Novel quinazoline derivatives as SOS1 inhibitors and their uses

Abstract

The present invention relates to a novel quinazoline-derived compound as an SOS1 inhibitor and its use. Specifically, the present invention relates to a novel quinazoline-derived compound having inhibitory activity against the binding of SOS1 to RAS family proteins and / or RAC1, its pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds.

Description

Technical Field

[0001] The present invention relates to a novel quinazoline-derived compound and its use as an SOS1 inhibitor. Specifically, it relates to a novel quinazoline-derived compound having an 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. Background Art

[0002] As is well known, Rat Sarcoma virus (RAS) is a family of proteins present in 20% to 30% of human cancers, which are identified as Kirstin RAS oncogene homolog (KRAS), Neuroblastoma RAS oncogene homolog (NRAS), and Harvey Rat Sarcoma virus oncogene (HRAS). RAS regulates cell proliferation through the RAF / MEK / ERK pathway that causes activation of mitogen-activated protein kinase (MAPK), and the PI3K / Akt / mTOR pathway involving phosphatidylinositol 3-kinase (PI3K). Cancer-related mutations in RAS family proteins inhibit the intrinsic GAP-induced GTPase activity, thereby increasing the number of GTP-bound / active RAS family proteins.

[0003] On the other hand, RAS proteins act as molecular switches, and GTP and GDP exist in cells in an active state (GTP-bound) and an inactive state (GDP-bound). Activated GTP-bound RAS activates effector proteins through binding to the homologous RAS-binding domain (RBD), thereby recruiting other proteins and then generating downstream signals with various functions. The active state of RAS is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). The binding of GTPase-activating proteins (GAP), such as NF1, increases the GTPase activity of RAS family proteins.

[0004] Binding guanine nucleotide exchange factor (GEF), such as Son of Sevenless 1 (SOS1), promotes the release of GDP from RAS family proteins, thereby enabling RAS family proteins to bind and activate GTP. Son of Sevenless (SOS) proteins exist in two subtypes, SOS1 and SOS2, and only SOS1 is phosphorylated by ERK. Growth factor-induced SOS1 phosphorylation is mainly mediated by ERK, and ERK 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.

[0005] The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multi-domain protein, including a Dbl homology domain (DH), followed by two tandem N-terminal histone domains (HDs), a plextrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins: a catalytic site that binds to GDP-bound RAS family proteins and promotes guanine nucleotide exchange, and an allosteric site that binds to GTP-bound RAS family proteins, resulting in a further increase in the catalytic GEF function of SOS1. Selective pharmacological inhibition of the binding of SOS1 to the catalytic site of RAS family proteins is expected to prevent SOS1-mediated activation of RAS family proteins in the GTP-bound form.

[0006] These SOS1 inhibitor compounds are expected to thus inhibit signal transduction (i.e., ERK phosphorylation) in cells downstream of RAS family proteins. Accordingly, novel SOS1 inhibitor compounds that bind to the catalytic site of SOS1 (confirmed by crystallography) and simultaneously prevent the binding and activation of RAS family proteins are being developed. Specifically, substances are being developed that have a significant inhibitory effect (low IC 50 value) on the interaction between SOS1 and RAS family proteins, particularly KRAS among the RAS family proteins, thereby inducing a significant reduction in ERK phosphorylation in KRAS mutant cancer cell lines.

[0007] The inventors of the present invention have found a novel quinazoline derivative compound as an SOS1 inhibitor, which has an inhibitory activity on the binding of SOS1 to RAS family proteins and / or RAC1, thereby completing the present invention. Summary of the Invention

[0008] Technical Solution

[0009] An object of the present invention is to provide a novel quinazoline-derived compound that can excellently inhibit the binding of SOS1 to RAS family proteins and / or RAC1.

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound.

[0011] Technical Solution

[0012] In one embodiment of the present invention, there is provided a compound selected from the following: a compound represented by the following Chemical Formula 1, and a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate of the compound represented by Chemical Formula 1:

[0013] [Chemical Formula 1]

[0014]

[0015] In Chemical Formula 1,

[0016] R 1 is hydrogen or C 1-4 alkyl;

[0017] R 2 is hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0018] R 3 is R 3a or -L 2 -

[0019] R 3a each independently is any one selected from the following: halogen, hydroxyl, cyano, amino, amine, nitro, oxo group (=O), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, -CF 2 H, -(CH 2 ) r -NH(CO)-R a 、-(CH 2 ) r -NR a R b and R a and R b each independently is selected from the group consisting of: hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -CF 2 H and C 3-8 carbocyclic group;

[0020] r is an integer in the range of 0 to 1;

[0021] m is an integer in the range of 0 to 5;

[0022] L 2 is a chemical bond, -O-(CH 2 ) p or -CH=CH-(CH 2 ) q ;

[0023] p is an integer in the range of 0 to 3;

[0024] q is an integer in the range of 0 to 2;

[0025] each independently is C 6-10 aryl, C 4-10 heteroaryl, C 3-10 carbocyclic group, C 2-10 heterocyclic group or C 9-12 bicyclic heterocyclic group, where the C 6-10 aryl, C 4-10 heteroaryl, C 3-10 carbocyclic group, C 2-10 heterocyclic group or C 9-12 bicyclic heterocyclic group is unsubstituted or substituted by one or more R 3a ;

[0026] X 1 is -O(R 4 ) or -N(R 5 )(R 6 );

[0027] R 4 is hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic group, C 2-9 heterocyclic group, C 6-10 aryl, C 4-10 heteroaryl, C 8-16 spirocarbocyclic group, C 6-14 heterospirocarbocyclic group, C 8-16 fused carbocyclic group, C 6-14 fused heterocyclic group, C 8-16 bridged carbocyclic group or C 6-14 bridged heterocyclic group, which is unsubstituted or substituted by halogen, hydroxy, nitro, oxo group (=O), cyano, halo C 1-6 alkyl, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d substituted, where R c and R d are each independently hydrogen or C 1-6 alkyl;

[0028] R 5 and R 6 are each hydrogen, C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic, C 2-9 heterocyclic, C 6-10 aryl, C 4-10 heteroaryl, C 8-16 spirocarbocyclic, C 6-14 heterospirocarbocyclic, C 8-16 fused carbocyclic, C 6-14 fused heterocyclic, C 8-16 bridged carbocyclic or C 6-14 bridged heterocyclic, where C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic, C 2-9 heterocyclic, C 6-10 aryl, C 4-10 heteroaryl, C 8-16 spirocarbocyclic, C 6-14 heterospirocarbocyclic, C 8-16 fused carbocyclic, C 6-14 fused heterocyclic, C 8-16 bridged carbocyclic or C 6-14 bridged heterocyclic is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, hydroxy, nitro, oxo group (=O), cyano, halo-C 1-6 alkyl, C 1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f , wherein R e and R f are each independently hydrogen or C 1-6 alkyl; and

[0029] Alternatively, said -N(R 5 )(R 6 ) is C 2-9 heterocyclic group, C 6-14 heterospirocarbocyclic group, C 6-14 fused heterocyclic group, C 6-14 bridged heterocyclic group or C 4-10 heteroaryl, in each of which, R 5 and R 6 are connected to each other and bonded to the nitrogen atom in said -N(R 5 )(R 6 ) to form a ring, wherein C 2-9 heterocyclic group, C 6-14 heterospirocarbocyclic group, C 6-14 fused heterocyclic group, C 6-14 bridged heterocyclic group or C 4-10 heteroaryl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, hydroxyl, nitro, oxo group (=O), cyano, halo C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h , wherein R g and R h are each independently hydrogen, C1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halo-C 1-6 Alkoxy or C 3-8 Carbocyclic group;

[0030] L 1 Is a chemical bond, -C(O)-, -O- or -NH-;

[0031] n is an integer in the range of 0 to 2; and

[0032] Is C 3-10 Carbocyclic group, C 2-9 Heterocyclic group, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclic group, C 6-14 Fused heterocyclic group or C 6-14 Bridged heterocyclic group, wherein C 3-10 Carbocyclic group, C 2-9 Heterocyclic group, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclic group, C 6-14 Fused heterocyclic group or C 6-14 Bridged heterocyclic group is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, hydroxy, nitro, oxo group (=O), halo-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O) 2 -C 1-4 Alkyl, -C(O)-NR i R j 、-C(O)OR i 、-OR i And -NR i R j ; Wherein R i And R j Are each independently hydrogen or C 1-6 Alkyl.

[0033] In another embodiment of the present invention, there is provided a pharmaceutical composition and a pharmaceutical preparation for preventing or treating various diseases related to inhibiting the binding of SOS1 to RAS family proteins and / or RAC1, and the composition and preparation comprise a therapeutically effective amount of the compound described above.

[0034] In another embodiment of the present invention, a method for inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in a subject or cell is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound.

[0035] In another embodiment of the present invention, a method for inhibiting tyrosine kinase in a subject or cell is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound.

[0036] In another embodiment of the present invention, a method for preventing or treating cancer in a subject is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound.

[0037] In another embodiment of the present invention, the use of the above-described compound or a pharmaceutically acceptable salt thereof for preventing or treating cancer or tumor is provided.

[0038] Advantageous effects

[0039] The quinazoline-derived compound of Formula 1 of the present invention has excellent ability to inhibit the binding of SOS1 to RAS family proteins and / or RAC1, has anti-cancer activity against cancers associated with cell proliferation caused by abnormal SOS1 activity, and can be used as a therapeutic agent.

[0040] Embodiments

[0041] All technical terms used in the present invention, unless otherwise defined, have the meanings commonly understood by those of ordinary skill in the relevant art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent ones also fall within the scope of the present invention. In addition, even if not specifically stated, the numerical values described herein are considered to include the meaning of "about". The contents of all publications incorporated herein by reference are incorporated herein by reference in their entirety.

[0042] In Formula 1, the residues listed as R 1 to R 6 are used as commonly understood by those skilled in the art.

[0043] In the present invention, unless otherwise specified, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Specifically, the term "halogen" may refer to, but is not limited to, fluorine or chlorine.

[0044] As used herein, the term "alkyl" refers to a saturated straight-chain or branched-chain monovalent hydrocarbon group, unless otherwise specified.

[0045] In the present 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.

[0046] Unless otherwise specified, the term "alkynyl" as used herein refers to a monovalent group derived from an unsaturated straight-chain or branched-chain hydrocarbon moiety having at least one carbon-carbon triple bond.

[0047] The alkyl, alkenyl, and alkynyl groups described above can be straight (i.e., straight-chain) or branched. By definition, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5, or 6, or it can be 1, 2, 3, or 4. Examples of alkyl groups include: methyl; ethyl; propyl, including n-propyl and isopropyl; butyl including n-butyl, sec-butyl, isobutyl, and tert-butyl; pentyl, including n-pentyl, 1-methylbutyl, isopentyl, neopentyl, and tert-pentyl; hexyl including n-hexyl, 3,3-dimethylbutyl, and isohexyl. Each of the double bonds and triple bonds in alkenyl and alkynyl groups can be located at 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, propadiynyl (= propargyl), 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 site, provided that each compound is stable enough and suitable for the desired purpose, such as being used as a pharmaceutical substance.

[0048] In the present invention, unless otherwise specified, the term "carbocyclic group" refers to a cyclic alkyl group that can be substituted or unsubstituted and can refer to a monocyclic or bicyclic aliphatic ring. Preferably, examples of carbocyclic groups include, but are not limited to, aryl, carbocyclic, spirocarbocyclic, fused carbocyclic, and bridged carbocyclic groups. More preferably, examples of -1-carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, or all possible isomers thereof.

[0049] In the present 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 can be substituted or unsubstituted. Preferably, examples of heterocyclic groups include, but are not limited to, heteroaryl, heterocyclic, heterospirocarbocyclic, fused heterocyclic, and bridged heterocyclic groups. More preferably, examples of heterocyclic groups include, but are not limited to, piperazinyl, piperidinyl, piperazin-1-oxide, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuryl, diazabicyclooctyl, diazaspirooctyl, and similar groups. For example, in the case of a C 2-10 heterocyclic group, C 2-10Represents the carbon number, referring to the ring size of a 3-membered or higher-membered ring containing one or more heteroatoms.

[0050] In the present invention, unless otherwise specified, the term "aryl" refers to an aromatic group which may be substituted or unsubstituted. For example, aryl includes but is not limited to phenyl, biphenyl, naphthyl, toluoyl, naphthalenyl, anthryl and all their isomers.

[0051] In the present 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 which may be substituted or unsubstituted. Preferably, examples of monocyclic heteroaryl include but are not limited to thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and similar groups. Preferably, examples of bicyclic heteroaryl include but are not limited to indolyl, benzothienyl, benzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, purinyl, purinyl and similar groups.

[0052] In the present invention, the numerical range represented by the term "to" refers to a range including the numerical values described before and after the term "to" as the lower limit and the upper limit respectively.

[0053] As used in the present invention, 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 "inhibiting the activity of the binding" refers to preventing the SOS1-mediated activation of the GTP-bound form of RAS family proteins.

[0054] 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 inhibiting ERK phosphorylation. Specifically, an "SOS1 inhibitor compound" refers to a compound that binds to the catalytic site of SOS1, thereby preventing the binding of SOS1 to RAS family proteins or preventing the activation of RAS family proteins.

[0055] In the present invention, unless otherwise specified, the term "enantiomer" refers to various possible stereoisomers and geometric isomers of the compounds of the present invention. Since the compounds of Formula 1 according to one aspect of the present invention may have asymmetric carbon centers (no carbon present), the compounds may exist as enantiomers (R or S isomers), racemates, diastereoisomers or any mixture thereof. All such isomers and mixtures are included within the scope of the present invention. The optically active (R)- and (S)-isomers can be resolved using conventional techniques or prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituents can be in the E or Z form. When the compound contains a disubstituted carbocyclic group, the compound can be in the cis or trans form. In addition, when the compound of Formula 1 includes a bridged ring, the compound can exist as exo- or endo-isomers. In addition, all tautomeric forms can also be included.

[0056] In the present invention, unless otherwise specified, the term "asymmetric carbon atom" refers to a carbon atom in a molecule that contains four different atoms, groups of atoms or functional groups bonded to the carbon atom. In the case of a compound containing such an asymmetric carbon atom, the said compound has the property of optical rotation or optical isomers. Specifically, a compound having the structure of Formula 1 and having an asymmetric carbon atom can be a compound having the structure shown in the following Formula 1a or Formula 1b. On the other hand, a 1:1 mixture of a pair of enantiomers is called a "racemic" mixture.

[0057] [Formula 1a]

[0058]

[0059] In Formula 1a, R 1 to R 3 、X 1 、L 1 、 m and n are defined in the same manner as in Formula 1.

[0060] [Formula 1b]

[0061]

[0062] In Formula 1b, R 1 to R 3 、X 1 、L 1 、 m and n are defined in the same manner as in Formula 1.

[0063] In one aspect, the compounds of Formula 1, their optical isomers and their diastereoisomers may exist in the form of 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".

[0064] In one aspect, the compounds of Formula 1, their optical isomers, their diastereoisomers and their solvates may exist in the form of pharmaceutically acceptable salts.

[0065] In the present invention, the term "pharmaceutically acceptable salt" should have low toxicity to the human body and should 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

[0066] Preferred salt forms of the compounds of the present invention include salts formed with inorganic acids or organic acids. In this case, acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like can be used as inorganic acids. In addition, acids such as acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used as organic acids. Organic bases that can be used to prepare organic base addition salts are tris(hydroxymethyl)methylamine, 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. It will be apparent to those of ordinary skill in the art that other acids or bases can be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

[0067] These salts can be prepared by conventional methods. For example, salts can be prepared by: dissolving the compound of Formula 1 in a water-miscible solvent, such as methanol, ethanol, acetone and 1,4-dioxane; adding the free acid or free base to the resulting solution; and crystallizing the resulting product.

[0068] Details of the pharmaceutical compositions describing one aspect of the present invention can be directly applied to the prophylactic or therapeutic methods of another aspect of the present invention.

[0069] In the present invention, the term "treatment" is used as a concept encompassing all meanings including the treatment, amelioration, alleviation or management of diseases.

[0070] As used herein, the terms "preventing" or "prevention" refer to preventing a disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder, but who has not yet experienced or exhibited a lesion or symptom of the disease.

[0071] As used herein, the terms "subject" or "patient" refer to any mammal, such as an animal, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates and humans.

[0072] Hereinafter, the present invention will be described in more detail.

[0073] [Chemical Formula 1]

[0074]

[0075] In Chemical Formula 1,

[0076] R 1 is hydrogen or C 1-4 alkyl;

[0077] R 2 is hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 2-6 alkenyl or C 2-6 alkynyl;

[0078] R 3 is R 3a or -L 2 -

[0079] R 3a each independently is halogen, hydroxy, cyano, amino, amine, nitro, oxo group (=O), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, -CF 2 H, -(CH 2 ) r -NH(CO)-R a or -(CH 2 ) r -NR a R b wherein R a and R b each independently is selected from the group consisting of: hydrogen, C 1-6 alkyl, halo C 1-6Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -CF 2 H and C 3-8 Carbocyclic group;

[0080] r is an integer in the range of 0 to 1;

[0081] m is an integer in the range of 0 to 5;

[0082] L 2 is a chemical bond, -O-(CH 2 ) p or -CH=CH-(CH 2 ) q ;

[0083] p is an integer in the range of 0 to 3;

[0084] q is an integer in the range of 0 to 2;

[0085] Each independently is C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclic group, C 2-10 Heterocyclic group or C 9-12 Bicyclic heterocyclic group, where the C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclic group, C 2-10 Heterocyclic group or C 9-12 Bicyclic heterocyclic group is unsubstituted or substituted by one or more R 3a substituents,

[0086] X 1 is -O(R 4 ) or -N(R 5 )(R 6 );

[0087] R 4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclic group, C 2-9 Heterocyclic group, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclic group, C 6-14 Heterospirocarbocyclic group, C 8-16Fused carbocyclic group, C 6-14 Fused heterocyclic group, C 8-16 Bridged carbocyclic group or C 6-14 Bridged heterocyclic group, wherein each is unsubstituted or substituted by halogen, hydroxy, nitro, oxo group (=O), cyano, halo C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d substituted, wherein R c and R d are each independently hydrogen or C 1-6 alkyl;

[0088] R 5 and R 6 are each hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic group, C 2-9 heterocyclic group, C 6-10 aryl, C 4-10 heteroaryl, C 8-16 spirocarbocyclic group, C 6-14 heterospirocarbocyclic group, C 8-16 fused carbocyclic group, C 6-14 fused heterocyclic group, C 8-16 bridged carbocyclic group or C 6-14 bridged heterocyclic group, wherein C 1-6 alkyl, hydroxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic group, C 2-9 heterocyclic group, C 6-10 aryl, C 4-10 heteroaryl, C 8-16 spirocarbocyclic group, C 6-14 heterospirocarbocyclic group, C 8-16 fused carbocyclic group, C 6-14Fused heterocyclic group, C 8-16 Bridged carbocyclic group or C 6-14 The bridged heterocyclic group is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, hydroxy, nitro, oxo group (=O), cyano, halo C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f , where R e and R f are each independently hydrogen or C 1-6 alkyl; or

[0089] Alternatively, said -N(R 5 )(R 6 ) is C 2-9 heterocyclic group, C 6-14 heterospirocarbocyclic group, C 6-14 fused heterocyclic group, C 6-14 bridged heterocyclic group or C 4-10 heteroaryl, wherein in each of them, R 5 and R 6 are connected to each other and combined with the nitrogen atom in the -N(R 5 )(R 6 ) to form a ring, where C 2-9 heterocyclic group, C 6-14 heterospirocarbocyclic group, C 6-14 fused heterocyclic group, C 6-14 bridged heterocyclic group or C 4-10 heteroaryl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, hydroxy, nitro, oxo group (=O), cyano, halo C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo C 1-6 alkoxy, -S(O)-C 1-4 alkyl, -S(O) 2 -C 1-4 alkyl, -C(O)-NR g Rh 、-C(O)OR g 、-OR g and-NR g R h , where R g and R h are independently hydrogen, C 1-6 Alkyl, Hydroxyl-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, halogen C 1-6 Alkoxy or C 3-8 Carbocyclic group;

[0090] L 1 is a chemical bond, -C(O)-, -O- or -NH-;

[0091] n is an integer ranging from 0 to 2; and

[0092] C 3-10 Carbocyclic group, C 2-9 Heterocyclic group, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocyclic carbocyclic group, C 6-14 Condensed heterocyclic group or C 6-14 A bridged heterocyclic group, wherein C 3-10 Carbocyclic group, C 2-9 Heterocyclic group, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocyclic carbocyclic group, C 6-14 Condensed heterocyclic group or C 6-14 The bridged heterocyclic group is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen, hydroxy, nitro, oxo (=O), halogen C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O) 2 -C 1-4 Alkyl, -C(O)-NR i R j 、-C(O)OR i 、-OR i and-NR i R j ; where R i and R j are independently hydrogen or C 1-6 alkyl.

[0093] Preferably, among the compounds selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their diastereomers, their hydrates and their solvates, each independently is C 6-10 aryl or C 4-10 heteroaryl.

[0094] Preferably, among the compounds selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their diastereomers, their hydrates and their solvates, R 3a each independently is halogen, hydroxyl, cyano, amino, amine, nitro, C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkoxy, -CF 2 H, C 6-10 aryl, C 3-6 cycloalkyl, -(CH 2 ) r -C 2-6 heterocycloalkyl, -(CH 2 ) r -NH(CO)-R a or -(CH 2 ) r -NR a R b ; wherein R a and R b each independently is hydrogen, C 1-6 alkyl, -CF 3 or -CF 2 H.

[0095] Preferably, among the compounds selected from the compounds of Formula 1 of the present invention, their pharmaceutically acceptable salts, their optical isomers, their diastereomers, their hydrates and their solvates, R 4 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 -6 alkoxy, C 3-10 carbocyclic group or C 2-9 heterocyclic group, R 5 and R 6 each independently is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-10 carbocyclic group or C 2-9 heterocyclic group, or the said -N(R 5)(R 6 ) is C 2-9 heterocyclic group.

[0096] In another embodiment of the present invention, the compound represented by Chemical Formula 1 can be represented by the following Chemical Formula 2:

[0097] [Chemical Formula 2]

[0098]

[0099] In Chemical Formula 2,

[0100] L 1 is a chemical bond, -C(O)-, -O-, or -NH-;

[0101] n is an integer in the range of 0 to 2; and

[0102] Z 1 and Z 2 are each independently hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not both hydrogen at the same time;

[0103] R 4a is hydrogen, C 1-6 alkyl, C 3-10 carbocyclic group, or C 2-9 heterocyclic group;

[0104] is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl, where morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl, or azetidinyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 .

[0105] In another embodiment of the present invention, the compound represented by Chemical Formula 1 can be represented by the following Chemical Formula 3:

[0106] [Chemical Formula 3]

[0107]

[0108] In Chemical Formula 3,

[0109] L 3 is a chemical bond or -C(O)-;

[0110] n is an integer in the range of 0 to 2; and

[0111] Z 1 and Z 2 are each independently hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not both hydrogen at the same time;

[0112] R 5a and R 5b are each independently hydrogen, C 1-6 alkyl, C 1 -6 alkoxy, C 3-10 carbocyclic group or C 2-9 heterocyclic group, or

[0113] Alternatively, -N(R 5a )(R 5b ) is a C 2-9 heterocyclic group, where R 5a and R 5b are connected to each other and combined with the nitrogen atom contained in the -N(R 5a )(R 5b ) to form a ring;

[0114] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, where morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 .

[0115] In another embodiment of the present invention, the compound shown in Chemical Formula 2 can be represented as the following Chemical Formula 4:

[0116] [Chemical Formula 4]

[0117]

[0118] In Chemical Formula 4,

[0119] L 4 is a chemical bond, -C(O)- or -O-;

[0120] n is an integer in the range of 0 to 2; and

[0121] Z 1 and Z 2 are each independently hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not both hydrogen at the same time;

[0122] is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, where the morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH 3 .

[0123] In another embodiment of the present invention, the compound shown in Chemical Formula 3 can be represented as the following Chemical Formula 5:

[0124] [Chemical Formula 5]

[0125]

[0126] In Chemical Formula 5,

[0127] L 5 is a chemical bond or -C(O)-;

[0128] n is an integer in the range of 0 to 2; and

[0129] Z 1 and Z 2 are each independently hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not both hydrogen at the same time;

[0130] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, where the morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen or -CH 3 .

[0131] In addition, preferred examples of the compound of Chemical Formula 1 of the present invention include, but are not limited to, the following compounds:

[0132] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0133] (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone;

[0134] (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone;

[0135] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholinyl)methanone;

[0136] (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone;

[0137] (R)-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0138] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone;

[0139] (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone;

[0140] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone;

[0141] (R)-2,2,2-Trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholin-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide;

[0142] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone;

[0143] (4-((1-(4-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholinyl)methanone;

[0144] (4-((1-(4-(2-((Aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0145] (4-((1-(4-(2-((Hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0146] (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone;

[0147] (R)-(4-((1-(5-Amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0148] (R)-(4-((1-(3-Amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0149] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone;

[0150] (R)-(4-((1-(3-Amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0151] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone;

[0152] (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0153] (R)-3-Amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile;

[0154] (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0155] (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0156] (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0157] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone;

[0158] (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone;

[0159] (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0160] (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0161] (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0162] (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0163] Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone;

[0164] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholinyl)methanone;

[0165] (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-amine;

[0166] (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-amine;

[0167] (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine;

[0168] (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine;

[0169] (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine;

[0170] (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine;

[0171] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0172] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0173] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholinyl)methanone;

[0174] (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0175] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0176] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0177] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)((R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0178] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0179] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholinyl)methanone;

[0180] (R)-N4-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-(morpholinylmethyl)quinazolin-4,6-diamine;

[0181] (R)-(4-((1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0182] (R)-(4-((1-(3-Amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0183] (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0184] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone;

[0185] (R)-(4-((1-(3-Amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0186] (R)-4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholinyl)methanone;

[0187] (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholinyl)methanone;

[0188] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone;

[0189] (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone;

[0190] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone;

[0191] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholinyl)methanone;

[0192] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone;

[0193] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone;

[0194] (4-(((R)-1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone;

[0195] (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone;

[0196] (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone;

[0197] (4-(((R)-1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone;

[0198] (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone;

[0199] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; and

[0200] (R)-N 4 -(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine.

[0201] In the present invention, the method for preparing the compound of Formula 1 is not particularly limited. For example, the compound of Formula 1 can be synthesized by the preparation methods of Reaction Scheme 1 or Reaction Scheme 2 below:

[0202] [Reaction Scheme 1]

[0203]

[0204] In Reaction Scheme 1, R 1 、R 2 、R 3 、R 4 、m and are defined the same as in Formula 1, but are not limited thereto.

[0205] [Step 1]

[0206] 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 sulfuric acid and nitric acid, the mixture was slowly added dropwise to the reaction product in the temperature range of 0°C to 5°C. After the addition was completed, the solution was refluxed at 95°C to 110°C for 1 to 3 hours. After the reaction was completed, it 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 solution obtained by concentration under reduced pressure gave the target compound.

[0207] [Step 2]

[0208] B (1 equivalent), sodium acetate (2.2 equivalents), sodium hydroxide (3 equivalents), and copper (0.01 equivalent) 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 completed, the solution was cooled to room temperature, filtered through a filter filled with diatomaceous earth, and washed with water. The aqueous layer obtained by filtration was acidified to pH 1 - 2 with 6N hydrochloric acid. The acidified aqueous solution was extracted 3 times with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and filtered under reduced pressure. The organic layer obtained by filtration was concentrated under reduced pressure to give the target compound.

[0209] [Step 3]

[0210] C (1 equivalent) and sulfuric acid (1 equivalent) prepared in [Step - 2] were dissolved in methanol and stirred and refluxed at 65°C to 75°C for 60 to 70 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated solution was extracted 3 times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and filtered under reduced pressure. The organic layer obtained by filtration was concentrated under reduced pressure to give the target compound.

[0211] [Step 4]

[0212] D (1 equivalent), methyl iodide (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 completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue obtained was dissolved in distilled water and ethyl acetate, and extracted 3 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 the organic layer was concentrated under reduced pressure. The residue obtained was purified by MPLC to give the target compound.

[0213] [Step 5]

[0214] Dissolve E (1 equivalent) prepared in [Step 4] in a mixed solution of ethyl acetate and ethanol, and add Pd / C thereto. Stir the reaction solution in a hydrogen atmosphere at 45 °C to 55 °C for 16 to 24 hours. After the reaction is completed, filter the reaction solution through a filter filled with diatomaceous earth and wash with water. Concentrate the filtered organic layer under reduced pressure, purify the obtained residue by MPLC to obtain the target compound.

[0215] [Step 6]

[0216] Dissolve F (1 equivalent) obtained in [Step 5] in tetrahydrofuran, and slowly add dropwise 4% potassium hydroxide. Stir it at 65 °C to 75 °C for 2 to 4 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, remove the organic layer to obtain an aqueous layer. Acidify the aqueous layer with 6N hydrochloric acid to pH 1 - 2 to obtain a solid product. Filter the obtained solid product under reduced pressure, and wash the residual solid after filtration with distilled water. Dry the solid obtained by filtration in an oven dryer at 50 °C to 60 °C to obtain the target compound.

[0217] [Step 7]

[0218] Dissolve G (1 equivalent) obtained in [Step 6], acetamidine hydrochloride (2 equivalents), and sodium acetate (2 equivalents) in 2 - methoxyethanol, and reflux the solution with stirring at 140 °C to 160 °C for 12 to 20 hours. After the reaction is completed, cool the reaction solution to room temperature, add dropwise distilled water, and stir at 0 °C to 5 °C for 0.5 to 1 hour to obtain a solid product. Filter the obtained solid product under reduced pressure, and wash the solid obtained by filtration with distilled water. Dry the solid obtained by filtration in an oven dryer at 50 °C - 60 °C to obtain the target compound.

[0219] [Step 8]

[0220] Dissolve H (1 equivalent) obtained in [Step 7], amine (1.5 equivalents), HATU (3 equivalents), and DIPEA (5 equivalents) in DMF, and reflux the obtained solution with stirring at room temperature for 2 to 3 hours. After the reaction is completed, cool the reaction solution to room temperature to obtain a solid product. Filter the obtained solid product under reduced pressure, and wash the solid obtained by filtration with distilled water to obtain the target compound.

[0221] [Step 9]

[0222] Dissolve I (1 equivalent) obtained in [Step 8] in phosphoryl chloride, and reflux at 105 °C to 114 °C for 1 to 2.5 hours. After the reaction is completed, cool the reaction solution to room temperature, and add dropwise an aqueous solution of sodium bicarbonate for neutralization. Extract with ethyl acetate 3 times, dry with anhydrous sodium sulfate, and then concentrate under reduced pressure. Purify the obtained residue by MPLC to obtain the target compound.

[0223] [Step 10]

[0224] Dissolve J (1 equivalent), aniline (1.1 equivalents), and DIPEA (4 equivalents) obtained in [Step 9] in DMF, and stir and reflux at 95 to 110 °C for 12 to 15 hours. After the reaction is completed, cool the reaction solution to room temperature and add water dropwise. Extract 3 times with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography to obtain the target compound.

[0225] [Reaction Scheme 2]

[0226]

[0227] In Reaction Scheme 2, R 1 、R 2 、R 3 、R 4 、m and are defined the same as in Chemical Formula 1, but not limited thereto.

[0228] [Step 1]

[0229] Mix methyl 3-methoxy-4-methylbenzoate (1 equivalent) with acetic acid and water, and then add bromine (1.1 equivalents) dropwise thereto. After the dropwise addition is completed, reflux the solution at 50 to 60 °C for 1 to 2 hours. After the reaction is completed, cool to room temperature and add an aqueous sodium bicarbonate solution dropwise. Extract the aqueous solution with a hexane / ethyl ether solution, dry the organic layer with anhydrous sodium sulfate, and filter under reduced pressure. Concentrate the filtrate under reduced pressure to obtain the target compound.

[0230] [Step 2]

[0231] Dissolve B (1 equivalent), N-bromosuccinimide (0.9 equivalent), and azobisisobutyronitrile (0.2 equivalent) obtained in [Step 1] in chloroform, and stir and reflux at 65 to 70 °C for 1.5 to 3 hours. After the reaction is completed, cool to room temperature and add an aqueous sodium bicarbonate solution dropwise. After extraction with ethyl acetate, dry the obtained organic layer with anhydrous sodium sulfate. Filter the dried organic layer under reduced pressure and concentrate the organic layer under reduced pressure. Purify the obtained residue by MPLC to obtain the target compound.

[0232] [Step 3]

[0233] Dissolve C (1 equivalent), amine (1.1 equivalents), and potassium carbonate (2 equivalents) obtained in [Step 2] in acetonitrile and stir at 20 to 30 °C for 17 to 20 hours. After the reaction is completed, cool to room temperature and add an aqueous sodium bicarbonate solution dropwise. After extraction with ethyl acetate, dry the obtained organic layer with anhydrous sodium sulfate. Filter the dried organic layer under reduced pressure and concentrate the organic layer under reduced pressure. Purify the obtained residue by MPLC to obtain the target compound.

[0234] [Step 4]

[0235] Dissolve D (1 equivalent), tert-butyl carbamate (1.1 equivalents), xantphos (0.2 equivalents), Pd2(dba) 3 dba (0.1 equivalent), and cesium carbonate (3 equivalents) in 1,4-dioxane and stir at 100 °C to 120 °C for 1 to 3 hours. After the reaction is completed, cool the product to room temperature, filter through a filter filled with diatomaceous earth, and wash with ethyl acetate. Concentrate the filtered organic layer under reduced pressure, purify the resulting residue by MPLC to obtain the target compound.

[0236] [Step 5]

[0237] Dissolve E (1 equivalent) obtained in [Step 4] in acetonitrile and dropwise add 4N hydrogen chloride dioxane solution thereto. Stir and reflux at 70 °C to 90 °C for 1 to 3 hours. After the reaction is completed, cool to room temperature and dropwise add an aqueous sodium bicarbonate solution for neutralization. Extract the reaction product with anhydrous sodium sulfate, dry, and then concentrate under reduced pressure. The residue is solidified with ethyl acetate and filtered under reduced pressure. Dry the filtered solid to obtain the target compound.

[0238] [Step 6]

[0239] Dissolve F (1 equivalent), aniline (1.5 equivalents), PyBOP (1.5 equivalents), and DBU (2.5 equivalents) obtained in the above [Step 5] in acetonitrile and stir at 75 °C to 85 °C for 4 to 6 hours. After the reaction is completed, cool the reaction solution to room temperature and dropwise add water. Extract with ethyl acetate three times, dry with anhydrous sodium sulfate, and then concentrate under reduced pressure. Purify the residue by column chromatography to obtain the target compound.

[0240] In the present invention, the method for preparing the compound of Chemical Formula 1 is not particularly limited. For example, the compound of Chemical Formula 1 can be synthesized by the preparation method of Reaction Scheme 3 below:

[0241] [Reaction Scheme 3]

[0242]

[0243] In Reaction Scheme 3, R1, R2, R3, R5, m, and are defined the same as in Chemical Formula 1, but are not limited thereto.

[0244] [Step 1]

[0245] 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 sulfuric acid and nitric acid, the mixture was slowly added dropwise to the reaction product in the temperature range of 0 °C to 5 °C. After the addition was completed, the solution was refluxed at 95 °C to 110 °C for 1 to 3 hours. After the reaction was completed, it 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 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The solution obtained by concentration under reduced pressure was concentrated to obtain the compound.

[0246] [Step 2]

[0247] B (1 equivalent) and sulfuric acid (1 equivalent) prepared in the above [Step 1] were dissolved in methanol and stirred and refluxed at 65 °C to 75 °C for 60 to 70 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrated solution was extracted 3 times with ethyl acetate, 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.

[0248] [Step 3]

[0249] 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 completed, 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.

[0250] [Step 4]

[0251] D (1 equivalent) obtained in [Step 3] and zinc powder (3.5 equivalents) were dissolved in a mixed solution of dioxane and distilled water, and the mixture was stirred and refluxed 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 addition was completed, the mixture was stirred and refluxed at 25 °C to 30 °C for 1 - 3 hours. After the reaction was completed, 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 3 times with ethyl acetate to obtain the 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.

[0252] [Step 5]

[0253] Dissolve E (1 equivalent) prepared in [Step 4] and acetonitrile (8 equivalents) in a 4N hydrochloric acid solution dissolved in dioxane. Use a sealed tube to stir the reaction solution at 85 °C to 95 °C for 2.5 to 3.5 hours. After the reaction is completed, filter the reaction solution through a filter and wash it with hexane. The obtained solid is neutralized with sodium bicarbonate and filtered under reduced pressure to obtain the target compound.

[0254] [Step 6]

[0255] Dissolve F (1 equivalent) obtained in the above [Step 5] in phosphorus oxychloride and stir at 110 °C to 130 °C for 2 - 4 hours. When the reaction is completed, remove the organic layer by concentration under reduced pressure. Dissolve the obtained residue in dichloromethane and neutralize it with an aqueous sodium bicarbonate solution at low temperature. Wash the organic layer with distilled water and dry it with anhydrous sodium sulfate. After filtering the dried organic layer under reduced pressure, concentrate it under reduced pressure. Purify the obtained residue by column chromatography to obtain the target compound.

[0256] [Step 7]

[0257] Dissolve G (1 equivalent), aniline (1.3 equivalents), and DIPEA (3 equivalents) obtained in the above [Step - 6] in DMF, and then stir and reflux at 85 °C to 100 °C for 12 to 15 hours. After the reaction is completed, cool the reaction solution to room temperature and add water dropwise. Extract it 3 times with ethyl acetate, dry it with anhydrous sodium sulfate, and then concentrate it under reduced pressure. Purify the residue by column chromatography to obtain the target compound.

[0258] [Step 8]

[0259] Dissolve H (1 equivalent) obtained in [Step 7] in a mixed solution of tetrahydrofuran, methanol, and water, and add sodium hydroxide (5 equivalents) thereto. Stir and reflux the solution at 25 °C to 30 °C for 1 to 3 hours. After the reaction is completed, add a 2N HCl aqueous solution dropwise to adjust the pH to 5 - 6, and wash it with ethyl acetate. Dry the obtained organic layer with anhydrous sodium sulfate and concentrate it under reduced pressure to obtain the target compound. Dissolve the unpurified target compound, amine (1.1 equivalents), HATU (1.3 equivalents), and DIPEA (3 equivalents) in DMF, and then stir and reflux at 25 °C to 30 °C for 1 to 3 hours. After the reaction is complete, extract the reaction product 3 times with ethyl acetate, dry it with anhydrous sodium sulfate, and then concentrate it under reduced pressure. Purify the obtained residue by column chromatography to obtain the target compound.

[0260] Although the preparation method of Chemical Formula 1 has been described by 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 construed as limiting the scope of the claims.

[0261] The pharmaceutical composition of the present invention can be used for preventing or treating various diseases related to inhibiting the binding of SOS1, because the compound of Formula 1 contained in the pharmaceutical composition can inhibit the binding of SOS1 to RAS family proteins and / or RAC1.

[0262] In one embodiment, the compound of the present invention has little inhibitory effect on cytochrome P450 enzyme (CYP) subtypes, thereby reducing side effects such as drug interactions that may occur due to reduced activity of CYP subtypes. Therefore, the compound of the present invention can be used for multiple agents (multiple drug use). In a specific embodiment, the compound of the present invention has the structure of Formula 2 or Formula 3 and has little inhibitory effect on cytochrome P450 enzyme subtypes. In a further specific embodiment, the compound of the present invention has the structure of Formula 4 or Formula 5 and is excellent in maintaining the activity against cytochrome P450 enzyme subtypes. For example, the compound of Formula 4 or 5 of the present invention shows an inhibitory effect on the activity of cytochrome P450 enzyme (CYP) subtypes, and its IC50 value is at least 20 μM.

[0263] In another embodiment of the present invention, there is provided a prophylactic or therapeutic pharmaceutical composition comprising a compound of Formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient.

[0264] In another embodiment of the present invention, there is provided a pharmaceutical preparation comprising the above pharmaceutical composition.

[0265] The pharmaceutical preparation of the present invention can be various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, etc., or parenteral dosage forms such as intramuscular injections, intravenous injections, subcutaneous injections, etc. Preferably, the pharmaceutical preparation can be an oral dosage form.

[0266] In addition, the pharmaceutical preparation can be formulated according to conventional methods by adding one or more non-toxic pharmaceutically acceptable additives such as carriers, adjuvants, and excipients to the active ingredient.

[0267] Excipients that can be used in the pharmaceutical preparation of the present invention include but are not limited to sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonizing agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavors, etc. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, tragacanth, alginic acid, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla essence, etc. can be used as excipients.

[0268] When the pharmaceutical preparation of the present invention is in oral dosage form, examples of the carriers used include, but are not limited to, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, etc.

[0269] When the pharmaceutical preparation of the present invention is in injectable dosage form, examples of the carriers include, but are not limited to, water, saline, glucose aqueous solution, pseudo-sugar solution, alcohol, ethylene glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0270] For using the compounds of the present invention as drugs, the said medicaments are prepared in the form of pharmaceutical preparations, which in addition to the active ingredient for oral or parenteral administration, also include pharmaceutically suitable organic or inorganic inert carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oil, polyalkylene glycol, etc. The pharmaceutical preparations can be in solid form such as tablets, dragees, suppositories or capsules, or in liquid form such as solutions, suspensions or emulsions. In addition, the pharmaceutical preparations optionally contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers. The pharmaceutical preparations may also contain salts or buffers for changing the osmotic pressure.

[0271] For parenteral administration, injection solutions or suspensions are particularly preferred.

[0272] Surfactant adjuvants (such as bile salts, animal or vegetable phospholipids or mixtures thereof) and liposomes or their components can also be used as carrier systems.

[0273] For oral administration, tablets, dragees or capsules containing talc and / or hydrocarbon excipients or binders are particularly suitable. For example, tablets, dragees or capsules containing lactose, corn starch or potato starch are preferred. It can also be administered in liquid form, for example in the form of fruit juice with added sweeteners.

[0274] In addition, based on an adult patient with a general body weight of 70 kg, the human dose of the compound of Formula 1 of the present invention is preferably in the range of 0.1 mg / day to 2,000 mg / day. The compounds of the present invention can be administered in divided doses, once a day or several times a day. However, the dose can vary according to the patient's health condition, age, weight and gender, dosage form and disease level, so the scope of the present invention is not limited to the above doses.

[0275] In another embodiment of the present invention, there is provided the use of the compound of Formula 1 of the present invention, its pharmaceutically acceptable salts, optical isomers, diastereomers, hydrates and solvates, or the pharmaceutically acceptable salts of the selected compounds for the prophylactic or therapeutic use of cancer or tumors.

[0276] In another embodiment of the present invention, a method for preventing or treating cancer is provided. The method includes administering to a subject a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof. Preferably, the subject is an individual or a patient, but is not limited thereto.

[0277] In yet another embodiment of the present invention, a method for treating cancer in a subject in need of administering a compound inhibitor and a standard of care formulation is provided. The method includes administering to the subject a therapeutically effective amount of the standard of care formulation, which includes: a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0278] In yet another embodiment of the present invention, a method for treating cancer in a subject in need of administering a composition is provided. The method includes administering to the subject a therapeutically effective amount of the composition, which includes: a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an optical isomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0279] In yet another embodiment of the present invention, a method for inhibiting the binding of SOS1 to a RAS family protein and / or RAC1 in a subject or a cell is provided. The method includes administering to the subject a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0280] In yet another embodiment of the present invention, a method for inhibiting a tyrosine kinase in a subject or a cell is provided. The method includes administering to the subject a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0281] In yet another embodiment of the present invention, a method for preventing or treating cancer in a subject is provided. The method includes administering to the subject a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0282] In yet another embodiment of the present invention, there is provided a method for preventing or treating cancer, which can be prevented or treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1 in a subject or cell. The method includes administering to the subject a compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, an enantiomer, a diastereomer, a hydrate, and a solvate, or a pharmaceutically acceptable salt thereof.

[0283] Hereinafter, the present invention will be described in more detail by way of examples and experimental examples. However, the examples and experimental examples are only for helping to understand the present invention, and the scope of the present invention is not limited thereto in any way.

[0284] Example 1 (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0285] [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0286]

[0287] 2-Bromoterephthalic acid (13.8 g, 56.32 mmol) was slowly added dropwise to 78 mL of sulfuric acid at 0 °C, and then stirred for 5 minutes to prepare a reaction solution. After mixing 7.5 mL of sulfuric acid and 17.5 mL of nitric acid, it was slowly added dropwise to the reaction solution at 0 °C. After the addition was completed, the mixture was stirred and refluxed at 100 °C for 2 hours. After the reaction was completed, the product was cooled to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted 3 times with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain 16 g of the title compound.

[0288] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 8.17 (s, 1H).

[0289] [Step 2] Preparation of 2-hydroxy-5-nitroterephthalic acid

[0290] Dissolve 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] in 60 mL of distilled water, and stir and reflux under microwave at 120 °C for 2 hours. After the reaction is completed, cool the solution to room temperature, filter it through a filter filled with diatomaceous earth, and wash it with water. Acidify the obtained aqueous layer to pH 1 - 2 with 6N hydrochloric acid. Extract the acidified aqueous solution with dichloromethane three times, dry the organic layer with anhydrous sodium sulfate, and filter it under reduced pressure. Concentrate the filtered organic layer under reduced pressure to obtain 7 g of the title compound with a yield of 85%.

[0291] 1 H-NMR(300MHz,DMSO-d 6 ):δ8.42(s,1H),7.15(s,1H)。

[0292] [Step 3] Preparation of dimethyl 2-hydroxy-5-nitroterephthalate

[0293]

[0294] Dissolve 2-hydroxy-5-nitroterephthalic acid (7 g, 30.82 mmol) and sulfuric acid (35 mL, 653.04 mmol) prepared in [Step 2] in 330 mL of methanol, and stir and reflux at 70 °C for 65 hours. After the reaction is completed, cool the reaction solution to room temperature and concentrate it under reduced pressure. Extract it with ethyl acetate three times, dry the organic layer with anhydrous sodium sulfate, and filter it under reduced pressure. Concentrate the filtered organic layer under reduced pressure to obtain 7.9 g of the title compound.

[0295] 1 H-NMR(300MHz,DMSO-d 6 ):δ8.43(s,1H),6.85(s,1H),3.83(s,1H)。

[0296] [Step 4] Preparation of dimethyl 2-methoxy-5-nitroterephthalate

[0297]

[0298] Dissolve dimethyl 2-hydroxy-5-nitroterephthalate (7.9 g, 30.82 mmol) obtained in [Step 3], iodomethane (15.3 mL, 246.56 mmol) and potassium carbonate (34 g, 246.56 mmol) in 310 mL of acetone, and stir and reflux at 60 °C for 21 hours. After completion of the reaction, cool the reaction solution to room temperature and concentrate it under reduced pressure. Dissolve the obtained residue in a mixture of distilled water and ethyl acetate (volume ratio 1:1), and extract it 3 times with ethyl acetate to obtain an organic layer. Dry the obtained organic layer with anhydrous sodium sulfate. Filter the dried organic layer under reduced pressure and concentrate the organic layer under reduced pressure. Purify the obtained residue by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 6.1 g of the title compound with a yield of 73%.

[0299] 1 H-NMR(300MHz,CDCl 3 ):δ8.57(s,1H),7.15(s,1H),4.05(s,3H),3.98(s,3H),3.96(s,3H).

[0300] [Step 5] Preparation of dimethyl 2-amino-5-methoxyterephthalate

[0301]

[0302] Dissolve dimethyl 2-methoxy-5-nitroterephthalate (6.1 g, 22.50 mmol) prepared in the above [Step 4] in a mixed solution of 122 mL of ethyl acetate and ethanol (1:4 volume / volume), and add Pd / C (600 mg, 10 wt%) thereto. Stir the reaction solution in a hydrogen atmosphere at 50 °C for 20 hours. After completion of the reaction, filter the reaction solution through a filter filled with diatomaceous earth and wash it with methanol. Concentrate the obtained organic layer under reduced pressure, and purify the obtained residue by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 5 g of the title compound with a yield of 93%.

[0303] 1 H-NMR(300MHz,CDCl 3 ):δ7.38(s,1H),7.05(s,1H),5.50(s,2H),3.86(s,6H),3.80(s,3H).

[0304] [Step 6] Preparation of 2-amino-5-methoxyterephthalic acid

[0305]

[0306] Dissolve dimethyl 2-amino-5-methoxyterephthalate (5 g, 20.93 mmol) obtained in [Step 5] in 115 mL of tetrahydrofuran, and slowly add dropwise 115 mL of 4% potassium hydroxide. It was stirred at 70 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the organic layer, and an aqueous layer was obtained. The aqueous layer was acidified with 2N hydrochloric acid until the pH became 1 to 2. As a result, a solid product was obtained. The solid product obtained by filtration under reduced pressure was washed with distilled water. The solid obtained by filtration was dried in an oven dryer at 55 °C to obtain 4.3 g of the title compound with a yield of 98%.

[0307] 1 H-NMR(300MHz,DMSO-d 6 ):δ7.30(s,1H),7.01(s,1H),3.70(s,3H)。

[0308] [Step 7] Preparation of 6-methoxy-2-methyl-4-oxo-1,4-dihydroquinazoline-7-carboxylic acid

[0309]

[0310] Dissolve 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] in 86 mL of methoxyethanol, and stir at 150 °C under reflux for 15 hours. After the reaction was complete, the reaction solution was cooled to room temperature, distilled water was added dropwise, and it was stirred at 0 °C for 0.5 hour to obtain a solid product. The solid product obtained by filtration under reduced pressure was washed with distilled water. The solid obtained by filtration was dried in an oven dryer at 55 °C to obtain 3.3 g of the title compound with a yield of 69%.

[0311] 1 H-NMR(300MHz,DMSO-d 6 ):δ13.19(s,1H),12.26(s,1H),7.70(s,1H),7.57(s,1H),3.90(s,3H),2.34(s,3H)。

[0312] [Step 8] Preparation of 6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1 H )-one;

[0313]

[0314] Dissolve 6-methoxy-2-methyl-4-oxo-1,4-dihydroquinazoline-7-carboxylic acid (300 mg, 1.28 mmol), morpholine (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] in 4.5 mL of DMF and stir at room temperature under reflux for 2.5 hours. After the reaction is completed, cool the reaction solution to room temperature to obtain a solid product. Filter the obtained solid product under reduced pressure, wash the filtered solid with ethyl acetate to obtain 255 mg of the title compound with a yield of 66%.

[0315] 1 H-NMR(300MHz,DMSO-d 6 ):δ12.24(s,1H),7.55(s,1H),7.41(s,1H),3.90(s,3H),3.68(m,4H),3.52(m,2H),3.11(m,2H),2.51(s,3H).

[0316] [Step 9] Preparation of (4-chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholine)methanone

[0317]

[0318] Dissolve 6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1H)-one (255 mg, 0.84 mmol) obtained in the above [Step 8] in 14 mL of phosphoryl chloride and reflux at 110 °C for 2 hours. After the reaction is completed, cool to room temperature and add an aqueous sodium bicarbonate solution dropwise for neutralization. Extract the reaction product 3 times with anhydrous sodium sulfate, dry it, and then concentrate it under reduced pressure. Purify the residue by MPLC (methylene chloride:methanol = 25:1 to 10:1 (v / v)) to obtain 221 mg of the title compound with a yield of 82%.

[0319] 1 H-NMR(300MHz,DMSO-d 6 ):δ7.86(s,1H),7.52(s,1H),4.01(s,3H),3.67(m,4H),3.50(m,2H),3.14(m,2H),2.50(s,3H).

[0320] [Step 10] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy- 2-methylquinazolin-7-yl)(morpholinyl)methanone

[0321]

[0322] (4-Chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (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. The mixture was stirred and refluxed at 100 °C for 13 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then water was added dropwise thereto. It was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (methylene chloride:methanol = 23:1 (v / v)) to obtain 60 mg of the title compound with a yield of 56%.

[0323] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0324] MS(ESI+,m / z):490.2[M+H] +

[0325] Example 2: (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0326] [Step 1] Preparation of (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7- yl)(morpholinyl)methanone

[0327]

[0328] The same steps of Example 1 were repeated except that 1-(4-bromothiophen-2-yl)ethan-1-amine (100 mg, 0.47 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride, and DMAc was used instead of DMF in [Step 10] of Example 1, to obtain 156 mg of the title compound with a yield of 68%.

[0329] 1 H-NMR(300MHz,DMSO-d 6): 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).

[0330] [Step 2] Preparation of 2-(5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino) ethyl)thiophen-3-yl)benzaldehyde

[0331]

[0332] Dissolve (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (156 mg, 0.32 mmol), (2-formylphenyl)boronic acid (57 mg, 0.38 mmol), Pd(PPh 3 ) 4 (40 mg, 0.03 mmol), and potassium carbonate (177 mg, 1.28 mmol) in a mixed solution of 3 mL of dioxane and water (5:1), and stir the solution at 100 °C for 5 hours. After the reaction is complete, cool the product to room temperature, filter it through a filter filled with diatomaceous earth, and wash it with dichloromethane. After adding water dropwise to the collected organic layer, extract it 3 times with dichloromethane, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure. Purify the residue by MPLC (dichloromethane:methanol = 100:1 to 10:1 (v / v)) to obtain 143 mg of the title compound with a yield of 88%.

[0333] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 10.08 (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).

[0334] [Step 3] Preparation of (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2- yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone

[0335]

[0336] Dissolve 2-(5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde (143 mg, 0.28 mmol), 2.0 M methylamine (0.3 mL, 0.55 mmol), acetic acid (0.03 mL, 0.55 mmol) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) prepared in the above [Step 2] in 2 mL of dichloroethane, and stir the solution at room temperature for 16 hours. After the reaction is completed, cool the reaction solution to room temperature, and neutralize it by dropwise adding an aqueous sodium bicarbonate solution. Extract it 3 times with ethyl acetate, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure. The residue is purified by MPLC (dichloromethane:methanol = 50:1 to 7:1 (v / v)) to obtain 80 mg of the title compound with a yield of 56%.

[0337] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0338] MS(ESI+,m / z):532.2[M+H] +

[0339] Example 3: ((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone

[0340]

[0341] Repeat the same steps of Example 1 except using cis-2,6-dimethylpiperazine (270 mg, 2.34 mmol) instead of morpholine in [Step 8] of Example 1 to obtain 14 mg of the title compound with a yield of 34%.

[0342] 1 H-NMR(300MHz,DMSO-d 6): δ 8.28 (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).

[0343] MS(ESI+, m / z): 517.3 [M+H] +

[0344] Example 4: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholinyl)methanone

[0345]

[0346] The same procedure as in Example 1 was repeated except that thiomorpholine (0.24 mL, 2.56 mmol) was used instead of morpholine in Example 1 [Step 8] to afford 60 mg of the title compound in 56% yield.

[0347] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.27 (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).

[0348] MS(ESI+, m / z): 506.2 [M+H] +

[0349] Example 5: (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone

[0350]

[0351] The same procedure as in Example 1 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (159 mg, 1.41 mmol) was used instead of morpholine in Example 1 [Step 8] to afford 9.2 mg of the title compound in 9% yield.

[0352] 1 H-NMR(300MHz,CD 3 OD): δ 7.82 (s, 1H), 7.52 (s, 1H), 7.00 (m, 2H), 6.83 (s, 1H), 5.66 (m, 1H), 4.02 (s, 3H), 3.94 (m, 2H), 3.84 (m, 2H), 3.66 (m, 2H), 3.18 (m, 4H), 2.49 (s, 3H), 1.67 (d, J = 6.9Hz, 3H).

[0353] MS(ESI+, m / z): 516.2 [M + H] +

[0354] Example 6: (R)-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0355]

[0356] The same procedure of Example 1 was repeated except that (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (25 mg, 0.11 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 10] of Example 1, to obtain 8 mg of the title compound with a yield of 17%.

[0357] 1 H-NMR(300MHz, DMSO-d 6 ): δ 8.40 (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).

[0358] MS(ESI+, m / z): 475.2 [M + H] +

[0359] Example 7: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone

[0360]

[0361] The same procedure as in Example 1 was repeated except that azetidine (0.1 mL, 1.40 mmol) was used instead of morpholine in [Step 8] of Example 1 to afford 28 mg of the title compound in 15% yield.

[0362] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0363] MS(ESI+,m / z):460.2[M+H] +

[0364] Example 8: (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone

[0365]

[0366] The same procedure as in Example 2 was repeated except that (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)boronic acid (74 mg, 0.27 mmol) was used instead of (2-formylphenyl)boronic acid in [Step 2] of Example 2 to afford 30 mg of the title compound in 48% yield.

[0367] 1 H-NMR(300MHz,CD 3 OD):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).

[0368] MS(ESI+,m / z):544.2[M+H] +

[0369] Example 9: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone

[0370]

[0371] The same procedure of Example 1 was repeated except that piperazine (26 mg, 0.41 mmol) was used instead of morpholine in [Step 8] of Example 1 to obtain 5 mg of the title compound in 9% yield.

[0372] 1 H-NMR (300 MHz, CD 3 OD): δ 8.09 (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).

[0373] MS (ESI+, m / z): 489.2 [M+H] +

[0374] Example 10: (R)-2,2,2-Trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide

[0375]

[0376] (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (30 mg, 0.061 mmol) prepared in [Step 1] of Example 1, trifluoroacetic anhydride (14 mg, 0.067 mmol) and DIPEA (10 mg, 0.078 mmol) were dissolved in 1 mL of dichloromethane and stirred at room temperature for 5 h with ice. After completion of the reaction, aqueous ammonium chloride solution was added dropwise to neutralize the reaction solution. It was extracted 3 times with dichloromethane, 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 obtain 7 mg of the title compound in 20% yield.

[0377] 1 H-NMR (300 MHz, CD 3OD): δ 8.11 - 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).

[0378] MS(ESI+, m / z): 586.2 [M + H] +

[0379] Example 11: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone

[0380] The same procedure of Example 1 was repeated except using 3-fluoroazetidine (258 mg, 1.07 mmol) instead of morpholine in Example 1 [Step 8] to obtain 30 mg of the title compound in 9% yield.

[0381] 1 H-NMR(300 MHz, CD 3 OD): 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)

[0382] MS(ESI+, m / z): 478.2 [M + H] +

[0383] Example 12: (4-((1-(4-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholinyl)methanone

[0384]

[0385] The same procedure of Example 2 was repeated except using 2.0 M dimethylamine (0.16 ml, 0.32 mmol) instead of 2.0 M methylamine in Example 2 [Step 3] to obtain 307 mg of the title compound in 8% yield.

[0386] 1 H-NMR(300 MHz, CD 3OD): δ 7.77 (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)

[0387] MS(ESI+, m / z): 546.2 [M + H] +

[0388] Example 13: (4 - ((1 - (4 - (2 - ((Aminomethyl)phenyl)thiophen - 2 - yl)ethyl)amino) - 6 - methoxy - 2 - methylquinazolin - 7 - yl)(morpholino)methanone

[0389]

[0390] The same procedure of Example 2 was repeated except using 2.0 M ammonia (0.22 ml, 0.45 mmol) instead of 2.0 M methylamine in Example 2 [Step 3] to afford 15 mg of the title compound in 13% yield.

[0391] 1 H - NMR(300 MHz, CD 3 OD): 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)

[0392] MS(ESI+, m / z): 518.2 [M + H] +

[0393] Example 14: (4 - ((1 - (4 - (2 - ((Hydroxymethyl)phenyl)thiophen - 2 - yl)ethyl)amino) - 6 - methoxy - 2 - methylquinazolin - 7 - yl)(morpholino)methanone

[0394]

[0395] The same procedure of Example 2 was repeated except using 2 - (hydroxymethyl)phenylboronic acid (0.14 ml, 0.92 mmol) instead of (2 - formylphenyl)boronic acid in Example 2 [Step 2] to afford 88 mg of the title compound in 20% yield.

[0396] 1H-NMR(300MHz,CD 3 OD):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)

[0397] MS(ESI+,m / z):519.2[M+H] +

[0398] Example 15: (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0399]

[0400] The same procedure of Example 1 was repeated except using (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (33 mg, 0.16 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 20 mg of the title compound in 27% yield.

[0401] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0402] MS(ESI+,m / z):475.2[M+H] +

[0403] Example 16: (R)-(4-((1-(5-Amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0404]

[0405] The same procedure of Example 1 was repeated except using (R)-3-(1-aminoethyl)-4-methyl-5-(trifluoromethyl)aniline hydrochloride (83 mg, 0.31 mmol) 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.

[0406] 1 H-NMR(300MHz,DMSO-d 6 ): δ 8.36 (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).

[0407] MS(ESI+, m / z): 504.2 [M+H] +

[0408] Example 17: (R)-(4-((1-(3-Amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0409]

[0410] The same procedure of Example 1 was repeated except using (R)-3-(1-aminoethyl)-5-fluoroaniline hydrochloride (46 mg, 0.24 mmol) 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.

[0411] 1 H-NMR(300MHz,CD 3 OD): δ 8.00 (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)

[0412] MS(ESI+, m / z): 440.2 [M+H] +

[0413] Example 18: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0414]

[0415] The same procedure of Example 1 was repeated except using thiomorpholine 1,1-dioxide (30 mg, 0.21 mmol) instead of morpholine in Example 1 [Step 8] to afford 23 mg of the title compound in 30% yield.

[0416] 1 H-NMR (300 MHz, CD 3 OD): δ 7.85 (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).

[0417] MS (ESI+, m / z): 538.1 [M+H] +

[0418] Example 19: (R)-(4-((1-(3-Amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0419]

[0420] The same procedure of Example 1 was repeated except using (R)-3-(1-aminoethyl)-2-methoxyaniline hydrochloride (49 mg, 0.31 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 30 mg of the title compound in 31% yield.

[0421] 1 H-NMR (300 MHz, DMSO-d 6): δ 8.24 (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).

[0422] MS(ESI+, m / z): 452.2 [M+H] +

[0423] Example 20: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone

[0424]

[0425] The same procedure of Example 1 was repeated except that thiazolidine (0.06 mL, 0.70 mmol) was used instead of morpholine in Example 1 [Step 8] to afford 18 mg of the title compound in 56% yield.

[0426] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.31 (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).

[0427] MS(ESI+, m / z): 492.2 [M+H] +

[0428] Example 21: (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0429]

[0430] Except for using (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (45 mg, 0.31 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10], the same steps of Example 1 were repeated to obtain 15 mg of the title compound with a yield of 16%.

[0431] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0432] MS(ESI+,m / z):436.2[M+H] +

[0433] Example 22: (R)-3-Amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile

[0434]

[0435] Except for using (R)-3-amino-5-(1-aminoethyl)benzonitrile hydrochloride (65 mg, 0.33 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10], the same steps of Example 1 were repeated to obtain 6 mg of the title compound with a yield of 6%.

[0436] 1 H-NMR(300MHz,CD 3 OD):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)

[0437] MS(ESI+,m / z):447.2[M+H] +

[0438] Example 23: (R)-(4-((1-(2,3-Dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0439]

[0440] The same procedure of Example 1 was repeated except that (R)-1-(2,3-dihydro-1H-inden-4-yl)ethan-1-amine (45 mg, 0.27 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 35 mg of the title compound in 31% yield.

[0441] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.29 (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)

[0442] MS (ESI+, m / z): 447.2 [M+H] +

[0443] Example 24: (R)-(4-((1-(3-Amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0444]

[0445] The same procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-cyclopropylaniline hydrochloride (57 mg, 0.27 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 23 mg of the title compound in 20% yield.

[0446] 1 H-NMR (300 MHz, DMSO-d 6): δ 8.18 (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)

[0447] MS(ESI+, m / z): 462.2 [M+H] +

[0448] Example 25: (R)-(4-((1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0449]

[0450] The same procedure of Example 1 was repeated except using (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (62 mg, 0.24 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 40 mg of the title compound in 36% yield.

[0451] 1 H-NMR(300 MHz, CD 3 OD): δ 7.84 (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).

[0452] MS(ESI+, m / z): 508.1 [M+H] +

[0453] Example 26: (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0454]

[0455] Except for using (R)-3-(1-aminoethyl)-2-methoxyaniline hydrochloride (58 mg, 0.31 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10], the same steps of Example 1 were repeated to obtain 33 mg of the title compound in 31% yield.

[0456] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0457] MS(ESI+,m / z):490.2[M+H] +

[0458] Example 27: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholinyl)methanone

[0459]

[0460] Except for using tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.11 g, 4.6 mmol) instead of iodomethane in Example 1 [Step 4], the same steps of Example 1 were repeated to obtain 25 mg of the title compound in 18% yield.

[0461] 1 H-NMR(300MHz,CD 3 OD):δ7.79(m,1H),7.58(s,1H),7.52(s,1H),7.01(m,1H),6.83(s,1H),5.67(m,1H),5.25(m,1H),3.94(m,4H),3.81(m,4H),3.62(m,2H),3.34(m,2H),2.49(s,3H),2.38(m,2H),1.68(d,J = 5.4Hz,3H).

[0462] MS(ESI+,m / z):546.2[M+H] +

[0463] Example 28: (R)-(4-((1-(3-Amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0464]

[0465] 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.

[0466] 1 H-NMR (300 MHz, CD 3 OD): δ 8.04 (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)

[0467] MS (ESI+, m / z): 488.2 [M+H] +

[0468] Example 29: (R)-(4-((1-(3-Amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0469]

[0470] 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.

[0471] 1 H-NMR (300 MHz, CD 3OD): δ 7.82 (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)

[0472] MS(ESI+, m / z): 472.2 [M + H] +

[0473] Example 30: (R)-(4-((1-(3-Amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0474]

[0475] The same procedure of Example 1 was repeated except using (R)-3-(1-aminoethyl)-5-(thiazol-5-yl)aniline hydrochloride (67 mg, 0.26 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 1 [Step 10] to afford 4 mg of the title compound in 4% yield.

[0476] 1 H-NMR(300 MHz, CD 3 OD): δ 8.89 (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)

[0477] MS(ESI+, m / z): 505.2 [M + H] +

[0478] Example 31: (R)-(4-((1-(3-(Ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0479]

[0480] After dissolving (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (50 mg, 0.10 mmol) obtained in Example 1 [Step 10] in 1 mL of dichloromethane, acetaldehyde (5.4 mg, 0.12 mmol) and 1.0 M titanium tetrachloride dichloromethane solution were added to the reaction solution (0.01 mL, 0.01 mmol), and then sodium cyanoborohydride (26 mg, 0.41 mmol) was added, followed by stirring overnight at room temperature. After completion of the reaction, 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 (dichloromethane:methanol = 20:1 (v / v)) to obtain 16 mg of the title compound, with a yield of 31%.

[0481] 1 H-NMR(300MHz,CD 3 OD):δ7.82(d,1H),7.51(s,1H),6.98(d,2H),6.71(s,1H),5.68(m,1H),4.02(s,3H),3.77(m,4H),3.63(m,2H),3.35(m,2H),3.28(m,2H),2.49(s,3H),1.68(d,J=6.9Hz,3H),1.25(m,3H).

[0482] MS(ESI+,m / z):518.2[M+H] +

[0483] Example 32: Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone

[0484]

[0485] The same procedure of Example 1 was repeated except that 2-methoxyethyl 4-methylbenzenesulfonate (3.2 g, 14.11 mmol) was used instead of iodomethane in Example 1 [Step 4] to obtain 7 mg of the title compound, with a yield of 6%.

[0486] 1 H-NMR(300MHz,DMSO-d 6): δ 8.31 (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).

[0487] MS(ESI+, m / z): 534.2 [M + H] +

[0488] Example 33: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholinyl)methanone

[0489]

[0490] The same procedure of Example 1 was repeated except using fluoroacetonitrile (7.1 mL, 125 mmol) instead of acetonitrile in Example 1 [Step 7], to afford 32 mg of the title compound in 34% yield.

[0491] 1 H-NMR(300 MHz, CD 3 OD): δ 7.92 (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).

[0492] MS(ESI+, m / z): 508.2 [M + H] +

[0493] Example 34: (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-amine

[0494] [Step 1] Preparation of methyl 2-bromo-5-methoxy-methylbenzoate

[0495]

[0496] 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 thereto. After the addition was completed, the mixture was stirred and refluxed at 60 °C for 1 hour. After the reaction was completed, it was cooled to room temperature, and an aqueous sodium bicarbonate solution was added dropwise. The aqueous solution was extracted 3 times with a hexane / ether (8:3) solution, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain 6.92 g of the title compound with a yield of 96%.

[0497] 1 H-NMR(300MHz,CDCl 3 ): δ 7.39(s, 1H), 7.26(s, 1H), 3.92(s, 3H), 3.84(s, 3H), 2.21(s, 3H).

[0498] [Step 2] Preparation of methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate

[0499]

[0500] Methyl 2-bromo-5-methoxy-methylbenzoate (6.92 g, 26.70 mmol), N-bromosuccinimide (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 and refluxed at 70 °C for 2 hours. After the reaction was completed, it was cooled to room temperature, and an aqueous sodium bicarbonate solution was added dropwise. After extraction 3 times with ethyl acetate, 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 obtained was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 5.98 g of the title compound with a yield of 66%.

[0501] 1 H-NMR(300MHz,CDCl 3 ): δ 7.59(s, 1H), 7.30(s, 1H), 4.45(s, 2H), 3.93(s, 3H), 3.91(s, 3H).

[0502] [Step 3] Preparation of methyl 2-bromo-5-methoxy-4-(morpholinylmethyl)benzoate

[0503]

[0504] Dissolve methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate (1.2 g, 3.55 mmol), morpholine (0.34 mL, 3.90 mmol), and potassium carbonate (981 mg, 7.10 mmol) obtained in [Step 2] in 20 mL of acetonitrile, and stir the solution at room temperature for 18 hours. After the reaction is completed, cool to room temperature and add an aqueous sodium bicarbonate solution dropwise. After extracting 3 times with ethyl acetate, dry the obtained organic layer with anhydrous sodium sulfate. Filter the dried organic layer under reduced pressure and concentrate the organic layer under reduced pressure. Purify the obtained residue by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 1.0 g of the title compound with a yield of 82%.

[0505] 1 H-NMR(300MHz,CDCl 3 ):δ7.68(s,1H),7.28(s,1H),3.93(s,3H),3.84(s,3H),3.73(m,4H),3.51(m,2H),2.49(m,4H)。

[0506] [Step 4] Preparation of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinylmethyl)benzoate

[0507]

[0508] Dissolve methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate (1.0 g, 2.90 mmol), tert-butyl carbamate (566 mg, 3.19 mmol), xantphos (336 mg, 0.58 mmol), Pd 2 (dba) 3 dba (266 mg, 0.29 mmol), and cesium carbonate (2.83 g, 8.71 mmol) in 25 mL of 1,4-dioxane, and stir the solution at 110 °C for 2 hours. After the reaction is completed, cool the product to room temperature, filter it through a filter filled with diatomaceous earth, and wash it with ethyl acetate. Concentrate the filtered organic layer under reduced pressure, and purify the obtained residue by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain the target compound.

[0509] 1 H-NMR(300MHz,CDCl 3 ):δ8.39(s,1H),7.41(s,1H),3.91(s,3H),3.81(s,3H),3.73(m,4H),3.56(s,2H),2.51(m,4H),1.52(s,9H)。

[0510] [Step 8] Preparation of 6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-ol

[0511]

[0512] Dissolve methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinomethyl)benzoate (950 mg, 2.49 mmol) obtained in [Step 4] in 10 mL of acetonitrile, and add dropwise thereto 10 mL of 4N hydrogen chloride di chloromethane solution. Stir the solution under reflux at 80 °C for 2 hours. After completion of the reaction, cool to room temperature, and add dropwise an aqueous sodium bicarbonate solution for neutralization. Extract the reaction product with dichloromethane three times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is solidified with ethyl acetate and filtered under reduced pressure. Dry the solid obtained by filtration to obtain 680 mg of the title compound, with a yield of 94%.

[0513] 1 H-NMR (300 MHz, CD 3 OD): 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).

[0514] Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinyl methyl)quinazolin-4-amine

[0515]

[0516] Dissolve 6-methoxy-2-methyl-7-(morpholinomethyl)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] in 3 mL of acetonitrile, and stir at 80 °C for 5 hours. After completion of the reaction, cool the reaction solution to room temperature, and then add dropwise water thereto. Extract with ethyl acetate three times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to obtain 14 mg of the title compound, with a yield of 8%.

[0517] 1 H-NMR (300 MHz, DMSO-d 6): δ 8.11 (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)

[0518] MS(ESI+, m / z): 476.2 [M + H] +

[0519] Example 35: (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine

[0520]

[0521] The same steps of Example 39 were repeated except using (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (125 mg, 0.51 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 39 [Step 6] to obtain 9 mg of the title compound with a yield of 5%.

[0522] 1 1H-NMR (300 MHz, DMSO-d 6 ): δ 8.11 (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)

[0523] MS(ESI+, m / z): 476.2 [M + H] +

[0524] Example 36: (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

[0525] [Step 1] Preparation of methyl 4-hydroxy-5-methoxy-2-nitrobenzoate

[0526]

[0527] Methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (11.7 g, 36.9 mmol) was dissolved in 250 mL of methanol, and Pd / C (1.2 g, 10 wt%) was added. The reaction solution was stirred at 50 °C for 20 h in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through a filter filled with diatomaceous earth and washed with methanol. The obtained organic layer was concentrated under reduced pressure, and the obtained 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.

[0528] 1 H-NMR(300MHz,CD 3 OD): 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).

[0529] [Step 2] Preparation of 7-hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one

[0530]

[0531] Methyl 4-hydroxy-5-methoxy-2-nitrobenzoate (7.0 g, 35.5 mmol) obtained in [Step 1] and 4N hydrogen chloride dioxane solution (71 mL, 284 mmol) were dissolved in 20 mL of 355 mmol acetonitrile, and the mixture was stirred and refluxed at 70 °C for 15 h. After completion of the reaction, the reaction solution was cooled to room temperature, and 30 mL of dichloromethane was added thereto. Then, the mixture was stirred for 0.5 h to obtain a solid product. The obtained solid was filtered under reduced pressure and dried in an oven dryer at 55 °C to give 9 g of the title compound in 82% yield.

[0532] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0533] [Step 3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(1H)-one

[0534]

[0535] Dissolve 7-hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one (1.8 g, 8.7 mmol) obtained in [Step 2] in 20 mL of DMF, and add tetrahydro-2H-pyran-4-yl methanesulfonate (1.7 g, 9.5 mmol) and cesium carbonate (3.4 g, 10.4 mmol) thereto. Stir it at 100 °C for 15 hours. After the reaction is complete, add water to the reaction solution, extract the reaction product with ethyl acetate three times, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure. Add 10 mL of acetone thereto and stir, then filter the precipitated crystals to obtain 250 mg of the title compound with a yield of 10%.

[0536] 1 H-NMR(300MHz,CD 3 OD):δ7.84(s,1H),7.58(s,1H),4.77(m,1H),4.13(m,2H),3.96(s,3H),3.64(m,2H),2.44(s,3H),2.22(m,2H),2.09(m,2H).

[0537] [Step 4] Preparation of 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline

[0538]

[0539] Dissolve 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(1H)-one (250 mg, 0.86 mmol) obtained in the above [Step 3] in 14 mL of phosphoryl chloride, and reflux it at 110 °C for 2 hours. After the reaction is completed, cool the reaction solution to room temperature, and neutralize it by dropwise adding an aqueous sodium bicarbonate solution. Extract it with ethyl acetate three times, dry it over anhydrous sodium sulfate, and then concentrate it under reduced pressure. It can be used for the next step without purification.

[0540] [Step 5] Preparation of (R)-N-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7- ((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

[0541]

[0542] Dissolve 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (100 mg, 0.33 mmol) obtained in the above [Step 4] in 1 mL of DMF, and add (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (92 mg, 0.36 mmol) and DIPEA (0.17 mL, 0.97 mmol). Stir the mixture at 100 °C for 13 hours. After the reaction is completed, cool the reaction solution to room temperature, and then add water dropwise thereto. Extract 3 times with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (methylene chloride:methanol = 23:1 (v / v)) to obtain 21 mg of the title compound with a yield of 13%.

[0543] 1 H-NMR(300MHz,CD 3 OD): δ 7.67 (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).

[0544] MS(ESI+, m / z): 477.2 [M+H] +

[0545] Example 37: (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

[0546]

[0547] Repeat the same steps of Example 44 except for using (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (69 mg, 0.28 mmol) 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 with a yield of 4.6%.

[0548] 1 H-NMR(300MHz,CD 3OD): 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).

[0549] MS(ESI+, m / z): 477.2 [M + H] +

[0550] Example 38: (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine

[0551]

[0552] The same procedure as in Example 44 was repeated except that (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (752 mg, 2.78 mmol) was used instead of tetrahydro-2H-pyran-4-yl methanesulfonate in Example 44 [Step 3] to obtain 15 mg of the title compound in 3.5% yield.

[0553] 1 H-NMR(300 MHz, CD 3 OD): δ 7.46 (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).

[0554] MS(ESI+, m / z): 491.2 [M + H] +

[0555] Example 39: (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine

[0556]

[0557] The same procedure as in Example 44 was repeated except that oxetan-3-ylmethyl 4-methylbenzenesulfonate (530 mg, 2.17 mmol) was used instead of tetrahydro-2H-pyran-4-yl methanesulfonate in Example 44 [Step 3] to obtain 20 mg of the title compound in 15% yield.

[0558] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.00 (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).

[0559] MS (ESI+, m / z): 463.2 [M+H] +

[0560] Example 40: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone

[0561] [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0562]

[0563] 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 thereto at 0 °C. After the addition was completed, the mixture was stirred and refluxed at room temperature for 17 hours. After the reaction was completed, the reaction solution was slowly added dropwise to ice water, and the mixture was stirred at room temperature for 1 hour. After stirring, the solid obtained was filtered under reduced pressure and washed with distilled water to obtain 61 g of the title compound with a yield of 69%.

[0564] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.34 (s, 1H), 8.17 (s, 1H).

[0565] [Step 4] Preparation of dimethyl 2-bromo-5-nitroterephthalate

[0566]

[0567] The 2-bromo-5-nitroterephthalic acid (61 g, 210.32 mmol) obtained in the above [Step 1] was dissolved in 2.2 L of methanol, and 240 mL of sulfuric acid was slowly added dropwise thereto at 0 °C. After the addition was completed, the mixture was stirred and refluxed at 90 °C for 17 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. 600 mL of distilled water was added dropwise thereto at 0 °C, and the mixture was stirred at room temperature for 0.5 hour. After stirring, filtration was carried out under reduced pressure to obtain 61 g of the title compound with a yield of 91%.

[0568] 1 H-NMR (300 MHz, DMSO-d 6 ): δ8.47(s,1H),8.28(s,1H),3.93-3.89(m,6H).

[0569] [Step 3] Preparation of dimethyl 2-(methylamino)-5-nitroterephthalate

[0570]

[0571] 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 and refluxed at 100° C. for 1 hour. After the reaction was completed, it was cooled to 0° C., 1.8 L of distilled water was added dropwise, and stirred at room temperature for 0.5 hour. After stirring, the mixture was filtered under reduced pressure to obtain 48.6 g of the title compound with a yield of 96%.

[0572] 1 H-NMR (300 MHz, DMSO-d 6 ): δ8.59(s,2H),6.95(s,1H),3.88(s,3H),3.86(s,3H),3.01-2.99(d,3H).

[0573] [Step 4] Preparation of Dimethyl 2-Amino-5-(methylamino)terephthalate

[0574]

[0575] The dimethyl 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 distilled water. In a mixed solution of alkane and distilled water (4: 1), and the mixture was stirred at room temperature under reflux for 0.5 hours. After stirring, the reaction solution was cooled to 0 ° C, and ammonium chloride (45.4g, 848.76mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred 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 (volume ratio 1: 1) was added dropwise to the obtained organic layer, and extracted with ethyl acetate 3 times. 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, and the obtained residue was purified by column chromatography (ethyl acetate: hexane = 1: 8 (v / v) to 1: 4 (v / v)) to obtain 31g of the title compound with a yield of 77%.

[0576] 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0577] [Step 5] Preparation of Methyl 4-Hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate

[0578]

[0579] Dissolve dimethyl 2-amino-5-(methylamino)terephthalate (31 g, 130.12 mmol) obtained in [Step 4] and acetonitrile (68 mL, 1301.20 mmol) in 260 mL of 4N hydrochloric acid. The mixture is stirred and refluxed in a sealed tube at 90 °C for 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature, filtered through a filter, and washed with hexane. The solid obtained by filtration is neutralized with an aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to obtain 30 g of the title compound with a yield of 93.2%.

[0580] 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0581] [Step 6] Preparation of Methyl 4-Chloro-2-methyl-6-(methylamino)quinazoline-7-carboxylate

[0582]

[0583] Dissolve methyl 4-hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate (6.1 g, 24.69 mmol) prepared in [Step 5] in 150 mL of phosphorus oxychloride. The mixture is stirred and refluxed at 120 °C for 3 hours. After the reaction is completed, the reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is dissolved in dichloromethane and neutralized with dichloromethane at low temperature. The organic layer is washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer is filtered under reduced pressure and concentrated under reduced pressure. The residue obtained is purified by column chromatography (dichloromethane:ethyl acetate = 45:55 (v / v)) to obtain 1.6 g of the title compound with a yield of 24%.

[0584] 1 H-NMR (300 MHz, DMSO-d 6): 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).

[0585] [Step 7] Preparation of (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6- (methylamino)quinazoline-7-carboxylate

[0586]

[0587] Dissolve methyl 4-chloro-2-methyl-6-(methylamino)quinazoline-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) in 30 mL of DMF. The mixture was stirred and refluxed at 90 °C for 13 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and then water was added dropwise thereto. Extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (methylene chloride:methanol = 23:1 (v / v)) to obtain 280 mg of the title compound with a yield of 29%.

[0588] 1 H-NMR (300 MHz, CDCl 3 ): 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).

[0589] [Step 8] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0590]

[0591] (R)-4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylate (280 mg, 0.64 mmol) obtained in [Step 7] was dissolved in a mixed solution of 20 mL of tetrahydrofuran, methanol and water (= 2:1:1), and then sodium hydroxide (129 mg, 3.23 mmol) was added. Then, the mixture was stirred and refluxed at room temperature for 2 hours. After the reaction was completed, 2N aqueous HCl solution was added dropwise to adjust the pH to 5 - 6, and it was washed with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)-carboxylic acid without purification. The obtained title compound, morpholine (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 stirred and refluxed at room temperature for 2.5 hours. After the reaction was complete, the reaction product was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (methylene chloride:methanol = 20:1 (v / v)) to obtain 30 mg of the title compound with a yield of 20%.

[0592] 1 H-NMR(300MHz,CD 3 OD):δ7.38(s,1H),7.28(s,1H),6.99(m,2H),6.82(s,1H),5.67(m,1H),3.73(m,8H),2.96(s,3H),2.46(s,3H),1.67(d,J=7.2Hz,3H).

[0593] MS(ESI+,m / z):489.2[M+H] +

[0594] Example 41: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0595]

[0596] The same steps of Example 49 were 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 with a yield of 12%.

[0597] 1 H-NMR(300MHz,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).

[0598] MS(ESI+, m / z): 503.2 [M+H] +

[0599] Example 42: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone

[0600]

[0601] The same steps of Example 49 were 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 a yield of 19%.

[0602] 1 H-NMR(300 MHz, DMSO-d 6 ): 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).

[0603] MS(ESI+, m / z): 529.3 [M+H] +

[0604] Example 43: (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0605]

[0606] The same steps of Example 49 were repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 49 [Step 7] to obtain 24 mg of the title compound in a yield of 38%.

[0607] 1H-NMR(300MHz,CD 3 OD): 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).

[0608] MS(ESI+, m / z): 489.2 [M + H] +

[0609] Example 44: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0610]

[0611] The same procedure of Example 49 was repeated except using 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) instead of methylamine hydrochloride in Example 49 [Step 3] to afford 12 mg of the title compound in 11% yield.

[0612] 1 H-NMR(300MHz,CD 3 OD): 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)

[0613] MS(ESI+, m / z): 533.2 [M + H] +

[0614] Example 45: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone

[0615]

[0616] The same procedure of Example 49 was repeated except using cyclopentylamine (4.7 g, 47.2 mmol) instead of methylamine hydrochloride in Example 49 [Step 3] to afford 22 mg of the title compound in 6% yield.

[0617] 1 H-NMR(300MHz,CD 3OD): 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).

[0618] MS(ESI+, m / z): 543.2 [M + H] +

[0619] Example 46: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0620]

[0621] The same procedure of Example 49 was repeated except that ethylamine (23 g, 47 mmol) dissolved in tetrahydrofuran was used instead of methanamine hydrochloride in Step 3 of Example 49 to obtain 120 mg of the title compound in 53% yield.

[0622] 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0623] MS(ESI+, m / z): 503.2 [M + H] +

[0624] Example 47: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0625]

[0626] The same procedure of Example 49 was repeated except that isopropylamine (3.86 mL, 47.1 mmol) was used instead of methanamine hydrochloride in Step 3 of Example 49 to obtain 3 mg of the title compound in 1% yield.

[0627] 1 H-NMR (300 MHz, CD 3OD): 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).

[0628] MS(ESI+, m / z): 517.2 [M + H] +

[0629] Example 48: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholinyl)methanone

[0630]

[0631] The same steps of Example 49 were repeated except that 4-aminotetrahydropyran 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 a yield of 56%.

[0632] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 7.42 (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).

[0633] MS(ESI+, m / z): 559.2 [M + H] +

[0634] Example 49: (R)-N 4 -(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-Dimethyl-7-(morpholinylmethyl)quinazolin-4,6-diamine

[0635] [Step 1] Preparation of Ethyl 2-(tert-Butoxycarbonyl)amino)-4-methylbenzoate

[0636]

[0637] Methyl 2-amino-4-methylbenzoate (6.2 g, 34.5 mmol), di-tert-butyl dicarbonate (20 mL, 86.2 mmol), triethylamine (12 mL, 86.2 mmol), and 4-dimethylaminopyridine (4.2 g, 34.5 mmol) were dissolved in 100 mL of tetrahydrofuran, and the mixture was stirred and refluxed at room temperature for 15 hours. After the reaction was completed, water was added dropwise. Then, the reaction product was extracted 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate = 5:1 (v / v)) to obtain 4.7 g of the title compound in a yield of 49%.

[0638] 1 H-NMR(300MHz,CDCl 3 ): 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).

[0639] [Step 2] Preparation of Ethyl 4-(Bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate

[0640]

[0641] Ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate (4.7 g, 16.8 mmol), N-bromosuccinimide (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 and refluxed at 70 °C for 1.5 hours. After the reaction was completed, the solution was cooled to room temperature and concentrated under reduced pressure to obtain 4.3 g of the title compound. Without purification, the next reaction was carried out.

[0642] [Step 3] Preparation of Ethyl 2-((tert-Butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate

[0643]

[0644] Ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate (4.3 g, 11.9 mmol), morpholine (2.0 mL, 23.8 mmol), and potassium carbonate (6.6 mg, 47.6 mmol) obtained in [Step 2] were dissolved in 40 mL of acetonitrile, and the mixture was stirred and refluxed at room temperature for 1 hour. Then, the reaction product was extracted 3 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 obtain 2.1 g of the title compound in a yield of 34%.

[0645] 1H-NMR(300MHz,CDCl 3 ): 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).

[0646] [Step 4] Preparation of 2-Methyl-7-(morpholinomethyl)quinazolin-4-ol

[0647]

[0648] Ethyl 2-((tert-butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate (2.1 g, 5.73 mmol) obtained in [Step 3] and acetonitrile (21 mL, 402.5 mmol) were dissolved in 21 mL of a dioxane solution of 4N hydrochloric acid. The mixture was stirred and refluxed in a sealed tube at 90 °C for 3 hours. After completion of the reaction, the solution was cooled to room temperature, filtered and washed with hexane. The solid obtained by filtration was neutralized with an aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to obtain 1.2 g of the title compound in 81% yield.

[0649] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0650] [Step 5] Preparation of 2-Methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol

[0651]

[0652] 2-Methyl-7-(morpholinomethyl)quinazolin-4-ol (1.2 g, 4.62 mmol) prepared in [Step 4] was dissolved in 12 mL of sulfuric acid. 2.4 mL of nitric acid was slowly added dropwise thereto at 0 °C. After completion of the reaction, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane and neutralized with an aqueous sodium hydroxide solution at low temperature. The obtained organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure and concentrated under reduced pressure to obtain 1.2 g of the title compound in 85% yield.

[0653] 1 H-NMR(300MHz,DMSO-d 6): 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).

[0654] [Step 6] Preparation of 6-Amino-2-methyl-7-(morpholinomethyl)quinazolin-4-ol

[0655]

[0656] Dissolve 2-methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol (450 g, 1.47 mmol) and zinc powder (340 g, 5.14 mmol) obtained in [Step 5] in a mixed solution of 5 mL of dioxane and distilled water (4:1). The mixture is stirred and refluxed at room temperature for 0.5 h. After stirring, the reaction solution is cooled to 0 °C, and ammonium chloride (400 g, 7.35 mmol) is slowly added dropwise. After the addition is complete, the mixture is stirred and refluxed at room temperature for 2 h. After the reaction is completed, the reaction solution is filtered through a filter filled with diatomaceous earth and washed with ethyl acetate. Distilled water (volume ratio 1:1) is added to the obtained organic layer, and extraction is carried out 3 times with ethyl acetate. The obtained organic layer is dried over anhydrous sodium sulfate. The dried organic layer is filtered under reduced pressure and concentrated under reduced pressure. The obtained residue is purified by column chromatography (dichloromethane:methanol = 10:1 (v / v)) to obtain 330 g of the title compound with a yield of 81%.

[0657] 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0658] [Step 7] Preparation of 2-Methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-ol

[0659]

[0660] Dissolve 6-amino-2-methyl-7-(morpholinomethyl)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] in 2 mL of dimethylformamide. The mixture is stirred and refluxed at 50 °C for 12 h. After the reaction is completed, the reaction solution is cooled to room temperature, and then water is added dropwise thereto. Extraction is carried out 3 times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography (dichloromethane:methanol = 13:1 (v / v)) to obtain 30 mg of the title compound with a yield of 18%.

[0661] 1 H-NMR (300 MHz, CDCl 3 ): 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).

[0662] [Step 8] Preparation of 2-Methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-yl 2,4,6-triisopropyl benzenesulfonate

[0663]

[0664] Dissolve 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-ol (30 mg, 0.10 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (48 mg, 0.12 mmol), 4-dimethylaminopyridine (3 mg, 0.01 mmol) and triethylamine (0.04 mL, 0.30 mmol) obtained in [Step 7] in 2 mL of dichloromethane. The mixture is stirred and refluxed at room temperature for 18 hours. After completion of the reaction, the resulting product is concentrated under reduced pressure, and the residue is purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to obtain 25 mg of the title compound with a yield of 43%.

[0665] [Step 9] Prepare (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-dimethyl-7-(morph quinazolin-4,6-diamine

[0666]

[0667] Dissolve 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate (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] in 2 mL of DMF. The mixture is stirred and refluxed at 90 °C for 22 hours. After completion of the reaction, water is added dropwise. The reaction product is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography (dichloromethane:methanol = 15:1 (v / v)) to obtain 3 mg of the title compound with a yield of 14%.

[0668] 1 H-NMR (300 MHz, CDCl 3): δ 7.52 (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).

[0669] MS(ESI+, m / z): 475.2 [M + H] +

[0670] Example 50: (R)-(4-((1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone

[0671]

[0672] The same procedure of Example 49 was repeated except using (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (235 mg, 0.98 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 49 [Step 7] to afford 23 mg of the title compound in 15% yield.

[0673] 1 H-NMR(300 MHz, CD 3 OD): 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).

[0674] MS(ESI+, m / z): 507.2 [M + H] +

[0675] Example 51: (R)-(4-((1-(3-Amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-morpholinyl)methanone

[0676]

[0677] The same procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)aniline hydrochloride (270 mg, 1.20 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 7] of Example 49 to give 70 mg of the title compound in 41% yield.

[0678] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0679] MS(ESI+, m / z): 471.2 [M + H] +

[0680] Example 52: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0681]

[0682] The same procedure of Example 49 was repeated except that 2.0 M ethylamine in tetrahydrofuran (23 mL, 47 mmol) 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 give 55 mg of the title compound in 41% yield.

[0683] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0684] MS(ESI+,m / z):503.2[M+H] +

[0685] Example 53: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone

[0686]

[0687] The same procedure of Example 49 was repeated except using thiazolidine (24 mg, 0.26 mmol) instead of morpholine in Example 49 [Step 8] to give 16 mg of the title compound in 24% yield.

[0688] 1 H-NMR(300MHz,DMSO-d 6 ):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).

[0689] MS(ESI+,m / z):491.2[M+H] +

[0690] Example 54: (R)-(4-((1-(3-Amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(N-morpholinyl)methanone

[0691]

[0692] The same procedure of Example 49 was repeated except using (R)-3-(1-aminoethyl)-5-(furan-3-yl)aniline hydrochloride (233 mg, 0.98 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Example 49 [Step 7] to give 15 mg of the title compound in 32% yield.

[0693] 1 H-NMR(300MHz,CD 3OD): 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).

[0694] MS(ESI+, m / z): 487.2 [M + H] +

[0695] Example 55: (R)-4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone

[0696]

[0697] The same procedure of 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 give 20 mg of the title compound in 23% yield.

[0698] 1 H-NMR(300 MHz, DMSO-d 6 ): 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).

[0699] MS(ESI+, m / z): 517.2 [M + H] +

[0700] Example 56: (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(N-morpholino)methanone

[0701]

[0702] Except for using 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) instead of methylamine hydrochloride in Step 3 of Example 49, and using (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step 7], the same steps of Example 49 were repeated to obtain 35 mg of the title compound with a yield of 30%.

[0703] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0704] MS(ESI+,m / z): 533.2 [M+H] +

[0705] Example 57: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone

[0706]

[0707] Except for using 1-methylpiperazine (0.03 mL, 0.25 mmol) instead of morpholine in Step 8 of Example 49, the same steps of Example 49 were repeated to obtain 20 mg of the title compound with a yield of 16%.

[0708] 1 H-NMR(300MHz,DMSO-d 6 ): 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).

[0709] MS(ESI+,m / z): 502.2 [M+H] +

[0710] Example 58: (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone

[0711]

[0712] The same procedure of Example 49 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in Step 8 of Example 49 to give 38 mg of the title compound in 31% yield.

[0713] 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0714] MS (ESI+, m / z): 515.2 [M + H] +

[0715] Example 59: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone

[0716]

[0717] The same procedure of Example 49 was repeated except that thiomorpholinyl 1,1-dioxide (35 mg, 0.26 mmol) was used instead of morpholine in Step 8 of Example 49 to give 5 mg of the title compound in 4% yield.

[0718] 1 H-NMR (300 MHz, CD 3 OD): 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).

[0719] MS (ESI+, m / z): 537.2 [M + H] +

[0720] Example 60: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholinyl)methanone

[0721]

[0722] The same procedure of Example 49 was repeated except that thiomorpholine (0.03 mL, 0.26 mmol) was used instead of morpholine in Step 8 of Example 49 to give 22 mg of the title compound in 18% yield.

[0723] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.07 (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).

[0724] MS (ESI+, m / z): 505.2 [M + H] +

[0725] Example 61: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone

[0726]

[0727] The same procedure of Example 49 was repeated except that piperazine (100 mg, 0.50 mmol) was used instead of morpholine in Step 8 of Example 49 to give 30 mg of the title compound in 13% yield.

[0728] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.06 (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).

[0729] MS (ESI+, m / z): 488.2 [M + H]+

[0730] Example 62: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone

[0731]

[0732] The same procedure of Example 49 was repeated except that azetidine hydrochloride (24 mg, 0.26 mmol) was used instead of morpholine in Step 8 of Example 49 to give 12 mg of the title compound in 11% yield.

[0733] 1 H-NMR (300 MHz, DMSO-d 6 ): δ 8.16 (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).

[0734] MS (ESI+, m / z): 459.2 [M+H] +

[0735] Example 63: (4-(((R)-1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone

[0736]

[0737] The same procedure of 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-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in Step 8 of Example 49 to give 40 mg of the title compound in 32% yield.

[0738] 1 H-NMR (300 MHz, DMSO-d 6): δ 9.56 (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).

[0739] MS(ESI+, m / z): 515.2 [M + H] +

[0740] Example 64: (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone

[0741]

[0742] Except for using (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mL, 0.98 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, and using thiomorpholinyl 1,1-dioxide (35 mg, 0.26 mmol) instead of morpholine in [Step 8], the same steps of Example 49 were repeated to obtain 8 mg of the title compound with a yield of 6%.

[0743] 1 H-NMR(300 MHz, DMSO-d 6 ): δ 8.09 (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).

[0744] MS(ESI+, m / z): 537.2 [M + H] +

[0745] Example 65: (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone

[0746]

[0747] The same procedure of Example 49 was repeated except using (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (165 mg, 0.98 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to give 3.5 mg of the title compound in 10% yield.

[0748] 1 H-NMR(300MHz,CD 3 OD): 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).

[0749] MS(ESI+, m / z): 435.2[M + H] +

[0750] Example 66: (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone

[0751]

[0752] The same procedure of Example 49 was repeated except using 2-methoxyethylamine (4.1 mL, 47.15 mmol) instead of methylamine hydrochloride in Step 3 of Example 49, and using (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (190 mg, 0.76 mmol) instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in Step 7 of Example 49, to give 40 mg of the title compound in 36% yield.

[0753] 1 H-NMR(300MHz, DMSO-d 6 ): δ 8.63(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).

[0754] MS(ESI+, m / z): 559.2[M + H] +

[0755] Example 67: (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone

[0756]

[0757] The same steps of Example 49 were repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in step 3 of Example 49, and (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.21 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in step 8, to obtain 2 mg of the title compound with a yield of 2%.

[0758] 1 H-NMR(300MHz,CD 3 OD): 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).

[0759] MS(ESI+,m / z): 581.2[M+H] +

[0760] Example 68: (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone

[0761]

[0762] The same steps of Example 49 were repeated except that 2-methoxyethan-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in step 3 of Example 49, and thiomorpholinyl 1,1-dioxide (55 mg, 0.40 mmol) was used instead of morpholine in step 8, to obtain 18 mg of the title compound with a yield of 8%.

[0763] 1 H-NMR(300MHz,DMSO-d 6): δ 8.07 (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).

[0764] MS(ESI+, m / z): 581.2 [M + H] +

[0765] Example 69: (R)-N 4 -(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 -(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine

[0766] [Step 1] Preparation of Methyl 5-Methoxy-2-nitro-4((tetrahydro-2H-pyran-4-yl)amino)benzoate

[0767]

[0768] Methyl 5-methoxy-2-nitrobenzoate (800 mg, 2.75 mmol), 4-aminotetrahydropyran hydrochloride (455 mg, 3.30 mmol), Pd 2 (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-dioxane. The mixture was stirred at 100 °C for 24 h. After completion of the reaction, the reaction solution was cooled to room temperature, and then water was added dropwise thereto. Next, the obtained product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MLPC (ethyl acetate:hexane = 1:1 (v / v)) to give 970 mg of the title compound in 91% yield.

[0769] 1 1H-NMR (300 MHz, CDCl 3 ): 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).

[0770] [Step 2] Preparation of methyl 2-amino-5-methoxy-4((tetrahydro-2H-pyran-4-yl)amino)benzoate

[0771]

[0772] Dissolve methyl 5-methoxy-2-nitro-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate (970 g, 3.12 mmol) and iron (715 mg, 10.94 mmol) obtained in [Step 1] in a mixed solution (4:1) of 10 mL of 1,4-dioxane and distilled water, and cool the mixture to 0 °C. Add the mixture to ammonium chloride (636 mg, 15.62 mmol) and stir at room temperature for 1 hour. After the reaction is completed, filter the reaction solution through a filter filled with diatomaceous earth and wash with dichloromethane. After adding water dropwise to the filtrate, extract with dichloromethane 3 times, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the obtained residue by MLPC (ethyl acetate:hexane = 1:1 (v / v)) to obtain 850 mg of the title compound with a yield of 97%.

[0773] 1 H-NMR(300MHz,CDCl 3 ): 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).

[0774] [Step 3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol

[0775]

[0776] Dissolve methyl 2-amino-5-methoxy-4-((tetrahydro-2H-pyran-4-yl)amino)benzoate (850 mg, 3.03 mmol) obtained in [Step 2] in 3 mL of acetonitrile, and add 6 mL of 4N hydrochloric acid dissolved in dioxane dropwise thereto. Stir the solution under reflux at 80 °C for 2 hours. After the reaction is completed, cool to room temperature and neutralize by dropping an aqueous sodium bicarbonate solution. Extract the reaction product with dichloromethane 3 times, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Solidify the residue with ethyl acetate and filter under reduced pressure. Dry the solid obtained by filtration to obtain 830 mg of the title compound with a yield of 95%.

[0777] 1 H-NMR(300MHz,DMSO-d 6): 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).

[0778] [Step 4] Preparation of 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinazolin-7-amine

[0779]

[0780] Dissolve 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol (200 mg, 0.69 mmol) obtained in [Step 3] in 2 mL of phosphoryl chloride, and reflux the mixture at 100 °C for 1 hour. After the reaction is completed, cool the reaction solution to room temperature, and add an aqueous sodium bicarbonate solution dropwise for neutralization. Extract 3 times with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate is used in the next step without purification.

[0781] [Step 5] Preparation of (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl- N 7 -(tetrahydro-2 H -pyran-4-yl)quinazolin-4,7-diamine

[0782]

[0783] Dissolve 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinazolin-7-amine (130 mg, 0.42 mmol) obtained in the above [Step 4] in 2 mL of DMF, and add (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline (163 mg, 0.67 mmol) and DIPEA (0.23 mL, 1.26 mmol) thereto. Stir the mixture at 90 °C for 13 hours. After the reaction is completed, cool the reaction solution to room temperature, and then add water dropwise thereto. Extract 3 times with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography (methylene chloride:methanol = 23:1 (v / v)) to obtain 2 mg of the title compound with a yield of 1%.

[0784] 1 H-NMR (300 MHz, CD 3 OD): 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).

[0785] MS (ESI+, m / z): 476.2 [M+H] +

[0786] [Table 1]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807] Experimental Example 1: Testing the ability of SOS1 to inhibit GTP substitution

[0808] To determine whether the substitution function of the binding of SOS1 to KRAS G12C is inhibited by the compounds of the above embodiments, a homogeneous time-resolved fluorescence (HTRF) assay was performed using G12C (#MSC-11-538) and SOS1-Strep (#MSC-11-502) purchased from Reaction Biology Corporation (Massachusetts, USA). Using the principle of time-resolved fluorescence energy transfer (TR-FRET), the activity of the SOS1 enzyme was determined by measuring the amount of GTP bound to the KRAS G12C protein. Based on the principle that terbium bound to the GST-binding antibody of the GST-KRAS G12C protein serves as the fluorescence resonance energy transfer (FRET) donor, and GTP bound to the KRAS G12C protein is labeled with the fluorophore DY-647P1 and serves as the acceptor, in this assay, when more GTP binds to the KRAS G12C protein through the substitution reaction of SOS1, a higher HTRF or FRET signal can be measured.

[0809] In summary, the glutathione S-transferase (GST)-labeled KRAS G12C protein (consisting of amino acid residues 2 to 169), the streptavidin-labeled SOS1 protein (consisting of amino acid residues 564 to 1049 as the catalytic domain), the anti-GST antibody (#61GSTKLA) purchased from CISBIO, and the nucleic acid (#NU-820-647P1) purchased from Jena Bioscience GmbH were mixed in a buffer solution formed by 10 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl 2 and 1 mM dithiothreitol (DTT), and 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 microplate reader. In this case, the excitation signal was measured at 320 nm, and the emission signal was measured at 615 / 665 nm. The fluorescence measurement value without the SOS1 protein was calculated as the background signal value, and the background signal value was subtracted from all measured HTRF values. The fluorescence measurement value without the synthetic compound was measured as the control value, and this value was selected as the reference point of 100%. For the compounds of each embodiment, fluorescence was measured at concentrations of 1.6, 8, 40, 200, 1,000 nM (5 points, 5-fold), and the 50% activity inhibition value (IC 50 ) of each compound was calculated using GraphPad Prism. As a result, the KRAS G12C-SOS1 binding inhibition ability of the compounds of each embodiment is shown in Table 2 below.

[0810] When the IC 50 value is below 50 nM, the inhibitory ability is expressed as +++. When the IC 50 value is greater than 50 nM and below 100 nM, the inhibitory ability is expressed as ++. When the IC 50 value is greater than 100 nM, the inhibitory ability is expressed as +.

[0811] [Table 2]

[0812]

[0813]

Claims

1. A compound selected from the following: the compound shown by Chemical Formula 1, and a pharmaceutically acceptable salt of the compound shown by Chemical Formula 1: [Chemical Formula 1] In Chemical Formula 1, R 1 is C 1 alkyl; R 2 is C 1 alkyl or halo-C 1-4 alkyl; R 3 is R 3a or -L 2 - R 3a each independently is a halogen, a hydroxyl group, a cyano group, an amino group, an amine, a nitro group, an oxo group (=O), C 1-6 alkyl, halo C 1-6 alkyl, amino C 1-6 alkyl, or -CF 2 H; r is an integer in the range of 0 to 1; m is an integer in the range of 1 to 3; L 2 is a chemical bond; p is an integer in the range of 0 to 3; q is an integer in the range of 0 to 2; is phenyl or C 4 heteroaryl; is phenyl, C 4 heteroaryl, tetrahydroisoquinolinyl, indenyl or cyclopropyl, wherein said phenyl is unsubstituted or substituted by amino C 1-6 alkyl or hydroxy-C 1-4 alkyl, X 1 is -O(R 4 ) or -N(R 5 )(R 6 ); R 4 is methyl substituted by or substituted with tetrahydrofuran or C 1-3 alkoxy; R 5 and R 6 each is hydrogen, C 1-3 alkyl, C 1-3 alkoxy, cyclopentane, or tetrahydropyridine; or L 1 is a chemical bond, -C(O)-, -O- or -NH-; n is 0 or 1; and is C 3-6 heterocyclic group, or C 6 fused heterocyclic group, wherein C 4-6 heterocyclic group, or C 6 fused heterocyclic group, which is unsubstituted or substituted by one or more functional groups selected from the group consisting of: halogen, oxo group (=O), C 1-6 alkyl group.

2. The compound according to claim 1, characterized in that the compound shown by Chemical Formula 1 is the compound shown by Chemical Formula 2: [Chemical Formula 2] In Chemical Formula 2, L 1 is a chemical bond, -C(O)-, -O- or -NH-; n is 0; and Z 1 and Z 2 each independently is -CH 3 ; R 4a is unsubstituted or methyl substituted with tetrahydrofuranyl or C 1-3 alkoxy; is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein the morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 .

3. The compound according to claim 1, characterized in that the compound shown by Chemical Formula 1 is the compound shown by Chemical Formula 3: [Chemical Formula 3] In Chemical Formula 3, L 3 is a chemical bond or -C(O)-; n is 0; and Z 1 and Z 2 each independently is hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not simultaneously hydrogen; R 5a and R 5b each independently is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkoxycyclopentane, or tetrahydropropenyl; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein the morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 .

4. The compound according to claim 2, characterized in that the compound shown by Chemical Formula 2 is the compound shown by Chemical Formula 4: [Chemical Formula 4] In Chemical Formula 4, L 4 is a chemical bond, -C(O)- or -O-; n is 0; and Z 1 and Z 2 each independently is hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , wherein Z 1 and Z 2 are not simultaneously hydrogen; is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, wherein the morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 。 5. The compound according to claim 3, characterized in that the compound shown by Chemical Formula 3 is the compound shown by Chemical Formula 5: [Chemical Formula 5] In Chemical Formula 5, L 5 is a chemical bond or -C(O)-; n is an integer in the range of 0 to 2; and Z 1 and Z 2 each independently is hydrogen, -F, -CF 2 H, -CF 3 , -CH 3 or -NH 2 , where Z 1 and Z 2 are not simultaneously hydrogen; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein the morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or substituted by one or more functional groups selected from the group consisting of halogen or -CH 3 .

6. The compound according to claim 1, characterized in that the compound shown by Chemical Formula 1 is selected from the following group: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R,5S)-3,5-dimethylpiperazin-1-yl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thio(morpholinyl))methanone; (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone; (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone; (4-((1-(4-(2-((Dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholinyl)methanone; (4-((1-(4-(2-((Aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (4-((1-(4-(2-((Hydroxymethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; (R)-(4-((1-(3-Amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-3-Amino-5-(1-((6-methoxy-2-methyl-7-(morpholin-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile; (R)-(4-((1-(2,3-Dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-(Ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholinyl)methanone; (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-amine; (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinylmethyl)quinazolin-4-amine; (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)-N-(1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine; (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine; (R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)((R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholinyl)methanone; (R)-N4-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-N6,2-dimethyl-7-(morpholinylmethyl)quinazolin-4,6-diamine; (R)-(4-((1-(5-Amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone; (R)-(4-((1-(3-Amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (R)-4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholinyl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone; (4-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone; (4-(((R)-1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; (R)-(4-((1-(3-Amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholinyl)methanone; (4-(((R)-1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone; (R)-(4-((1-(5-Amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; (R)-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholinyl)methanone; and (R)-N 4 -(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N7-(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine.

7. A prophylactic or therapeutic composition, characterized in that, it comprises the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. The pharmaceutical composition according to claim 7, characterized in that, the pharmaceutical composition is used for treating cancer or tumor, and the cancer or tumor can be treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

9. A pharmaceutical preparation comprising the pharmaceutical composition according to claim 7.

10. The pharmaceutical preparation according to claim 9, characterized in that, the pharmaceutical preparation is a tablet, pill, powder, capsule, syrup or emulsion.

11. The pharmaceutical preparation according to claim 9, characterized in that, it further comprises a pharmaceutically acceptable carrier.

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