Step 3]

[0061] The C (1 equivalent) and sulfuric acid (1 equivalent) prepared in [Step 2] were dissolved in methanol, and the mixture was stirred and refluxed at 65°C to 75°C for 60 to 70 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated solution was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain the target compound. [Step 4]

[0062] The D (1 equivalent), iodomethane (8 equivalents), and potassium carbonate (8 equivalents) obtained in [Step 3] were dissolved in acetone, and the mixture was stirred and refluxed at 50°C to 70°C for 16 to 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in distilled water and ethyl acetate, and extracted three times with ethyl acetate to obtain an organic layer. The obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC to obtain the target compound. [Step 5]

[0063] The E (1 equivalent) prepared in [Step 4] was dissolved in a mixed solution of ethyl acetate and ethanol, and Pd / C was added to it. The reaction solution was stirred at 45°C to 55°C under a hydrogen atmosphere for 16 to 24 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with water. The filtered organic layer was concentrated under reduced pressure, and the residue obtained was purified by MPLC to obtain the target compound. [Step 6]

[0064] The F (1 equivalent) obtained in [Step 5] was dissolved in tetrahydrofuran, and 4% potassium hydroxide was slowly added dropwise. The mixture was stirred at 65°C to 75°C for 2 to 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the organic layer and obtain an aqueous layer. The aqueous layer was acidified with 6N hydrochloric acid to a pH of 1-2, thus obtaining a solid product. The obtained solid product was filtered under reduced pressure, and the remaining solid after filtration was washed with distilled water. The filtered solid was dried in an oven dryer at 50°C to 60°C to obtain the target compound. [Step 7]

[0065] The G (1 equivalent), acetamiprine hydrochloride (2 equivalents), and sodium acetate (2 equivalents) obtained in [Step 6] were dissolved in 2-methoxyethanol, and the solution was stirred and refluxed at 140°C to 160°C for 12 to 20 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and distilled water was added dropwise, while the solution was stirred at 0°C to 5°C for 0.5 to 1 hour to obtain a solid product. The obtained solid product was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven desiccator at 50°C to 60°C to obtain the target compound. [Step 8]

[0066] The H (1 equivalent), amine (1.5 equivalent), HATU (3 equivalent), and DIPEA (5 equivalent) obtained in [Step 7] were dissolved in DMF, and the resulting solution was stirred under reflux at room temperature for 2 to 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid product was filtered under reduced pressure, and the filtered solid was washed with distilled water to obtain the target compound. [Step 9]

[0067] The I (1 equivalent) obtained in [Step 8] was dissolved in phosphine chloride and refluxed at 105°C to 114°C for 1 to 2.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature and neutralized by dropwise addition of an aqueous sodium bicarbonate solution. The result was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the target compound. [Step 10]

[0068] The J (1 equivalent), aniline (1.1 equivalent), and DIPEA (4 equivalent) obtained in [Step 9] were dissolved in DMF, and the solution was stirred under reflux at 95°C to 110°C for 12 to 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then water was added dropwise. The result 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 target compound. [Reaction 2]

[0069] In reaction formula 2, R1, R2, R3, R4, m, and others are the same as defined in chemical formula 1, but are not limited thereto. [Step 1]

[0070] Methyl 3-methoxy-4-methylbenzoate (1 equivalent) was mixed with acetic acid and water, and then bromine (1.1 equivalent) was added dropwise. After the dropwise addition was complete, the solution was refluxed at 50°C to 60°C for 1 to 2 hours. After the reaction was complete, the result was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. The aqueous solution was extracted with hexane / ether solution, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound. [Step 2]

[0071] The B (1 equivalent), N-bromobutyldiimidine (0.9 equivalent), and azobisisobutyronitrile (0.2 equivalent) obtained in [Step 1] were dissolved in chloroform and refluxed at 65°C to 70°C with stirring for 1.5 to 3 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. After extraction with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC to obtain the target compound. [Step 3]

[0072] The C (1 equivalent), amine (1.1 equivalent), and potassium carbonate (2 equivalent) obtained in [Step 2] were dissolved in acetonitrile and stirred at 20°C to 30°C for 17 to 20 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. After extraction with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC to obtain the target compound. [Step 4]

[0073] The D (1 equivalent), tributyl carbamate (1.1 equivalent), xantphos (0.2 equivalent), Pd2(dba)3dba (0.1 equivalent), and cesium carbonate (3 equivalent) obtained in [Step 3] were dissolved in 1,4-dimethylbenzene and stirred at 100°C to 120°C for 1 to 3 hours. After the reaction was complete, the result was cooled to room temperature, filtered through a filter filled with diatomaceous earth, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the residue obtained was purified by MPLC to obtain the target compound. [Step 5]

[0074] The E (1 equivalent) obtained in [Step 4] was dissolved in acetonitrile, and a 4N dichlorodimethyl chloride solution was added dropwise. The mixture was stirred and refluxed at 70°C to 90°C for 1 to 3 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous sodium bicarbonate solution was added dropwise to neutralize it. The reaction product was extracted with anhydrous sodium sulfate, dried, and then concentrated under reduced pressure. The residue was cured with ethyl acetate and filtered under reduced pressure. The solid obtained through filtration was dried to obtain the target compound. [Step 6]

[0075] The F (1 equivalent), aniline (1.5 equivalent), PyBOP (1.5 equivalent), and DBU (2.5 equivalent) obtained in [Step 5] above were dissolved in acetonitrile and stirred at 75°C to 85°C for 4 to 6 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then water was added dropwise. The result 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 target compound.

[0076] In this invention, the method for preparing the compound of Formula 1 is not specifically limited. For example, the compound of Formula 1 can be synthesized by the preparation method represented by the following reaction formula 3: [Reaction Formula 3] In reaction formula 3, R1, R2, R3, R5, m are the same as defined in Formula 1, but are not limited thereto. [Step 1]

[0077] 2-Bromophthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5°C to 5°C, and refluxed for 4 to 6 minutes. After mixing the sulfuric acid and nitric acid, the mixture was slowly added dropwise to the reaction product at a temperature ranging from 0°C to 5°C. After the dropwise addition was complete, the solution was refluxed at 95°C to 110°C for 1 to 3 hours. After the reaction was complete, the result was cooled to room temperature and refluxed at room temperature for 11 to 13 hours. Ice water was slowly added dropwise to the reaction product. The reaction product 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 produce the target compound. [Step 2]

[0078] The B (1 equivalent) and sulfuric acid (1 equivalent) prepared in [Step 1] above are dissolved in methanol, and the mixture is stirred and refluxed at 65°C to 75°C for 60 to 70 hours. After the reaction is complete, the reaction solution is cooled to room temperature and concentrated under reduced pressure. The concentrated solution is extracted three times with ethyl acetate, and the organic layer is dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer is concentrated under reduced pressure to obtain the target compound. [Step 3]

[0079] The C (1 equivalent), amine (5 equivalents), and DIPEA (10 equivalents) prepared in [Step 2] were dissolved in DMF and stirred and refluxed at 95°C to 105°C for 1 to 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and added dropwise to distilled water. The product was filtered under reduced pressure to obtain the target compound. [Step 4]

[0080] The D (1 equivalent) and zinc powder (3.5 equivalents) obtained in [Step 3] were dissolved in a mixed solution of dimethyl ether and distilled water, and the mixture was stirred under reflux at 25°C to 30°C for 0.5 to 1 hour. After stirring, the reaction solution was cooled to 0°C to 5°C, and ammonium chloride (5 equivalents) was added dropwise. After the dropwise addition, the mixture was stirred under reflux at 25°C to 30°C for 1 to 3 hours. After the reaction was complete, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with ethyl acetate. The obtained product was dissolved in distilled water and ethyl acetate, and then extracted three times with ethyl acetate to produce an organic layer. The obtained 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 residue was purified by column chromatography to obtain the target compound. [Step 5]

[0081] The E (1 equivalent) and acetonitrile (8 equivalents) prepared in [Step 4] were dissolved in a 4N hydrochloric acid solution dissolved in dimethyl ether, and the reaction solution was stirred at 85°C to 95°C for 2.5 to 3.5 hours using a sealed tube. After the reaction was complete, the reaction solution was filtered through a filter and washed with hexane. The resulting solid was neutralized with sodium bicarbonate and filtered under reduced pressure to obtain the target compound. [Step 6]

[0082] The F (1 equivalent) obtained in [Step 5] above was dissolved in phosphine chloride and stirred at 110°C to 130°C for 2 to 4 hours. When the reaction was complete, the organic layer was removed by concentration under reduced pressure, and the obtained residue was dissolved in dichloromethane and neutralized with an aqueous sodium bicarbonate solution 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 then concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain the target compound. [Step 7]

[0083] The G (1 equivalent), aniline (1.3 equivalents), and DIPEA (3 equivalents) obtained in [Step 6] above were dissolved in DMF, and then stirred under reflux at 85°C-100°C for 12 to 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and then water was added dropwise. The result 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 target compound. [Step 8]

[0084] The H (1 equivalent) obtained in [Step 7] was dissolved in a mixed solution of tetrahydrofuran, methanol, and water, and sodium hydroxide (5 equivalents) was added. The solution was stirred under reflux at 25°C to 30°C for 1 to 3 hours. After the reaction was complete, 2N HCl aqueous solution was added dropwise to adjust the pH to 5 to 6, and the product was then washed with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound. The unpurified target compound, amine (1.1 equivalents), HATU (1.3 equivalents), and DIPEA (3 equivalents) were dissolved in DMF, and then stirred under reflux at 25°C to 30°C for 1 to 3 hours. After the reaction was complete, the reaction product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography to obtain the target compound.

[0085] Although the preparation method of Formula 1 has been described with specific examples, the specific reaction conditions, such as the solvents, bases and amounts of reactants used, are not limited to those described herein and should not be regarded as limiting the scope of the rights.

[0086] The pharmaceutical composition of the present invention can be used for the prevention or treatment of various diseases related to the inhibition of SOS1 binding, because the chemical formula 1 compound contained in the pharmaceutical composition inhibits the binding of SOS1 to RAS family proteins and / or RAC1.

[0087] In one embodiment, the compounds of the present invention exhibit minimal inhibitory activity against cytochrome P450 enzyme (CYP) isoforms, thereby reducing side effects, such as drug-drug interactions, that may result from reduced activity of the P450 enzyme (CYP) isoforms. Therefore, the compounds of the present invention can be used for polypharmacy (multiple drug use). In a specific embodiment, the compounds of the present invention have a structure of chemical formula 2 or chemical formula 3 and exhibit minimal inhibitory activity against cytochrome P450 enzyme isoforms. In another specific embodiment, the compounds of the present invention have a structure of chemical formula 4 or chemical formula 5 and retain excellent activity against cytochrome P450 enzyme isoforms. For example, the compounds of chemical formula 4 or chemical formula 5 of the present invention exhibit an IC50 value of at least 20 μM regarding their inhibitory activity against cytochrome P450 enzyme (CYP) isoforms.

[0088] According to another embodiment of the present invention, a preventive or therapeutic pharmaceutical composition is provided, comprising a compound of formula 1 as an active ingredient and a pharmaceutically acceptable salt thereof.

[0089] According to another embodiment of the present invention, a pharmaceutical preparation is provided, which includes the above-mentioned pharmaceutical components.

[0090] The pharmaceutical preparations of the present invention may be in various oral dosage forms, such as tablets, pills, powders, capsules, syrups or emulsions, or in non-enteral dosage forms, such as injections administered intramuscularly, intravenously or subcutaneously. Preferably, the pharmaceutical preparations may be in oral dosage forms.

[0091] In addition, pharmaceutical preparations can be formulated by adding one or more non-toxic, pharmaceutically acceptable additives, such as those selected from the group consisting of carriers, adjuvants and excipients, to the active ingredient according to conventional methods.

[0092] Excipients that can be used in pharmaceutical preparations of the present invention include, but are not limited to, sweeteners, binders, solvents, solubilizers, humectants, emulsifiers, isotonics, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, and flavorings. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silicon dioxide, magnesium aluminum silicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, citrus flavoring, strawberry flavoring, and vanilla flavoring.

[0093] When the pharmaceutical preparation of the present invention is an oral dosage form, examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc and the like, but are not limited thereto.

[0094] When the pharmaceutical preparation of the present invention is in the form of an injection, examples of the carrier include water, physiological saline, aqueous glucose solution, pseudoglucose solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc., but are not limited thereto.

[0095] For use as pharmaceutical preparations, the compounds according to the present invention are prepared in the form of pharmaceutical formulations, which, in addition to the active ingredients for oral or intestinal administration, include pharmaceutically suitable organic or inorganic inert carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oil, polyvinyl alcohol, and the like. Pharmaceutical formulations may be in solid form, such as lozenges, sugar-coated pills, suppositories, or capsules, or in liquid form, such as solutions, suspensions, or emulsions. They may also optionally contain adjuvants, such as preservatives, stabilizers, humectants, or emulsifiers. They may also contain salts or buffers for altering osmotic pressure.

[0096] For non-enteral administration, injectable solutions or suspensions are particularly preferred.

[0097] Surfactant adjuvants (e.g., bile salts, animal or plant phospholipids or mixtures thereof) and liposomes or components thereof may also be used as carrier systems.

[0098] For oral administration, tablets, sugar-coated pills, or capsules containing talc and / or a catalytic agent or binder are particularly suitable. For example, tablets, sugar-coated pills, or capsules containing lactose, corn starch, or potato starch are preferred. They can also be administered in liquid form, such as in fruit juice with added sweeteners.

[0099] Furthermore, based on an average adult patient weighing 70 kg, the human dose of the compound of Formula 1 according to the present invention is preferably in the range of 0.1 mg / day to 2,000 mg / day. The compound according to the present invention can be administered in divided doses, once daily or several times daily. However, the dosage may vary depending on the patient's health condition, age, weight and sex, dosage form and disease severity, and therefore the scope of the present invention is not limited to the dosages provided above.

[0100] According to yet another embodiment of the present invention, a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of selected compounds, is provided for preventive or therapeutic use in cancer or tumors.

[0101] According to yet another embodiment of the present invention, a method for preventing or treating cancer is provided, the method comprising administering to an individual a compound selected from compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of selected compounds. Preferably, "individual" refers to an individual or a patient, but is not limited thereto.

[0102] According to yet another embodiment of the present invention, a method is provided for treating cancer in an individual who requires administration of a compound inhibitor and a standard-of-care formulation, the method comprising administering to the individual a therapeutically effective amount of a standard-of-care formulation comprising: a compound selected from the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a non-mirror image isomer thereof, a hydrate thereof, and a solvate thereof; or a pharmaceutically acceptable salt thereof of the selected compound.

[0103] According to yet another embodiment of the present invention, a method for treating cancer in an individual requiring administration of a composition is provided, the method comprising administering to the individual a therapeutically effective amount of a composition comprising: a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof; or pharmaceutically acceptable salts of the selected compounds.

[0104] According to yet another embodiment of the present invention, a method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in an individual or cell is provided, the method comprising administering to an individual a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of the selected compounds.

[0105] According to yet another embodiment of the present invention, a method for inhibiting tyrosine kinase in an individual or cell is provided, the method comprising administering to an individual a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of the selected compounds.

[0106] According to yet another embodiment of the present invention, a method for preventing or treating cancer in an individual is provided, the method comprising administering to the individual a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of the selected compounds.

[0107] According to yet another embodiment of the present invention, a method is provided for preventing or treating cancer that can be prevented or treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in an individual or cell. The method includes administering to an individual a compound selected from the compounds of Formula 1 of the present invention, pharmaceutically acceptable salts thereof, optical isomers, non-mirror image isomers, hydrates and solvates thereof, or pharmaceutically acceptable salts of selected compounds.

[0108] In the following, the invention will be described in more detail with the aid of examples and experimental examples. However, the examples and experimental examples are presented only to help understand the invention, and the scope of the invention is not limited thereto in any sense. Example 1 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0109] 13.8 g (56.32 mmol) of 2-bromoterephthalic acid was slowly added dropwise to 78 mL of sulfuric acid at 0 °C, followed by stirring for 5 minutes to prepare a reaction solution. After mixing 7.5 mL of sulfuric acid and 17.5 mL of nitric acid, the mixture was slowly added dropwise to the reaction solution at 0 °C. After the dropwise addition was complete, stirring and reflux were carried out at 100 °C for 2 hours. After the reaction was complete, the product was cooled to room temperature and stirred for 12 hours. When the reaction was complete, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain 16 g of the title compound.

[0110] 1H-NMR (300 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.17 (s, 1H). [Step 2] Preparation of 2-hydroxy-5-nitroterephthalic acid

[0111] The 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] were dissolved in 60 mL of distilled water and stirred under reflux at 120 °C for 2 hours in a microwave. After the reaction was complete, the solution was cooled to room temperature, filtered through a diatomaceous earth filter, and washed with water. The aqueous layer obtained by filtration was acidified with 6N hydrochloric acid until the pH was 1-2. The acidified aqueous solution was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to obtain 7 g of the title compound in 85% yield.

[0112] 1H-NMR (300 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.15 (s, 1H). [Step 3] Preparation of dimethyl 2-hydroxy-5-nitroterephthalate

[0113] The 2-hydroxy-5-nitroterephthalic acid (7 g, 30.82 mmol) prepared in [Step 2] and sulfuric acid (35 mL, 653.04 mmol) were dissolved in 330 mL of methanol, and the mixture was stirred under reflux at 70 °C for 65 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The result was extracted three times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered organic layer was concentrated under reduced pressure to give 7.9 g of the title compound.

[0114] 1H-NMR (300 MHz, DMSO-d6): δ 8.43 (s, 1H), 6.85 (s, 1H), 3.83 (s, 1H). [Step 4] Preparation of dimethyl 2-methoxy-5-nitroterephthalate

[0115] Dimethyl 2-hydroxy-5-nitroterephthalate (7.9 g, 30.82 mmol), iodomethane (15.3 mL, 246.56 mmol), and potassium carbonate (34 g, 246.56 mmol) obtained in [Step 3] were dissolved in 310 mL of acetone and stirred under reflux at 60 °C for 21 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in a mixture of distilled water and ethyl acetate (1:1 v / v) and extracted three times with ethyl acetate to produce an organic layer. The obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 6.1 g of the title compound in 73% yield.

[0116] 1H-NMR (300 MHz, CDCl3): δ 8.57 (s, 1H), 7.15 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H). [Step 5] Preparation of dimethyl 2-amino-5-methoxyterephthalate

[0117] Dimethyl 2-methoxy-5-nitroterephthalate (6.1 g, 22.50 mmol) prepared in [Step 4] above was dissolved in 122 mL of a mixture of ethyl acetate and ethanol (1:4 v / v), and Pd / C (600 mg, 10 wt%) was added. The reaction solution was stirred at 50 °C under a hydrogen atmosphere for 20 hours. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth filter and washed with methanol. The resulting organic layer was concentrated under reduced pressure, and the residue obtained was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 5 g of the title compound in 93% yield.

[0118] ¹H-NMR (300 MHz, CDCl₃): δ 7.38 (s, 1H), 7.05 (s, 1H), 5.50 (s, 2H), 3.86 (s, 6H), 3.80 (s, 3H). [Step 6] Preparation of 2-amino-5-methoxyterephthalic acid

[0119] The dimethyl 2-amino-5-methoxyterephthalate (5 g, 20.93 mmol) obtained in [Step 5] 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. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the organic layer and obtain an aqueous layer. The aqueous layer was acidified with 2N hydrochloric acid until the pH was 1 to 2, thus obtaining a solid product. The obtained solid product was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 55 °C to give 4.3 g of the title compound in 98% yield.

[0120] 1H-NMR (300 MHz, DMSO-d6): δ 7.30 (s, 1H), 7.01 (s, 1H), 3.70 (s, 3H). [Step 7] Preparation of 6-methoxy-2-methyl-4-sideoxy-1,4-dihydroquinazoline-7-carboxylic acid

[0121] The 2-bromo-5-methoxyterephthalic acid (4.3 g, 20.51 mmol), acetamide hydrochloride (3.86 g, 41.02 mmol), and sodium acetate (3.38 mg, 40.77 mmol) prepared in [Step 6] were dissolved in 86 mL of methoxyethanol and stirred under reflux at 150 °C for 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and distilled water was added dropwise. The solution was stirred at 0 °C for 0.5 hours to obtain a solid product. The solid product was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven desiccator at 55 °C to obtain 3.3 g of the title compound in a yield of 69%.

[0122] 1H-NMR (300 MHz, DMSO-d6): δ 13.19 (s, 1H), 12.26 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 3.90 (s, 3H), 2.34 (s, 3H). [Step 8] Preparation of 6-methoxy-2-methyl-7-(olyolin-4-carbonyl)quinazolin-4(1H)-one;

[0123] The 6-methoxy-2-methyl-4-sideoxy-1,4-dihydroquinazolin-7-carboxylic acid (300 mg, 1.28 mmol), α-oxoline (0.18 mL, 1.92 mmol), HATU (1.44 g, 3.84 mmol), and DIPEA (1.2 mL, 6.40 mmol) obtained in [Step 7] were dissolved in 4.5 mL of DMF, and the solution was stirred under reflux at room temperature for 2.5 hours. After the reaction was complete, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid product was filtered under reduced pressure, and the filtered solid was washed with ethyl acetate to give 255 mg of the title compound in 66% yield.

[0124] ¹H-NMR (300 MHz, DMSO-d6): δ 12.24 (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). [Step 9] Preparation of (4-chloro-6-methoxy-2-methylquinazolin-7-yl)(α-line) methyl ketone

[0125] 255 mg, 0.84 mmol, of 6-methoxy-2-methyl-7-(othioline-4-carbonyl)quinazolin-4(1H)-one obtained in [Step 8] above was dissolved in 14 mL of phosphatidyl chloride, and this solution was refluxed at 110 °C for 2 hours. After the reaction was complete, the product was cooled to room temperature and neutralized by dropwise addition of an aqueous sodium bicarbonate solution. The reaction product was extracted three times with anhydrous sodium sulfate, dried, and then 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.

[0126] 1H-NMR (300 MHz, DMSO-d6): δ 7.86 (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). [Step 10] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0127] The (4-chloro-6-methoxy-2-methylquinazolin-7-yl)(α-line) methyl ketone (70 mg, 0.22 mmol) prepared in [Step 9], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (57 mg, 0.24 mmol) synthesized by the method disclosed in WO2018115380, and DIPEA (0.15 mL, 0.88 mmol) were dissolved in 1 mL of DMF, and the mixture was stirred under reflux at 100 °C for 13 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The result 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 60 mg of the title compound in 56% yield.

[0128] 1H-NMR (300 MHz, 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]+ Example 2: (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(N-bromothiophen-2-yl)methyl ketone [Step 1] Preparation of (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-bromothiophen-2-yl)methyl ketone

[0129] The same procedure of Example 1 was repeated except that 1-(4-bromothiophene-2-yl)ethane-1-amine (100 mg, 0.47 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride and DMAc was used instead of DMF in Example 1 [Step 10] to obtain 156 mg of the title compound in 68% yield.

[0130] ¹H-NMR (300 MHz, DMSO-d6): δ 8.40 (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). [Step 2] Preparation of 2-(5-(1-((6-methoxy-2-methyl-7-(α-lin-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde

[0131] The (4-((1-(4-bromothiophene-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl) methyl ketone (156 mg, 0.32 mmol), (2-methoxyphenyl)boronic acid (57 mg, 0.38 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), and potassium carbonate (177 mg, 1.28 mmol) prepared in [Step 1] above were dissolved in 3 mL of a mixed solution of dimethyl ether and water (5:1), and the solution was stirred at 100 °C for 5 hours. After the reaction was completed, the result was cooled to room temperature, filtered through a filter filled with diatomaceous earth, and washed with dichloromethane. After water was added dropwise to the collected organic layer, the mixture was extracted three times with dichloromethane, and the resulting product was 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.

[0132] 1H-NMR (300 MHz, 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). [Step 3] Preparation of (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(N-hydroxyl) methyl ketone

[0133] The 2-(5-(1-((6-methoxy-2-methyl-7-(othioline-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde (143 mg, 0.28 mmol), 2.0 M methylamine (0.3 mL, 0.55 mmol), acetic acid (0.03 mL, 0.55 mmol), and sodium triethoxyborohydride (117 mg, 0.55 mmol) prepared in [Step 2] above were dissolved in 2 mL of dichloroethane, and the solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature and neutralized by adding sodium bicarbonate aqueous solution dropwise. The result was extracted three times with ethyl acetate, 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 obtain 80 mg of the title compound in 56% yield.

[0134] 1H-NMR (300 MHz, 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]+ Example 3: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R, 5S)-3,5-dimethylpiperazolin-1-yl)methyl ketone

[0135] The same procedure as in Example 1 was repeated except that cis-2,6-dimethylpiperazine (270 mg, 2.34 mmol) was used instead of cis-2,6-dimethylpiperazine (step 8) to obtain 14 mg of the title compound in 34% yield.

[0136] 1H-NMR (300 MHz, 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]+ Example 4: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thio(N-hydroxylinyl)) methyl ketone

[0137] The same procedure as in Example 1 was repeated except that thiocarbazoline (0.24 mL, 2.56 mmol) was used instead of carbazoline in Example 1 [Step 8] to obtain 60 mg of the title compound in 56% yield.

[0138] 1H-NMR (300 MHz, 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]+ Example 5: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) methyl ketone

[0139] The same procedure as in Example 1 was repeated except that hexahydro-1H-furano[3,4-c]pyrrole (159 mg, 1.41 mmol) was used instead of α-line in Example 1 [Step 8] to obtain 9.2 mg of the title compound in 9% yield.

[0140] 1H-NMR (300 MHz, 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= 6.9 Hz, 3H). MS (ESI+, m / z): 516.2 [M+H]+ Example 6: (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0141] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline 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 17% yield.

[0142] 1H-NMR (300 MHz, 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]+ Example 7: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azacyclobutane-1-yl)methyl ketone

[0143] The same procedure as in Example 1 was repeated except that aziridine (0.1 mL, 1.40 mmol) was used instead of taurine in Step 8 of Example 1 to obtain 28 mg of the title compound in 15% yield.

[0144] 1H-NMR (300 MHz, 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]+ Example 8: (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0145] The same procedure as in Example 2 was repeated except that (2-(tributoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-yl)boronic acid (74 mg, 0.27 mmol) was used instead of (2-methoxyphenyl)boronic acid in Step 2 of Example 2 to obtain 30 mg of the title compound in 48% yield.

[0146] 1H-NMR (300 MHz, 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]+ Example 9: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazolin-1-yl)methyl ketone

[0147] The same procedure as in Example 1 was repeated except that piperidine (26 mg, 0.41 mmol) was used instead of thioline in Example 1 [Step 8] to obtain 5 mg of the title compound in 9% yield.

[0148] 1H-NMR (300 MHz, 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]+ Example 10: (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(oline-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide

[0149] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl) methyl ketone (30 mg, 0.061 mmol), trifluoroacetic anhydride (14 mg, 0.067 mmol), and DIPEA (10 mg, 0.078 mmol) prepared in Step 1 of Example 1 were dissolved in 1 mL of dichloromethane, and the solution was stirred at room temperature for 5 hours. After the reaction was complete, an aqueous solution of ammonium chloride was added dropwise to neutralize the reaction solution. The mixture was extracted three times with dichloromethane, and the results were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 50:1 to 10:1 (v / v)) to give 7 mg of the title compound in 20% yield.

[0150] 1H-NMR (300 MHz, 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]+ Example 11: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluorozahexacyclobutane-1-yl)methyl ketone

[0151] The same procedure as in Example 1 was repeated except that 3-fluorozahexacyclobutane (258 mg, 1.07 mmol) was used instead of α-phosphorus in Step 8 of Example 1 to obtain 30 mg of the title compound in 9% yield.

[0152] ¹H-NMR (300 MHz, CD3OD): δ 8.03 (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]+ Example 12: (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazoline-7-yl)(N-pyrinyl)methyl ketone

[0153] The same procedure as in Example 2 was repeated except that 2.0M dimethylamine (0.16 ml, 0.32 mmol) was used instead of 2.0M methylamine in Step 3 of Example 2 to obtain 307 mg of the title compound in 8% yield.

[0154] 1H-NMR (300 MHz, 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]+ Example 13: (4-((1-(4-(2-((aminomethyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0155] The same procedure as in Example 2 was repeated except that 2.0M ammonia (0.22 ml, 0.45 mmol) was used instead of 2.0M methylamine in Step 3 of Example 2 to obtain 15 mg of the title compound in 13% yield.

[0156] ¹H-NMR (300 MHz, CD3OD): δ 7.78 (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]+ Example 14: (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0157] The same procedure as in Example 2 was repeated except that 2-(hydroxymethyl)phenylboronic acid (0.14 ml, 0.92 mmol) was used instead of (2-methoxyphenyl)boronic acid in Step 2 of Example 2 to obtain 88 mg of the title compound in 20% yield.

[0158] ¹H-NMR (300 MHz, CD3OD): δ 7.76 (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]+ Example 15: (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0159] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (33 mg, 0.16 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 10 of Example 1 to obtain 20 mg of the title compound in 27% yield.

[0160] 1H-NMR (300 MHz, 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]+ Example 16: (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0161] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-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 to obtain 15 mg of the title compound in 13% yield.

[0162] 1H-NMR (300 MHz, 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]+ Example 17: (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0163] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-fluoroaniline 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.

[0164] 1H-NMR (300 MHz, 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]+ Example 18: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-disideloxythio(N-hydroxylinyl))methyl ketone

[0165] The same procedure as in Example 1 was repeated except that thiocarbamoline 1,1-dioxide (30 mg, 0.21 mmol) was used instead of carbamoline in Example 1 [Step 8] to obtain 23 mg of the title compound in 30% yield.

[0166] 1H-NMR (300 MHz, 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= 6.9 Hz, 3H). MS (ESI+, m / z): 538.1 [M+H]+ Example 19: (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0167] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (49 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 10] of Example 1 to obtain 30 mg of the title compound in 31% yield.

[0168] 1H-NMR (300 MHz, 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]+ Example 20: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methyl ketone

[0169] The same procedure as in Example 1 was repeated except that thiazoline (0.06 mL, 0.70 mmol) was used instead of thiazoline in Example 1 [Step 8] to obtain 18 mg of the title compound in 56% yield.

[0170] 1H-NMR (300 MHz, 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]+ Example 21: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0171] The same procedure as in 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 to obtain 15 mg of the title compound in 16% yield.

[0172] 1H-NMR (300 MHz, 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]+ Example 22: (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(oline-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile

[0173] The same procedure as in Example 1 was repeated except that (R)-3-(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.

[0174] ¹H-NMR (300 MHz, CD3OD): δ 7.80 (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]+ Example 23: (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0175] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride was used instead of (R)-1-(2,3-dihydro-1H-indene-4-yl)ethane-1-amine (45 mg, 0.27 mmol) in step 10 of Example 1 to obtain 35 mg of the title compound in 31% yield.

[0176] 1H-NMR (300 MHz, 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]+ Example 24: (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0177] The same procedure as in 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.

[0178] 1H-NMR (300 MHz, 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]+ Example 25: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0179] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-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.

[0180] 1H-NMR (300 MHz, 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= 7.4 Hz, 3H). MS (ESI+, m / z): 508.1 [M+H]+ Example 26: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0181] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (58 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 10] of Example 1 to obtain 33 mg of the title compound in 31% yield.

[0182] 1H-NMR (300 MHz, 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]+ Example 27: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(N-pyrinyl)methyl ketone

[0183] The same procedure as in Example 1 was repeated except that tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.11 g, 4.6 mmol) was used instead of iodomethane in Step 4 of Example 1 to obtain 25 mg of the title compound in 18% yield.

[0184] 1H-NMR (300 MHz, 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= 5.4 Hz, 3H). MS (ESI+, m / z): 546.2 [M+H]+ Example 28: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0185] The same procedure as in 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.

[0186] 1H-NMR (300 MHz, 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]+ Example 29: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0187] The same procedure as in 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 to obtain 10 mg of the title compound in 10% yield.

[0188] 1H-NMR (300 MHz, 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]+ Example 30: (R)-(4-((1-(3-amino-5-(thiazolyl-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0189] The same procedure as in Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(thiazolyl-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.

[0190] 1H-NMR (300 MHz, 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]+ Example 31: (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0191] After dissolving (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl) methyl ketone (50 mg, 0.10 mmol) obtained in Example 1 [Step 10] in 1 mL of dichloromethane, acetaldehyde (5.4 mg, 0.12 mmol) and a 1.0 M titanium tetrachloride solution in dichloromethane were added to the reaction solution (0.01 mL, 0.01 mmol), followed by the addition of sodium cyanobromide (26 mg, 0.41 mmol), and the mixture was stirred overnight at room temperature. After the reaction was complete, the product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to give 16 mg of the title compound in 31% yield.

[0192] 1H-NMR (300 MHz, 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= 6.9 Hz, 3H), 1.25 (m, 3H). MS (ESI+, m / z): 518.2 [M+H]+ Example 32: Methyl(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0193] The same procedure as in Example 1 was repeated except that 2-methoxyethyl 4-methylbenzenesulfonic acid (3.2 g, 14.11 mmol) was used instead of iodomethane in Step 4 of Example 1 to obtain 7 mg of the title compound in 6% yield.

[0194] 1H-NMR (300 MHz, 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]+ Example 33: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0195] The same procedure as in Example 1 was repeated except that fluoroacetonitrile (7.1 mL, 125 mmol) was used instead of acetonitrile in Step 7 of Example 1 to obtain 32 mg of the title compound in 34% yield.

[0196] 1H-NMR (300 MHz, 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= 7.2 Hz, 3H). MS (ESI+, m / z): 508.2 [M+H]+ Example 34: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((N-hydroxylinyl)methyl)quinazolin-4-amine [Step 1] Preparation of methyl 2-bromo-5-methoxy-methylbenzoate

[0197] Methyl 3-methoxy-4-methylbenzoate (5 g, 27.74 mmol) was mixed with 40 mL of acetic acid and 40 mL of water, and bromine (1.5 mL, 30.52 mmol) was added dropwise. After the dropwise addition was complete, the mixture was stirred and refluxed at 60 °C for 1 hour. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. The aqueous solution was extracted three times with a hexane / diethyl ether (8:3) solution, the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure, and the filtered solution was concentrated under reduced pressure to give 6.92 g of the title compound in 96% yield.

[0198] ¹H-NMR (300 MHz, CDCl₃): δ 7.39 (s, ¹H), 7.26 (s, ¹H), 3.92 (s, ³H), 3.84 (s, ³H), 2.21 (s, ³H). [Step 2] Preparation of methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate

[0199] Methyl 2-bromo-5-methoxy-methylbenzoate (6.92 g, 26.70 mmol), N-bromobutyldiimidide (4.28 g, 24.60 mmol), and azobisisobutyronitrile (853 mg, 5.19 mmol) obtained in [Step 1] were dissolved in 130 mL of chloroform, and the solution was stirred under reflux at 70 °C for 2 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. After extraction 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 the organic layer was concentrated under reduced pressure. The 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.

[0200] 1H-NMR (300 MHz, CDCl3): δ 7.59 (s, 1H), 7.30 (s, 1H), 4.45 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H). [Step 3] Preparation of methyl 2-bromo-5-methoxy-4-((N-α-linyl)methyl)benzoate.

[0201] Methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate (1.2 g, 3.55 mmol), α-phosphorus (0.34 mL, 3.90 mmol), and potassium carbonate (981 mg, 7.10 mmol) obtained in [Step 2] were dissolved in 20 mL of acetonitrile, and the solution was stirred at room temperature for 18 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise. After extraction 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 the organic layer was concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 1.0 g of the title compound in 82% yield.

[0202] ¹H-NMR (300 MHz, CDCl₃): δ 7.68 (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). [Step 4] Preparation of methyl 2-((tributoxycarbonyl)amino)-5-methoxy-4-((N-phosphoryl)methyl)benzoate

[0203] The methyl 2-bromo-5-methoxy-4-((N-phospholinyl)methyl)benzoate (1.0 g, 2.90 mmol), tributyl carbamate (566 mg, 3.19 mmol), xantphos (336 mg, 0.58 mmol), Pd2(dba)3dba (266 mg, 0.29 mmol), and cesium carbonate (2.83 g, 8.71 mmol) obtained in [Step 3] were dissolved in 25 mL of 1,4-dimethylbenzene, and the solution was stirred at 110 °C for 2 hours. After the reaction was complete, the product was cooled to room temperature, filtered through a diatomaceous earth filter, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the residue obtained was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain the target compound.

[0204] 1H-NMR (300 MHz, CDCl3): δ 8.39 (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). [Step 8] Preparation of 6-methoxy-2-methyl-7-((N-α-linyl)methyl)quinazolin-4-ol

[0205] Methyl 2-((tributoxycarbonyl)amino)-5-methoxy-4-((N-hydroxylinyl)methyl)benzoate (950 mg, 2.49 mmol) obtained in [Step 4] was dissolved in 10 mL of acetonitrile, and 10 mL of 4N dichlorodimethylhydrochloride solution was added dropwise to the solution. The solution was stirred at 80 °C under reflux for 2 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous sodium bicarbonate solution was added dropwise to neutralize it. The reaction product was extracted three times with dichloromethane, dried under anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was cured with ethyl acetate and filtered under reduced pressure. The solid obtained by filtration was dried to produce 680 mg of the title compound with a yield of 94%.

[0206] ¹H-NMR (300 MHz, CD3OD): δ 7.70 (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). Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((N-α-linyl)methyl)quinazolin-4-amine

[0207] The 6-methoxy-2-methyl-7-((N-α-linyl)methyl)quinazolin-4-ol (100 mg, 0.34 mmol), (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) obtained in [Step 8] were dissolved in 3 mL of acetonitrile and stirred at 80 °C for 5 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The product 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.

[0208] 1H-NMR (300 MHz, 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]+ Example 35: (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((N-hydroxylinyl)methyl)quinazolin-4-amine

[0209] The same procedure as in Example 39 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 39 to obtain 9 mg of the title compound in 5% yield. 1H-NMR (300 MHz, 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]+ Example 36: (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4-amine [Step 1] Preparation of methyl 4-hydroxy-5-methoxy-2-nitrobenzene

[0210] Methyl 4-(benzoxy)-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 to the solution. The reaction solution was stirred at 50 °C under a hydrogen atmosphere for 20 hours. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth filter and washed with methanol. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to give 7 g of the title compound in 96% yield.

[0211] ¹H-NMR (300 MHz, CD3OD): δ 7.29 (s, ¹H), 6.24 (s, ¹H), 6.84 (m, ¹H), 4.87 (bs, 2H), 3.91 (s, 3H), 3.81 (s, 3H). [Step 2] Preparation of 7-hydroxy-6-methoxy-2-methylquinazoline-4(¹H)-one

[0212] Methyl 4-hydroxy-5-methoxy-2-nitrobenzene (7.0 g, 35.5 mmol) obtained in [Step 1] and a solution of 4N dichlorodimethyl chloride (71 mL, 284 mmol) were dissolved in 20 mL of 355 mmol acetonitrile, and the solution was stirred under reflux at 70 °C for 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and 30 mL of dichloromethane was added. The mixture was then stirred for 0.5 hours to give a solid product. The obtained solid was filtered under reduced pressure and dried in an oven desiccator at 55 °C to give 9 g of the title compound in 82% yield.

[0213] ¹H-NMR (300 MHz, DMSO-d6): δ 11.2 (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). [Step 3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4(1H)-one

[0214] The 7-hydroxy-6-methoxy-2-methylquinazoline-4(1H)-one (1.8 g, 8.7 mmol) obtained in [Step 2] was dissolved in 20 mL of DMF, and tetrahydro-2H-piperan-4-yl methanesulfonate (1.7 g, 9.5 mmol) and cesium carbonate (3.4 g, 10.4 mmol) were added to the solution. The mixture was stirred at 100 °C for 15 hours. After the reaction was complete, water was added to the reaction solution, and the reaction product was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After adding 10 mL of acetone and stirring, the precipitated crystals were filtered to give 250 mg of the title compound in 10% yield.

[0215] ¹H-NMR (300 MHz, CD3OD): δ 7.84 (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). [Step 4] Preparation of 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolino

[0216] The 6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4(1H)-one (250 mg, 0.86 mmol) obtained in [Step 3] above was dissolved in 14 mL of phosphine chloride, and this solution was refluxed at 110 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and neutralized by adding sodium bicarbonate aqueous solution dropwise. The result was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This substance was used in the next step without purification. [Step 5] Preparation of (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4-amine

[0217] The 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazoline (100 mg, 0.33 mmol) obtained 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 to the solution. The mixture was stirred at 100 °C for 13 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The product 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:methanol = 23:1 (v / v)) to give 21 mg of the title compound in 13% yield.

[0218] 1H-NMR (300 MHz, 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]+ Example 37: (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4-amine

[0219] The same procedure as in Example 44 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (69 mg, 0.28 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 5 of Example 44 to obtain 5.7 mg of the title compound in a yield of 4.6%.

[0220] ¹H-NMR (300 MHz, CD3OD): δ 7.73 (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]+ Example 38: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)methoxy)quinazolin-4-amine

[0221] The same procedure as in Example 44 was repeated except that methyl 4-methylbenzenesulfonic acid (tetrahydro-2H-piperan-4-yl) methyl ester (752 mg, 2.78 mmol) was used instead of tetrahydro-2H-piperan-4-yl methanesulfonate in Step 3 of Example 44 to obtain 15 mg of the title compound in 3.5% yield.

[0222] 1H-NMR (300 MHz, CD3OD): δ7.46 (s, 1H), 7.00 (s, 3H), 6.83 (s, 1H), 5.67(q, 1H), 4.08~4.10 (m, 7H), 3.73(m, 2H), 3.50 (t, 2h\H), 2.54 (s, 3H), 1.89(m, 2H), 1.68(d, 3H), 1.57(m, 2H). MS (ESI+, m / z): 491.2 [M+H]+ Example 39: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxecyclobutane-3-ylmethoxy)quinazolin-4-amine

[0223] The same procedure as in Example 44 was repeated except that 4-methylbenzenesulfonate oxetane-3-ylmethyl ester (530 mg, 2.17 mmol) was used instead of tetrahydro-2H-piperan-4-yl ester of methanesulfonate in Step 3 of Example 44 to obtain 20 mg of the title compound in 15% yield.

[0224] 1H-NMR (300 MHz, 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]+ Example 40: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0225] 2-Bromoterephthalic acid (75 g, 306.12 mmol) was dissolved in 490 mL of sulfuric acid, and 98 mL of nitric acid was slowly added dropwise at 0 °C. After the dropwise addition was complete, the mixture was stirred and refluxed at room temperature for 17 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, and the mixture was stirred at room temperature for 1 hour. After stirring, the resulting solid was filtered under reduced pressure and washed with distilled water to give 61 g of the title compound in 69% yield.

[0226] 1H-NMR (300 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.17 (s, 1H). [Step 4] Preparation of dimethyl 2-bromo-5-nitroterephthalate

[0227] The 2-bromo-5-nitroterephthalic acid (61 g, 210.32 mmol) obtained in [Step 1] above was dissolved in 2.2 L of methanol, and 240 mL of sulfuric acid was slowly added dropwise at 0 °C. After the dropwise addition was complete, the mixture was stirred and refluxed at 90 °C for 17 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. 600 mL of distilled water was added dropwise at 0 °C, and the mixture was stirred at room temperature for 0.5 hours. After stirring, the product was filtered under reduced pressure to give 61 g of the title compound in 91% yield.

[0228] ¹H-NMR (300 MHz, DMSO-d6): δ 8.47 (s, ¹H), 8.28 (s, ¹H), 3.93–3.89 (m, 6H). [Step 3] Preparation of dimethyl 2-(methylamino)-5-nitroterephthalate

[0229] The dimethyl 2-bromo-5-nitroterephthalate (60 g, 188.63 mmol), methylamine hydrochloride (63.6 g, 941.94 mmol), and DIPEA (492 g, 2829.48 mmol) obtained in [Step 2] were dissolved in 900 mL of DMF, and the mixture was stirred under reflux at 100 °C for 1 hour. After the reaction was complete, the solution was cooled to 0 °C, and 1.8 L of distilled water was added dropwise to the solution while stirring at room temperature for 0.5 hours. After stirring, the product was filtered under reduced pressure to give 48.6 g of the title compound in 96% yield.

[0230] ¹H-NMR (300 MHz, DMSO-d6): δ 8.59 (s, 2H), 6.95 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.01–2.99 (d, 3H). [Step 4] Preparation of dimethyl 2-amino-5-(methylamino)terephthalate

[0231] The 2-(methylamino)-5-nitroterephthalate (45.5 g, 169.63 mmol) obtained in [Step 3] and zinc powder (39.4 g, 593.71 mmol) were dissolved in 460 mL of a mixture of dimethyl ether and distilled water (4:1), and the mixture was stirred under reflux 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 dropwise addition was complete, stirring and reflux were carried out at room temperature for 2 hours. After the reaction was complete, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with ethyl acetate. Distilled water was added dropwise to the obtained organic layer (at a 1:1 volume ratio), and the mixture was extracted three times with ethyl acetate. The obtained organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate:hexane = 1:8 (v / v) to 1:4 (v / v)) to give 31 g of the title compound in 77% yield.

[0232] ¹H-NMR (300 MHz, DMSO-d6): δ 7.39 (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). [Step 5] Preparation of methyl 4-hydroxy-2-methyl-6-(methylamino)quinazolin-7-carboxylate.

[0233] The 2-amino-5-(methylamino)terephthalate dimethyl ester (31 g, 130.12 mmol) obtained in [Step 4] and acetonitrile (68 mL, 1301.20 mmol) were dissolved in 260 mL of 4N hydrochloric acid, and the mixture was stirred in a sealed tube at 90°C under reflux for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a filter, and washed with hexane. The solid obtained after filtration was neutralized with an aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to obtain 30 g of the title compound in 93.2% yield.

[0234] ¹H-NMR (300 MHz, DMSO-d6): δ 12.03 (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). [Step 6] Preparation of methyl 4-chloro-2-methyl-6-(methylamino)quinazolin-7-carboxylate.

[0235] Methyl 4-hydroxy-2-methyl-6-(methylamino)quinazolin-7-carboxylate (6.1 g, 24.69 mmol) prepared in [Step 5] was dissolved in 150 mL of phosphatidyl chloride, and the mixture was stirred under reflux at 120 °C for 3 hours. When the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane and neutralized with dichloromethane 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, and 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.

[0236] 1H-NMR (300 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.57 (m, 1H), 6.92 (s, 1H), 3.93 (s, 3H), 2.94 (d, 3H), 2.66 (s, 3H). [Step 7] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-carboxylic acid methyl ester

[0237] Methyl 4-chloro-2-methyl-6-(methylamino)quinazolin-7-carboxylate (600 mg, 2.26 mmol) prepared in [Step 6], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (705 mg, 2.93 mmol) synthesized by the method disclosed in WO2018115380, and DIPEA (1.21 mL, 6.78 mmol) were dissolved in 30 mL of DMF, and the mixture was stirred under reflux at 90 °C for 13 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The result 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.

[0238] 1H-NMR (300 MHz, CDCl3): δ 8.46 (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). [Step 8] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0239] The (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)carboxylic acid ester (280 mg, 0.64 mmol) obtained in [Step 7] was dissolved in 20 mL of a mixture of tetrahydrofuran, methanol, and water (= 2:1:1), followed by the addition of sodium hydroxide (129 mg, 3.23 mmol). The mixture was then stirred under reflux at room temperature for 2 hours. After the reaction was complete, 2N HCl aqueous solution was added dropwise to adjust the pH to 5 or 6, and the product was subsequently washed with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)carboxylic acid, without purification. The obtained title compound, α-lactone (0.62 mL, 0.72 mmol), HATU (272 g, 0.18 mmol), and DIPEA (0.26 mL, 1.43 mmol) were dissolved in 5 mL of DMF, and the mixture was stirred under reflux at room temperature for 2.5 hours. After the reaction was complete, the product 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.

[0240] ¹H-NMR (300 MHz, CD3OD): δ 7.38 (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 = 7.2 Hz, 3H). MS (ESI+, m / z): 489.2 [M+H]+ Example 41: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0241] The same procedure as in Example 49 was repeated except that dimethylamine hydrochloride (2.3 g, 28 mmol) was used instead of methylamine hydrochloride in [Step 3] of Example 49 to obtain 40 mg of the title compound in 12% yield.

[0242] ¹H-NMR (300 MHz, DMSO-d6): δ 7.77 (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]+ Example 42: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(N-pyrolinyl)methyl ketone

[0243] The same procedure as in Example 49 was repeated except that pyrrolidine (2.0 g, 28 mmol) was used instead of methylamine hydrochloride in Example 49 [Step 3] to obtain 60 mg of the title compound in 19% yield.

[0244] ¹H-NMR (300 MHz, DMSO-d6): δ 8.17 (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]+ Example 43: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0245] The same procedure as in 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 [Step 7] of Example 49 to obtain 24 mg of the title compound in 38% yield.

[0246] ¹H-NMR (300 MHz, CD3OD): δ 7.38 (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 = 7.2 Hz, 3H). MS (ESI+, m / z): 489.2 [M+H]+ Example 44: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-hydroxylyl)methyl ketone

[0247] The same procedure as in Example 49 was repeated except that 2-methoxyethyl-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Example 49 [Step 3] to obtain 12 mg of the title compound in 11% yield.

[0248] ¹H-NMR (300 MHz, CD3OD): δ 7.39 (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 = 6.9 Hz, 3H) MS (ESI+, m / z): 533.2 [M+H]+ Example 45: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone

[0249] The same procedure as in Example 49 was repeated except that cyclopentylamine (4.7 g, 47.2 mmol) was used instead of methylamine hydrochloride in Example 49 [Step 3] to obtain 22 mg of the title compound in 6% yield.

[0250] ¹H-NMR (300 MHz, CD3OD): δ 7.44 (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]+ Example 46: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0251] The same procedure as in Example 49 was repeated except that ethylamine (23 g, 47 mmol) dissolved in tetrahydrofuran was used instead of methylamine hydrochloride in Example 49 [Step 3] to obtain 120 mg of the title compound in 53% yield.

[0252] ¹H-NMR (300 MHz, DMSO-d6): δ 8.74 (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]+ Example 47: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0253] The same procedure as in Example 49 was repeated except that isopropylamine (3.86 mL, 47.1 mmol) was used instead of methylamine hydrochloride in Example 49 [Step 3] to obtain 3 mg of the title compound in 1% yield.

[0254] ¹H-NMR (300 MHz, CD3OD): δ 7.36 (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]+ Example 48: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-piperan-4-yl)amino)quinazolin-7-yl)(N-pyrinyl)methyl ketone

[0255] The same procedure as in Example 49 was repeated except that 4-aminotetrahydropiperanone hydrochloride (3.89 g, 28.29 mmol) was used instead of methylamine hydrochloride in [Step 3] of Example 49 to obtain 130 mg of the title compound in 56% yield.

[0256] 1H-NMR (300 MHz, 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 (br, 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]+ Example 49: (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-((N-hydroxylinyl)methyl)quinazolin-4,6-diamine [Step 1] Preparation of ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate

[0257] Methyl 2-amino-4-methylbenzoate (6.2 g, 34.5 mmol), dibutyl decarbonate (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 the mixture was stirred under reflux at room temperature for 15 hours. After the reaction was complete, water was added dropwise. Subsequently, the reaction product 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.

[0258] ¹H-NMR (300 MHz, CDCl₃): δ 10.35 (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). [Step 2] Preparation of ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate

[0259] Ethyl 2-((tributoxycarbonyl)amino)-4-methylbenzoate (4.7 g, 16.8 mmol), N-bromobutyldiimidine (3.0 g, 16.8 mmol), and azobisisobutyronitrile (0.55 mg, 3.3 mmol) obtained in [Step 1] were dissolved in 100 mL of chloroform, and the mixture was stirred under reflux at 70 °C for 1.5 hours. After the reaction was complete, the solution was cooled to room temperature and concentrated under reduced pressure to produce 4.3 g of the title compound. Without purification, the next reaction was carried out. [Step 3] Preparation of ethyl 2-((tributoxycarbonyl)amino)-4-((N-α-linyl)methyl)benzoate

[0260] Ethyl 4-(bromomethyl)-2-((tributoxycarbonyl)amino)benzoate (4.3 g, 11.9 mmol), α-oxoline (2.0 mL, 23.8 mmol), and potassium carbonate (6.6 mg, 47.6 mmol) obtained in [Step 2] were dissolved in 40 mL of acetonitrile, and the mixture was stirred under reflux at room temperature for 1 hour. After the reaction was complete, water was added dropwise. Subsequently, the reaction product 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 yield 2.1 g of the title compound in 34% yield.

[0261] 1H-NMR (300 MHz, CDCl3): δ 10.34 (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). [Step 4] Preparation of 2-methyl-7-((N-α-linyl)methyl)quinazolin-4-ol

[0262] Ethyl 2-((tributoxycarbonyl)amino)-4-((N-hydroxylinyl)methyl)benzoate (2.1 g, 5.73 mmol) obtained in [Step 3] and acetonitrile (21 mL, 402.5 mmol) were dissolved in 21 mL of 4N hydrochloric acid dissolved in dimethyl ether, and the mixture was stirred under reflux at 90 °C in a sealed tube for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through a filter, and washed with hexane. The solid obtained after filtration was neutralized with an aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to give 1.2 g of the title compound in 81% yield.

[0263] ¹H-NMR (300 MHz, DMSO-d6): δ 12.17 (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). [Step 5] Preparation of 2-methyl-7-((N-α-linyl)methyl)-6-nitroquinazolin-4-ol

[0264] The 2-methyl-7-((N-N-hydroxyl)methyl)quinazolin-4-ol (1.2 g, 4.62 mmol) prepared in [Step 4] 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 stirred under reflux at 70 °C for 3 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane and neutralized with an aqueous sodium hydroxide solution at low temperature. The resulting 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 produce 1.2 g of the title compound in 85% yield.

[0265] ¹H-NMR (300 MHz, DMSO-d6): δ 12.57 (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). [Step 6] Preparation of 6-amino-2-methyl-7-((N-α-linyl)methyl)quinazolin-4-ol

[0266] The 2-methyl-7-((N-α-linyl)methyl)-6-nitroquinazolin-4-ol (450 g, 1.47 mmol) and zinc powder (340 g, 5.14 mmol) obtained in [Step 5] were dissolved in 5 mL of a mixture of dimethyl ether and distilled water (4:1), and the mixture was stirred under reflux at room temperature for 0.5 hours. After stirring, the reaction solution was cooled to 0°C, and ammonium chloride (400 g, 7.35 mmol) was slowly added dropwise. After the dropwise addition was complete, stirring and reflux were carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with ethyl acetate. Distilled water was added to the obtained organic layer (at a 1:1 volume ratio), and the mixture was extracted three times with ethyl acetate and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure. The residue obtained was purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to produce 330 g of the title compound with a yield of 81%.

[0267] ¹H-NMR (300 MHz, DMSO-d6): δ 11.76 (m, 1H), 7.26 (d, 2H), 5.62 (s, 2H), 3.60 (m, 6H), 2.38 (m, 4H), 2.26 (s, 3H). [Step 7] Preparation of 2-methyl-6-(methylamino)-7-((N-α-linyl)methyl)quinazolin-4-ol

[0268] The 6-amino-2-methyl-7-((N-α-linyl)methyl)quinazolin-4-ol (155 mg, 0.56 mmol), iodomethane (70 mg, 0.50 mmol), and calcium carbonate (84 mg, 0.84 mmol) obtained in [Step 6] were dissolved in 2 mL of dimethylformamide, and the mixture was stirred under reflux at 50 °C for 12 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The product 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.

[0269] ¹H-NMR (300 MHz, CDCl₃): δ 9.75 (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). [Step 8] Preparation of 2,4,6-triisopropylbenzenesulfonic acid 2-methyl-6-(methylamino)-7-((N-α-linyl)methyl)quinazolin-4-yl ester

[0270] The 2-methyl-6-(methylamino)-7-((N-hydroxyl)methyl)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) obtained in [Step 7] were dissolved in 2 mL of dichloromethane, and the mixture was stirred under reflux at room temperature for 18 hours. After the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to produce 25 mg of the title compound in 43% yield. [Step 9] Preparation of (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-((N-hydroxylinyl)methyl)quinazolin-4,6-diamine

[0271] The 2,4,6-triisopropylbenzenesulfonic acid 2-methyl-6-(methylamino)-7-((N-hydroxyl)methyl)quinazolin-4-yl ester (25 mg, 0.04 mmol), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (15 mg, 0.05 mmol), and triethylamine (0.025 mL, 0.18 mmol) prepared in [Step 8] were dissolved in 2 mL of DMF, and the mixture was stirred under reflux at 90 °C for 22 hours. After the reaction was complete, water was added dropwise. The reaction product 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 yield 3 mg of the title compound in 14% yield.

[0272] 1H-NMR (300 MHz, CDC13): 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]+ Example 50: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0273] The same procedure as in Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-fluoromethyl)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.

[0274] ¹H-NMR (300 MHz, CD3OD): δ 7.38 (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 = 6.9 Hz, 3H). MS (ESI+, m / z): 507.2 [M+H]+ Example 51: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0275] The same procedure as in 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 41% yield.

[0276] 1H-NMR (300 MHz, DMSO-d6): δ 9.15 (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]+ Example 52: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone

[0277] The same procedure as in Example 49 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 49, 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 Step 7 of Example 49, to obtain 55 mg of the title compound in 41% yield.

[0278] 1H-NMR (300 MHz, DMSO-d6): δ 8.53 (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]+ Example 53: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methyl ketone

[0279] The same procedure as in Example 49 was repeated except that thiazoline (24 mg, 0.26 mmol) was used instead of thiazoline in Step 8 of Example 49 to obtain 16 mg of the title compound in 24% yield.

[0280] 1H-NMR (300 MHz, 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]+ Example 54: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-pyrinyl)methyl ketone

[0281] The same procedure as in 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.

[0282] 1H-NMR (300 MHz, CD3OD): δ 7.80 (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 = 7.2 Hz, 3H). MS (ESI+, m / z): 487.2 [M+H]+ Example 55: (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(N-hydroxyl)methyl ketone

[0283] The same procedure as in Example 49 was repeated except that isopropylamine (1.7 mL, 3.14 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], to obtain 20 mg of the title compound in 23% yield.

[0284] 1H-NMR (300 MHz, DMSO-d6): δ 8.03 (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]+ Example 56: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone

[0285] The same procedure as in Example 49 was repeated except that 2-methoxyethyl-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], to obtain 35 mg of the title compound in 30% yield.

[0286] 1H-NMR (300 MHz, DMSO-d6): δ 8.06 (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]+ Example 57: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methyl ketone

[0287] The same procedure as in Example 49 was repeated except that 1-methylpiperazine (0.03 mL, 0.25 mmol) was used instead of α-porphyrin in Example 49 [Step 8] to obtain 20 mg of the title compound in 16% yield.

[0288] 1H-NMR (300 MHz, DMSO-d6): δ 8.32 (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]+ Example 58: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone

[0289] The same procedure as in Example 49 was repeated except that hexahydro-1H-furano[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of α-line in Step 8 of Example 49 to obtain 38 mg of the title compound in 31% yield.

[0290] ¹H-NMR (300 MHz, DMSO-d6): δ 9.12 (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]+ Example 59: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-disideloxythio(N-hydroxyl))methyl ketone

[0291] The same procedure as in Example 49 was repeated except that thio(N-phospholinyl)1,1-dioxide (35 mg, 0.26 mmol) was used instead of phospholin in Example 49 [Step 8] to obtain 5 mg of the title compound in 4% yield.

[0292] ¹H-NMR (300 MHz, CD3OD): δ 7.42 (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]+ Example 60: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thio(N-hydroxyl))methyl ketone

[0293] The same procedure as in Example 49 was repeated except that thiocarbazoline (0.03 mL, 0.26 mmol) was used instead of carbazoline in Example 49 [Step 8] to obtain 22 mg of the title compound in 18% yield.

[0294] 1H-NMR (300 MHz, 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, 3H), 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]+ Example 61: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazolin-1-yl)methyl ketone

[0295] The same procedure as in Example 49 was repeated except that piperidine (100 mg, 0.50 mmol) was used instead of piperidine in Step 8 of Example 49 to obtain 30 mg of the title compound in 13% yield.

[0296] 1H-NMR (300 MHz, 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]+ Example 62: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azacyclobutane-1-yl)methyl ketone

[0297] The same procedure as in Example 49 was repeated except that aziridine hydrochloride (24 mg, 0.26 mmol) was used instead of α-porphyrin in Example 49 [Step 8] to obtain 12 mg of the title compound in 11% yield.

[0298] 1H-NMR (300 MHz, 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]+ Example 63: (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone

[0299] The same procedure as in Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (230 mL, 0.96 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, and hexahydro-1H-furano[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of α-line in Step 8 of Example 49, to obtain 40 mg of the title compound in 32% yield.

[0300] 1H-NMR (300 MHz, 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]+ Example 64: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-disideloxythio(N-hydroxylinyl))methyl ketone

[0301] The same procedure as in Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mL, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 7] of Example 49, and thio(N-hydroxyl)1,1-dioxide (35 mg, 0.26 mmol) was used instead of thioline in [Step 8], to obtain 8 mg of the title compound in 6% yield.

[0302] 1H-NMR (300 MHz, 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]+ Example 65: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone

[0303] The same procedure as in 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.

[0304] 1H-NMR (300 MHz, CD3OD): δ 7.37 (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]+ Example 66: (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone

[0305] The same procedure as in Example 49 was repeated except that 2-methoxyethylamine (4.1 mL, 47.15 mmol) was used instead of methylamine hydrochloride in Step 3 of Example 49, and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (190 mg, 0.76 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to obtain 40 mg of the title compound in 36% yield.

[0306] 1H-NMR (300 MHz, 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]+ Example 67: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-disideloxythio(N-hydroxylinyl))methyl ketone

[0307] The same procedure as in Example 49 was repeated except that 2-methoxyethane-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, 0.21 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 8], to obtain 2 mg of the title compound in 2% yield.

[0308] 1H-NMR (300 MHz, CD3OD): δ 7.40 (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]+ Example 68: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-disideloxythio(N-hydroxylinyl))methyl ketone

[0309] The same procedure as in Example 49 was repeated except that 2-methoxyethane-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in [Step 3] of Example 49, and thio(N-phosphoryl)1,1-dioxide (55 mg, 0.40 mmol) was used instead of phosphoryl in [Step 8] to obtain 18 mg of the title compound in 8% yield.

[0310] 1H-NMR (300 MHz, 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]+ Example 69: (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-piperan-4-yl)quinazolin-4,7-diamine [Step 1] Preparation of methyl 5-methoxy-2-nitro-4-((tetrahydro-2H-piperan-4-yl)amino)benzoate

[0311] Methyl-bromo-5-methoxy-2-nitrobenzoate (800 mg, 2.75 mmol), 4-aminotetrahydropiperanone hydrochloride (455 mg, 3.30 mmol), Pd2(OAc)2 (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-dimethylbenzene, and the mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The product was then extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MLPC (ethyl acetate:hexane = 1:1 (v / v)) to yield 970 mg of the title compound in 91% yield.

[0312] ¹H-NMR (300 MHz, CDCl₃): δ 7.07 (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). [Step 2] Preparation of methyl 2-amino-5-methoxy-4-((tetrahydro-2H-piperan-4-yl)amino)benzoate

[0313] Methyl 5-methoxy-2-nitro-4-((tetrahydro-2H-piperan-4-yl)amino)benzoate (970 g, 3.12 mmol) and iron (715 mg, 10.94 mmol) obtained in [Step 1] were dissolved in 10 mL of a mixture of 1,4-dimethyl benzoate and distilled water (4:1), and the mixture was cooled to 0°C. The mixture was added to ammonium chloride (636 mg, 15.62 mmol) and stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was filtered through a diatomaceous earth filter and washed with dichloromethane. After water was added dropwise to the filtrate, the mixture was extracted three times with dichloromethane, and the product was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MLPC (ethyl acetate:hexane = 1:1 (v / v)) to yield 850 mg of the title compound in 97% yield.

[0314] ¹H-NMR (300 MHz, CDCl₃): δ 6.88 (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). [Step 3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)amino)quinazolin-4-ol

[0315] Methyl 2-amino-5-methoxy-4-(tetrahydro-2H-piperan-4-yl)amino)benzoate (850 mg, 3.03 mmol) obtained in [Step 2] was dissolved in 3 mL of acetonitrile, and 6 mL of 4N hydrochloric acid dissolved in dimethyl methacrylate was added dropwise. The solution was stirred at 80 °C under reflux for 2 hours. After the reaction was complete, the product was cooled to room temperature, and an aqueous solution of sodium bicarbonate was added dropwise to neutralize it. The reaction product was extracted three times with dichloromethane, dried under anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was cured with ethyl acetate and filtered under reduced pressure. The solid obtained by filtration was dried to yield 830 mg of the title compound with a yield of 95%.

[0316] ¹H-NMR (300 MHz, DMSO-d6): δ 7.23 (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). [Step 4] Preparation of 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-piperan-4-yl)quinazolin-7-amine

[0317] The 6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)amino)quinazoline-4-ol (200 mg, 0.69 mmol) obtained in [Step 3] was dissolved in 2 mL of phosphine chloride, and the mixture was refluxed at 100°C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and neutralized by adding sodium bicarbonate aqueous solution dropwise. The result was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to the next process without purification. [Step 5] Preparation of (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-piperan-4-yl)quinazoline-4,7-diamine

[0318] The 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-piperan-4-yl)quinazolin-7-amine (130 mg, 0.42 mmol) obtained 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 to the solution. The mixture was stirred at 90 °C for 13 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water was added dropwise. The product 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.

[0319] 1H-NMR (300 MHz, CD3OD): δ7.52 (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]+ [Table 1] Compound numbering structure name MS[M+H]+ 1H-NMR spectrum (300 MHz) 1 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phosphonyl)methyl ketone 490.2 1 H-NMR (300 MHz, 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). 2 (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 532.2 1H-NMR (300 MHz, 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). 3 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R, 5S)-3,5-dimethylpiperazolin-1-yl)methyl ketone 517.3 1 H-NMR (300 MHz, 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). 4 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thio(N-hydroxyl))methyl ketone 506.2 1 H-NMR (300 MHz, 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). 5 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone 516.2 1 H-NMR (300 MHz, 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= 6.9 Hz, 3H). 6 (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phosphonyl)methyl ketone 475.2 1 H-NMR (300 MHz, 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). 7 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azacyclobutane-1-yl)methyl ketone 460.2 1H-NMR (300 MHz, 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). 8 (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinoline-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 544.2 1 H-NMR (300 MHz, 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). 9 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazolin-1-yl)methyl ketone 489.2 1 H-NMR (300 MHz, 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). 10 (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(oline-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide 586.2 1 H-NMR (300 MHz, 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). 11 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluorozacricyclobutan-1-yl)methyl ketone 478.2 1 H-NMR (300 MHz, 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). 12 (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(N-phospholinyl)methyl ketone 546.2 1 H-NMR (300 MHz, 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). 13 (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 518.2 1 H-NMR (300 MHz, 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). 14 (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 519.2 1 H-NMR (300 MHz, 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). 15 (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 475.2 1 H-NMR (300 MHz, 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). 16 (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 504.2 1 H-NMR (300 MHz, 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). 17 (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 440.2 1 H-NMR (300 MHz, 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). 18 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxythio(N-hydroxylinyl))methyl ketone 538.1 1H-NMR (300 MHz, 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= 6.9 Hz, 3H). 19 (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 452.2 1 H-NMR (300 MHz, 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). 20 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolin-3-yl)methyl ketone 492.2 1 H-NMR (300 MHz, 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). twenty one (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 436.2 1 H-NMR (300 MHz, 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). twenty two (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(α-lin-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile 447.2 1 H-NMR (300 MHz, 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) twenty three (R)-(4-((1-(2,3-dihydro-1H-indene-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 447.2 1H-NMR (300 MHz, 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) twenty four (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 462.2 1 H-NMR (300 MHz, 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) 25 (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 508.1 1 H-NMR (300 MHz, 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= 7.4 Hz, 3H). 26 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 490.2 1 H-NMR (300 MHz, 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). 27 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(N-hydroxyl)methyl ketone 546.2 1 H-NMR (300 MHz, 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= 5.4 Hz, 3H). 28 (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phosphonyl)methyl ketone 488.2 1H-NMR (300 MHz, 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) 29 (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phosphonyl)methyl ketone 472.2 1 H-NMR (300 MHz, 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) 30 (R)-(4-((1-(3-amino-5-(thiazo-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-phosphonyl)methyl ketone 505.2 1 H-NMR (300 MHz, 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) 31 (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 518.2 1 H-NMR (300 MHz, 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= 6.9 Hz, 3H), 1.25 (m, 3H). 32 Methyl(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(N-pyrinyl) methyl ketone 534.2 1 H-NMR (300 MHz, 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). 33 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(N-hydroxylinyl)methyl ketone 508.2 1H-NMR (300 MHz, 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= 7.2 Hz, 3H). 34 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((N-phospholinyl)methyl)quinazolin-4-amine 476.2 1 H-NMR (300 MHz, 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) 35 (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((N-phospholinyl)methyl)quinazolin-4-amine 476.2 1 H-NMR (300 MHz, 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) 36 (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4-amine 477.2 1 H-NMR (300 MHz, 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) 37 (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazolin-4-amine 477.2 1 H-NMR (300 MHz, 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) 38 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)methoxy)quinazolin-4-amine 491.2 1 H-NMR (300 MHz, CD3OD): δ7.46 (s, 1H), 7.00 (s, 3H), 6.83 (s, 1H), 5.67(q, 1H), 4.08~4.10 (m, 7H), 3.73(m, 2H), 3.50 (t, 2h\H), 2.54 (s, 3H), 1.89 (m, 2H), 1.68 (d, 3H), 1.57 (m, 2H) 39 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetane-3-ylmethoxy)quinazolin-4-amine 463.2 1 H-NMR (300 MHz, 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) 40 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 489.2 [M+H] + 1 H-NMR (300 MHz, 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= 7.2 Hz, 3H). 41 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 503.2 [M+H] + 1 H-NMR (300 MHz, 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). 42 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(N-pyrolinyl)methyl ketone 529.3 [M+H] + 1 H-NMR (300 MHz, 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). 43 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 489.2 [M+H] + 1 H-NMR (300 MHz, 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= 7.2 Hz, 3H). 44 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-phospholinyl)methyl ketone 533.2 [M+H] + 1 H-NMR (300 MHz, 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= 6.9 Hz, 3H). 45 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 543.2 [M+H] + 1 H-NMR (300 MHz, 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). 46 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 503.2 [M+H] + 1 H-NMR (300 MHz, 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). 47 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 517.2 [M+H] + 1 H-NMR (300 MHz, 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). 48 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-piperan-4-yl)amino)quinazolin-7-yl)(N-pyrinyl)methyl ketone 559.2 [M+H] + 1 H-NMR (300 MHz, 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(br, 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). 49 (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 2-Dimethyl-7-((N-α-phosphoryl)methyl)quinazolin-4,6-diamine 475.2 [M+H] + 1 H-NMR (300 MHz, 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). 50 (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 507.2 [M+H] + 1H-NMR (300 MHz, CD3OD): δ 7.38 (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 = 6.9 Hz, 3H). 51 (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone 471.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 9.15 (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). 52 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(N-hydroxyl)methyl ketone 503.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 8.53 (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). 53 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolin-3-yl)methyl ketone 491.2 [M+H] + 1 H-NMR (300 MHz, 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). 54 (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-pyrinyl)methyl ketone 487.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.80 (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 = 7.2 Hz, 3H). 55 (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(N-hydroxyl)methyl ketone 517.2 [M+H] + 1H-NMR (300 MHz, DMSO-d6): δ 8.03 (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). 56 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-hydroxylinyl)methyl ketone 533.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 8.06 (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). 57 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methyl ketone 502.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 8.32 (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). 58 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone 515.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 9.12 (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). 59 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxythio(N-hydroxylinyl))methyl ketone 537.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.42 (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). 60 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thio(N-hydroxyl))methyl ketone 505.2 [M+H] + 1H-NMR (300 MHz, 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, 3H), 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). 61 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazolin-1-yl)methyl ketone 488.2 [M+H] + 1 H-NMR (300 MHz, 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). 62 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azacyclobutane-1-yl)methyl ketone 459.2 [M+H] + 1 H-NMR (300 MHz, 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). 63 (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone 515.2 [M+H] + 1 H-NMR (300 MHz, 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). 64 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxythio(N-hydroxyl))methyl ketone 537.2 [M+H] + 1 H-NMR (300 MHz, 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). 65 (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-phospholinyl)methyl ketone 435.2 [M+H] + 1H-NMR (300 MHz, CD3OD): δ 7.37 (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). 66 (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl)methyl ketone 559.2 [M+H] + 1 H-NMR (300 MHz, 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). 67 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxythio(N-hydroxylinyl))methyl ketone 581.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.40 (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). 68 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-disidel-oxythio(N-hydroxylinyl))methyl ketone 581.2 [M+H] + 1 H-NMR (300 MHz, 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). 69 (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 -(tetrahydro-2H-piperan-4-yl)quinazolin-4,7-diamine 476.2 1 H-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). Experimental Example 1: Testing the ability of SOS1 to inhibit GTP substitution

[0320] To determine whether the substitution function of SOS1 binding to KRAS G12C was inhibited by the aforementioned example compounds, uniform time-of-flight fluorescence (HTRF) assays were performed using G12C (#MSC-11-538) and SOS1-Strep (#MSC-11-502) purchased from Reaction Biology (MA, USA). The activity of the SOS1 enzyme was determined using the time-of-flight fluorescence energy transfer (TR-FRET) principle by measuring the amount of GTP bound to the KRAS G12C protein. Based on the principle that the zirconia of the GST-binding antibody bound to the GST-KRAS G12C protein acts as a donor for fluorescence resonance energy transfer (FRET), and that the GTP bound to the KRAS G12C protein is labeled with the fluorescent agent DY-647P1 and acts as a receptor, according to this assay, a higher HTRF or FRET signal was measured when more GTP was bound to the KRAS G12C protein via the SOS1 substitution reaction.

[0321] In summary, the glutathione S-transferase (GST)-labeled KRAS G12C protein (composed of amino acid residues 2 to 169), streptavidin-labeled SOS1 protein (composed of amino acid residues 564 to 1049 as the catalytic region), anti-GST antibody (#61GSTKLA) purchased from CISBIO, and nucleic acid (#NU-820-647P1) purchased from Jena Bioscience were mixed 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 added to a 384-well plate and reacted at room temperature. Next, the FRET signal was measured using a Perkin Elmer Envision microdisk reader. In this case, the excitation signal was measured at 320 nm (excitation), and the emission signal was measured at 615 / 665 nm (emission). Fluorescence measurements excluding the SOS1 protein were calculated as background signal values, subtracted from all measured HTRF values. Fluorescence measurements excluding the synthetic compound were measured as control values, and these values ​​were selected as the 100% reference point. For each of the example compounds, fluorescence was measured at concentrations of 1.6, 8, 40, 200, and 1,000 nM (5 points, 5-fold), and the 50% inhibition value (IC50) for each compound was calculated using GraphPad Prism. Therefore, the KRAS G12C-SOS1 binding inhibitory activity of each of the example compounds is shown in Table 2 below.

[0322] When the IC50 value is 50 nM or less, the inhibition ability is expressed as +++. When the IC50 value is greater than 50 nM and less than 100 nM, the inhibition ability is expressed as ++. When the IC50 value is greater than 100 nM, the inhibition ability is expressed as +. [Table 2] Synthetic compounds IC 50 (nM) Synthetic compounds IC 50 (nM) Synthetic compounds IC 50 (nM) Example 1 +++ Example 24 ++ Example 47 ++ Example 2 ++ Example 25 +++ Example 48 + Example 3 + Example 26 +++ Example 49 ++ Example 4 ++ Example 27 ++ Example 50 +++ Example 5 + Example 28 +++ Example 51 +++ Example 6 ++ Example 29 +++ Example 52 ++ Example 7 + Example 30 ++ Example 53 +++ Example 8 + Example 31 ++ Example 54 ++ Example 9 +++ Example 32 + Example 55 +++ Example 10 + Example 33 + Example 56 +++ Example 11 + Example 34 + Example 57 ++ Example 12 ++ Example 35 +++ Example 58 +++ Example 13 ++ Example 36 ++ Example 59 +++ Example 14 + Example 37 + Example 60 +++ Example 15 + Example 38 + Example 61 +++ Example 16 ++ Example 39 + Example 62 ++ Example 17 +++ Example 40 +++ Example 63 +++ Example 18 +++ Example 41 ++ Example 64 +++ Example 19 + Example 42 + Example 65 ++ Example 20 +++ Example 43 +++ Example 66 Example 21 ++ Example 44 ++ Example 67 Example 22 + Example 45 ++ Example 68 +++ Example 23 ++ Example 46 ++ Example 69 +

Claims

1. A compound selected from compounds of Formula 1 and pharmaceutically acceptable salts, optical isomers, non-mirror image isomers, hydrates, and solvates of such Formula 1 compounds: [Formula 1] In Formula 1, R1 is hydrogen or C1-4 alkyl; R2 is hydrogen, C1-4 alkyl, halo-C1-4 alkyl, C2-6 alkenyl, or C2-6 alkynyl; R3 is R3a or -L2-; R3a is independently a halogen, hydroxyl, cyano, amino, amine, nitro, oxy-(=O), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo-C1-6 alkyl, amino-C1-6 alkyl, C1-6 alkoxy, hydroxy-C1-4 alkyl, -CF2H, -(CH2)r-NH(CO)-Ra or -(CH2)r-NRaRb, and Ra and Rb are independently selected from any of the following groups: hydrogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -CF2H and C3-8 carbocyclic; 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; p is an integer from 0 to 3; q is an integer in the range of 0 to 2; and each is independently a C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic or C9-12 bicyclic heterocyclic, wherein the C6-10 aryl, C4-10 heteroaryl, C3-10 carbocyclic, C2-10 heterocyclic or C9-12 bicyclic heterocyclic is unsubstituted or substituted with one or more R3a, and X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic, each of which is unsubstituted or untreated. Halogen, hydroxyl, nitro, lateral oxy (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRcRd, -C(O)ORc, -ORc or -NRcRd substitution, wherein Rc and Rd are each independently hydrogen or C1-6 alkyl;R5 and R6 are each hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C8-16 spirocyclic, C6-14 heterospirocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic, wherein C1-6 alkyl, hydroxyC1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic, C2-9 heterocyclic, or C6-10 aryl are used. C4-10 heteroaryl, C8-16 spirocyclocyclic, C6-14 heterospirocyclocyclic, C8-16 fused carbocyclic, C6-14 fused heterocyclic, C8-16 bridged carbocyclic, or C6-14 bridged heterocyclic unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen, hydroxyl, nitro, septyl group (=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NReRf, -C(O)O Re, -ORe, and -NReRf, wherein Re and Rf are each independently hydrogen or C1-6 alkyl, or, alternatively, -N(R5)(R6) is a C2-9 heterocyclic group, a C6-14 heterospirocyclic group, a C6-14 fused heterocyclic group, a C6-14 bridged heterocyclic group, or a C4-10 heteroaryl group, wherein in each case, R5 and R6 are linked to each other and bonded to one of the nitrogen atoms contained in -N(R5)(R6) to form a ring, wherein the C2-9 heterocyclic group, C6-14 heterospirocyclic group, C6-14 fused heterocyclic group, C6-14 bridged heterocyclic group, or C4-10 heteroaryl group is unsubstituted or selected from one or more of the following: The functional group substitutions of the following groups are: halogen, hydroxyl, nitro, oxy-(=O), cyano, halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRgRh, -C(O)ORg, -ORg, and -NRgRh, wherein Rg and Rh are each independently hydrogen, C1-6 alkyl, hydroxy-C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, or C3-8 carbocyclic; L1 is a direct bond, -C(O)-, -O-, or -NH-; n is an integer in the range of 0 to 2;And C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic, wherein the C3-10 carbocyclic, C2-9 heterocyclic, C6-10 aryl, C4-10 heteroaryl, C6-14 heterospirocarbocyclic, C6-14 fused heterocyclic or C6-14 bridged heterocyclic are unsubstituted or have been selected from one or more... The functional groups are substituted by: halogen, hydroxyl, nitro, oxy(=O), halogenated C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, -S(O)-C1-4 alkyl, -S(O)2-C1-4 alkyl, -C(O)-NRiRj, -C(O)ORi, -ORi, and -NRiRj, wherein Ri and Rj are each independently hydrogen or C1-6 alkyl.

2. The compound of claim 1, wherein each is independently a C6-10 aryl or a C4-10 heteroaryl.

3. The compound of claim 1, wherein each of R3a is independently a halogen, hydroxyl, cyano, amino, amine, nitro, C1-6 alkyl, halo-C1-6 alkyl, amino-C1-6 alkyl, C1-6 alkoxy, -CF2H, C6-10 aryl, C3-6 cycloyl, -(CH2)r-C2-6 heterocyclic, -(CH2)r-NH(CO)-Ra or -(CH2)r-NRaRb, wherein Ra and Rb are independently hydrogen, C1-6 alkyl, -CF3 or -CF2H.

4. The compound of claim 1, wherein R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic or C2-9 heterocyclic, and R5 and R6 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 carbocyclic or C2-9 heterocyclic, or the -N(R5)(R6) is a C2-9 heterocyclic.

5. The compound of claim 1, wherein the compound represented by chemical formula 1 is a compound represented by the following chemical formula 2: [chemical formula 2] In chemical formula 2, L1 is a direct bond, -C(O)-, -O- or -NH-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; R4a is hydrogen, C1-6 alkyl, C3-10 carbocyclic or C2-9 heterocyclic; it is arginyl, thioarginyl, dioxythioarginyl, piperyl, thiazodinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetyl or azirbutyl, wherein the arginyl, thioarginyl, dioxythioarginyl, piperyl, thiazodinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetyl or azirbutyl is unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen or -CH3.

6. The compound of claim 1, wherein the compound represented by chemical formula 1 is a compound represented by one of the following chemical formula 3: [Chemical Formula 3] In chemical formula 3, L3 is a direct bond or -C(O)-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where Z1 and Z2 are both hydrogen; R5a and R5b are each independently hydrogen, C1-6 alkyl, C1 -6 alkoxy, C3-10 carbocyclic, or C2-9 heterocyclic, or -N(R5a)(R5b) is a C2-9 heterocyclic group, wherein R5a and R5b are linked to each other and bonded to one of the nitrogen atoms contained in -N(R5a)(R5b) to form a ring; or α-linyl, di-oxythio-α-linyl, thio-α-linyl, piperyl, thiazolinyl, tetrahydropiperanyl, hexahydro-1H -furano[3,4-c]pyrrole, oxetane or azirone, wherein the phosphono, dioxythiophosphono, thiophosphono, piperyl, thiazolinyl, tetrahydropiperanyl, hexahydro-1H-furano[3,4-c]pyrrole, oxetane or azirone is unsubstituted or substituted with one or more functional groups selected from the group consisting of: halogen or -CH3.

7. The compound of claim 5, wherein the compound represented by chemical formula 2 is a compound represented by chemical formula 4: [chemical formula 4] In chemical formula 4, L4 is a direct bond, -C(O)- or -O-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where Z1 and Z2 are both hydrogen; and is α-linyl, thio-α-linyl, piperinyl, thiazodinyl or tetrahydropiperanyl, wherein the α-linyl, thio-α-linyl, piperinyl, thiazodinyl or tetrahydropiperanyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH3.

8. The compound of claim 6, wherein the compound represented by chemical formula 3 is a compound represented by chemical formula 5: [chemical formula 5] in chemical formula 5, L5 is a direct bond or -C(O)-; n is an integer in the range of 0 to 2; and Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; is α-linyl, dioxythioα-linyl, thioα-linyl, piperyl, thiazodinyl or hexahydro-1H-furano[3,4-c]pyrrole, wherein the α-linyl, dioxythioα-linyl, thioα-linyl, piperyl, thiazodinyl or hexahydro-1H-furano[3,4-c]pyrrole is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH3.

9. The compound of claim 1, wherein the compound of formula 1 is a compound selected from the group consisting of: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) methyl ketone; (6-methoxy-2-methyl-4-((1-(4-(2-(((methylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)quinazoline-7-yl)(N-pyrinyl) methyl ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)((3R,5S)-3,5-dimethylpiperazolin-1-yl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(thio(N-α-linyl)) ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) ketone; (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-α-linyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(azacyclobutane-1-yl) ketone; (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinoline-8-yl)thiophene-2-yl)ethyl)amino)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(piperazolinyl) ketone; (R)-2,2,2-trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(othioline-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-fluoroazacyclobutane-1-yl) ketone; (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophene-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(N-othioline) ketone; (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(N-pyrinyl)methyl ketone;(4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-flanylinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(1,1-disideloxythio(N-pyrinyl)) ketone; (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(thiazolinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(𠰌lin-4-carbonyl)quinazoline-4-yl)amino)ethyl)benzonitrile; (R)-(4-((1-(2,3-dihydro-1H-indene-4-yl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-𠰌linyl)methyl ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone;(R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(thiazoline-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; Methyl(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((N-α-linyl)methyl)quinazoline-4-amine; (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((N-hydroxyl)methyl)quinazoline-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazoline-4-amine; (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)oxy)quinazoline-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-piperan-4-yl)methoxy)quinazolin-4-amine; (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxocyclobutane-3-ylmethoxy)quinazolin-4-amine; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazoline-7-yl)(N-pyrrolidone); (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazoline-7-yl)(N-pyrrolidone);(R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(N-flanylinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)((R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazoline-7-yl)(N-α-linyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-piperan-4-yl)amino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-((N-pyrinyl)methyl)quinazoline-4,6-diamine; (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazoline-7-yl)(N-pyrinyl) ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(thiazolin-3-yl) ketone; (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(N-pyrinyl)methyl ketone; (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazoline-7-(yl)(N-pyrinyl)methyl ketone;(R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazoline-7-yl)(N-hydroxyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(4-methylpiperazolin-1-yl) methyl ketone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(1,1-dioxythio(N-hydroxyl)) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(thio(N-hydroxyl)) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-yl)(piperazolinyl) methyl ketone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azirmonobutane-1-yl) ketone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxythio(N-hydroxylinyl)) ketone; (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-hydroxyl) methyl ketone; (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furano[3,4-c]pyrrole-5(3H)-yl) methyl ketone; (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxythio(N-hydroxyl)) methyl ketone;(R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazoline-7-yl)(1,1-disideloxythio(N-hydroxylinyl)) methyl ketone; and (R)-N4-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-piperan-4-yl)quinazoline-4,7-diamine; 10. A preventive or therapeutic composition comprising a compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A pharmaceutical composition as claimed in claim 10, wherein the pharmaceutical composition is used to treat cancer or a tumor, which can be treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

12. A pharmaceutical preparation comprising the pharmaceutical ingredients as claimed in claim 10.

13. The pharmaceutical preparations as requested in item 12, wherein the pharmaceutical preparations are in the form of tablets, pills, powders, capsules, syrups or emulsions.

14. The pharmaceutical compound of claim 12 further comprises at least one of the group consisting of pharmaceutically acceptable carriers, sclerosing agents and excipients.

15. A method for inhibiting the binding of SOS1 to a RAS family protein and / or RAC1 in an individual or cell, the method comprising administering to the individual a pharmaceutically effective amount of any one of claims 1 to 9.

16. A method for inhibiting tyrosine kinase in an individual or cell, the method comprising administering to the individual a pharmaceutically effective amount of any one of claims 1 to 9.

17. A method for preventing or treating cancer in an individual, the method comprising administering to the individual a pharmaceutically effective amount of any one of claims 1 to 9.

18. Use of a compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the prevention or treatment of cancer or tumor.