Novel quinazoline derivative compounds as SOS1 inhibitors and uses thereof

Abstract

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

Description

Novel quinazoline derivative compounds as SOS1 inhibitors and their uses

[0001] The present invention relates to a novel quinazoline derivative compound as an inhibitor of SOS1 and its use, and more particularly, to a novel quinazoline derivative compound having an activity of inhibiting SOS1 binding to a RAS family protein and / or RAC1, a pharmacologically acceptable salt thereof, or a pharmaceutical composition comprising such a compound.

[0002] RAS family proteins are found in 20–30% of human cancers and are known to include KRAS (Kirstin rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog), and HRAS (Harvey murine sarcoma viral oncogene). RAS regulates cell proliferation through the RAF / MEK / ERK pathway leading to mitogen-activated protein kinase (MAPK) activation and the PI3K / Akt / mTOR pathway via phosphatidylinositide 3-kinase (PI3K). Cancer-associated mutations in RAS family proteins inhibit their intrinsic GAP-induced GTPase (GTPase) activity, thereby increasing the population of GTP-bound / active RAS family proteins.

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

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

[0005] The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein with two tandem N-terminal histone domains (HD), a Dbl homology domain (DH), a pleckstrin homology domain (PH), a helical linker (HL), a RAS exchange motif (REM), a CDC25 homology domain, and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins: a catalytic site that binds GDP-bound RAS family proteins and catalyzes guanine nucleotide exchange, and an allosteric site that binds GTP-bound RAS family proteins, resulting in further augmentation of the catalytic GEF function of SOS1. Selective pharmacological inhibition of SOS1 binding 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 consequently inhibit signaling downstream of RAS-family proteins (e.g., ERK phosphorylation). Therefore, novel SOS1 inhibitor compounds are being developed that bind to the SOS1 catalytic site (as confirmed by crystallography) and simultaneously prevent its binding to and activation of RAS family proteins, and have a marked inhibitory effect (low IC ) on the interaction of SOS1 with RAS family proteins, particularly KRAS. 50 ), and consequently, a substance that induces a significant decrease in ERK phosphorylation in KRAS mutant cancer cell lines is under development.

[0007] The present inventors have completed the present invention by confirming that a novel quinazoline derivative compound as an SOS1 inhibitor has an activity of inhibiting SOS1 binding to RAS family proteins and / or RAC1.

[0008] One object of the present invention is to provide a novel quinazoline derivative compound having excellent activity in inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

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

[0010] According to one embodiment of the present invention, a compound selected from the following chemical formula 1, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof is provided:

[0011] [Chemical Formula 1]

[0012]

[0013] In the above chemical formula 1,

[0014] R1 is hydrogen or C 1-4 It is alkyl;

[0015] R2 is hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkynylide;

[0016] R3 is R 3a or -L2- and;

[0017] Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a , -(CH2) r -NR a R b and R a class R b are each independently Hydrogen, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -CF2H and C 3-8 Selected from the group consisting of carbocyclyl;

[0018] r is an integer from 0 to 1;

[0019] m is an integer from 0 to 5;

[0020] L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and;

[0021] p is an integer from 0 to 3;

[0022] q is an integer from 0 to 2;

[0023] class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and in this case, C of 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with;

[0024] X1 is -O(R4) or -N(R5)(R6);

[0025] R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c , -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl;

[0026] R5 and R6 is each independently hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f It can be substituted with one or more functional groups selected from the group consisting of, where R e and R f are each independently hydrogen or C 1-6 It is alkyl,

[0027] Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the above C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h It can be substituted with one or more functional groups selected from the group consisting of, where R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy or C 3-8 It is carbocyclyl;

[0028] L1 is a direct bond, -C(O)-, -O- or -NH- and;

[0029] n is an integer from 0 to 2;

[0030] is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i and -NR i R j may be substituted with one or more functional groups selected from the group consisting of, wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

[0031] According to another embodiment of the present invention, pharmaceutical compositions and pharmaceutical preparations for preventing or treating various diseases associated with inhibition of SOS1 binding to RAS family proteins and / or RAC1, comprising the above-described compound in a therapeutically effective amount, are provided.

[0032] According to another embodiment of the present invention, a method is provided for inhibiting SOS1 binding to a RAS family protein and / or RAC1 in a subject or cell, comprising administering to the subject a pharmaceutically effective amount of the compound described above.

[0033] According to another embodiment of the present invention, a method of inhibiting tyrosine kinase in a sample or cell is provided, comprising administering to the sample a pharmaceutically effective amount of the above-described compound.

[0034] According to another embodiment of the present invention, a method for preventing or treating cancer in a subject is provided, comprising administering to the subject a pharmaceutically effective amount of the compound described above.

[0035] According to another embodiment of the present invention, there is provided a use of the compound or a pharmacologically acceptable salt thereof for the prevention or treatment of cancer or tumor.

[0036] The quinazoline derivative compound of chemical formula 1 in the present invention has excellent activity in inhibiting SOS1 binding to RAS family proteins and / or RAC1, and thus has an anticancer effect on cancer associated with cell proliferation due to abnormal SOS1 activity, and can be usefully used as a therapeutic agent therefor.

[0037] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods and samples are described herein, similar or equivalent methods are also included within the scope of the present invention. Furthermore, numerical values ​​described herein are deemed to include the meaning of "about," even if not explicitly stated. The contents of all publications cited as references herein are incorporated herein by reference in their entirety.

[0038] In the above chemical formula 1, the residues listed as R1 to R6 are used in the same meaning as generally understood by those skilled in the art.

[0039] In the present invention, unless otherwise stated, the term "halogen" refers to fluorine, chlorine, bromine or iodine, specifically, but not limited to, fluorine and chlorine.

[0040] In the present invention, unless otherwise stated, the term "alkyl" refers to a saturated, straight-chain or branched monovalent hydrocarbon radical.

[0041] In the present invention, unless otherwise stated, the term "alkenyl" refers to a monovalent hydrocarbon radical containing at least one carbon-carbon double bond, each double bond of which may have an E- or Z-configuration.

[0042] As used herein, the term "alkynyl" refers to a monovalent group derived from an unsaturated, straight-chain or branched hydrocarbon moiety having at least one carbon-carbon triple bond, unless otherwise stated.

[0043] These alkyl, alkenyl and alkynyl groups may be linear, i.e. straight-chain, or branched. Depending on their respective definitions, the number of carbon atoms in an alkyl group may be 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4. Examples of alkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl, 1-methylbutyl, isopentyl, pentyl including neopentyl and tert-pentyl, hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Each of the double bond and the triple bond in the alkenyl and alkynyl groups may be present at any position. Examples of alkenyl and alkynyl are ethenyl, prop-1-enyl, prop-2-enyl (= allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, prop-2-ynyl (= propargyl), but-2-ynyl, but-3-ynyl, hex-4-ynyl or hex-5-ynyl. However, the substituted alkyl, alkenyl and alkynyl groups may be substituted at any position, as long as each compound is sufficiently stable and suitable for the desired purpose, such as use as a pharmaceutical substance.

[0044] As used herein, the term "carbocyclyl" refers to a cyclic alkyl group which may be substituted or unsubstituted, unless otherwise specified, and may refer to a mono- or bicycloaliphatic group. Preferably, carbocyclyl includes, but is not limited to, aryl, carbocyclyl, spirocarbocyclyl, fused carbocyclyl, and bridged carbocyclyl. More preferably, carbocyclyl may include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohepsenyl, cyclooctyl, cyclooctenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamant-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-enyl, or all possible isomers thereof.

[0045] In the present invention, unless otherwise stated, the term "heterocyclyl" may mean a monocyclic or bicyclic or more substituted or unsubstituted cyclic alkyl containing one or more, specifically one to four, heteroatoms selected from O, N, and S. Preferably, heterocyclyl includes, but is not limited to, heteroaryl, heterocyclyl, heterospirocarbocyclyl, fused heterocyclyl, and bridged heterocyclyl. More preferably, heterocyclyl includes, but is not limited to, piperazinyl, piperidinyl, piperazinyl-1-oxide, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolinyl, tetrahydrofuranyl, diazabicyclooctanyl, diazaspiroctanyl, and similar groups. For example, C 2-10 In the case of heterocyclyl, the number of carbon atoms is indicated as C 2-10 It means a ring size of three or more members containing one or more heteroatoms.

[0046] The term "aryl" in the present invention, unless otherwise stated, represents an aromatic group which may be substituted or unsubstituted, and may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof.

[0047] In the present invention, the term "heteroaryl" means a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from O, N and S, for example, 1 to 4, unless otherwise specified. Preferably, examples of monocyclic heteroaryl include, but are not limited to, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and similar groups. Preferably, examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, furopyridinyl and similar groups.

[0048] In the present invention, the numerical range indicated using the term “to” refers to a range that includes the numerical values ​​described before and after the term “to” as the lower limit and the upper limit, respectively.

[0049] The term "binding of SOS1 to a RAS family protein and / or RAC1" as used in the present invention means binding of SOS1 to the catalytic site of SOS1 of a RAS family protein, and "inhibiting binding activity" means preventing SOS1-mediated activation of a RAS-family protein in a GTP-bound form.

[0050] The term "SOS1 inhibitor compound" as used in the present invention means a compound that inhibits signal transduction to downstream cells by RAS-family proteins, such as ERK phosphorylation, and specifically, "SOS1 inhibitor compound" means a compound that binds to the SOS1 catalytic site and prevents binding to and activation of RAS family proteins.

[0051] As used herein, the term "optical isomers" refers to various stereoisomers and geometric isomers that may exist for the compounds according to the present invention, unless otherwise specified. Compounds of formula 1 according to one aspect of the present invention may have an asymmetric carbon center (missing carbon), and therefore may exist as enantiomers (R or S isomers), racemates, diastereomers, or any mixtures thereof, and all of these isomers and mixtures are included in the scope of the present invention. The optically active (R)- and (S)-isomers may be resolved using conventional techniques, or may be prepared using chiral synthons or chiral reagents. When the compound contains a double bond, the substituent may be in the E or Z form. When the compound contains a disubstituted carbocyclyl, it may be in the cis- or trans form. Additionally, if the compound of the above formula 1 contains a bridged ring, it may exist as an exo or endo isomer. In addition, all tautomeric forms may also be included.

[0052] As used herein, the term "asymmetric carbon atom" refers to a carbon atom in a molecule that is bonded to four different atoms, atomic groups, or functional groups, unless otherwise specified. Compounds containing such asymmetric carbon atoms have optical rotation or optical isomers. Specifically, a compound having a structure of Chemical Formula 1 with the asymmetric carbon atom may be a compound having a structure of Chemical Formula 1a or Chemical Formula 1b below. Meanwhile, a 1:1 mixture of a pair of enantiomers is referred to as a "racemic" mixture.

[0053] [Chemical Formula 1a]

[0054]

[0055] In the above chemical formula 1a, , R1 to R3, X1, L1, , m and n are defined as in chemical formula 1.

[0056] [Chemical Formula 1b]

[0057]

[0058] In the above chemical formula 1b, , R1 to R3, X1, L1, The definitions of m and n are as in chemical formula 1.

[0059] The compound of formula 1, its optical isomers, and its diastereomers according to the above aspect may exist in the form of a solvate. The term "solvate" may include a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. A complex wherein the solvent molecule is water is also referred to as a "hydrate."

[0060] The compound of formula 1 according to the above aspect, its optical isomers, its diastereomers and its solvates may exist in the form of pharmaceutically acceptable salts.

[0061] The term "pharmaceutically acceptable salt" in the present invention means a salt that has low toxicity to the human body and does not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts of pharmaceutically acceptable free acids and base compounds of formula 1, alkali metal salts (sodium salts, etc.) and alkaline earth metal salts (calcium salts, etc.), organic base addition salts of organic bases and carboxylic acid structures of formula 1, amino acid addition salts, etc.

[0062] Preferred salt forms of the compound according to the present invention include salts with inorganic acids or organic acids. In this case, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, and hydrobromic acid can be used. In addition, organic acids such as acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, and glutamic acid can be used. Organic bases that can be used for preparing organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine. Amino acids that can be used for preparing amino acid addition salts include natural amino acids such as alanine and glycine. It will be apparent to those skilled in the art that other acids or bases may be used in addition to the inorganic acids, organic acids, organic bases and amino acids exemplified above.

[0063] The above salt can be prepared by a conventional method. For example, the compound of the above chemical formula 1 can be prepared by dissolving it in a solvent that can be mixed with water, such as methanol, ethanol, acetone, or 1,4-dioxane, adding a free acid or free base, and then crystallizing the resulting solution.

[0064] The details of the above preventive or therapeutic method can be applied as is to the above description of the pharmaceutical composition according to one aspect of the present invention.

[0065] In the present invention, the term “treatment” is used as a concept that includes treatment, improvement, amelioration or management of a disease.

[0066] The term "preventing" or "prevention" in the present invention refers to preventing a disease, for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or exhibit the pathology or signs of the disease.

[0067] The term "subject" or "patient" in the present invention means any animal including mammals, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and humans.

[0068] Hereinafter, the present invention will be described in more detail.

[0069] [Chemical Formula 1]

[0070]

[0071] In the above chemical formula 1,

[0072] R1 is hydrogen or C 1-4 It is alkyl;

[0073] R2 is hydrogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkynylide;

[0074] R3 is R 3a or -L2- and;

[0075] Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, haloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and R a class R b are each independently Hydrogen, C 1-6 Alkyl, haloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -CF2H and C 3-8 Selected from the group consisting of carbocyclyl;

[0076] r is an integer from 0 to 1;

[0077] m is an integer from 0 to 5;

[0078] L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and;

[0079] p is an integer from 0 to 3;

[0080] q is an integer from 0 to 2;

[0081] class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and in this case, C of 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with;

[0082] X1 is -O(R4) or -N(R5)(R6);

[0083] R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl;

[0084] R5 and R6 is each independently hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f It can be substituted with one or more functional groups selected from the group consisting of, where R e and R f are each independently hydrogen or C 1-6 It is alkyl,

[0085] Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the above C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo(=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h It can be substituted with one or more functional groups selected from the group consisting of, where R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, haloC 1-6 Alkoxy or C 3-8 It is carbocyclyl;

[0086] L1 is a direct bond, -C(O)-, -O- or -NH- and;

[0087] n is an integer from 0 to 2;

[0088] is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl, and in this case, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i and -NR i R j may be substituted with one or more functional groups selected from the group consisting of, wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

[0089] Preferably, a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof class Each of them is independently C 6-10 Aryl or C 4-10It may be heteroaryl.

[0090] Preferably, R is selected from the compounds of the present invention's chemical formula 1, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof. 3a are each independently halogen, hydroxy, cyano, amino, amine, nitro, C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, -CF2H, C 6-10 Aryl, C 3-6 Cyclyl, -(CH2) r -C 2-6 Heterocyclyl, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b and here R a and R b are each independently hydrogen, C 1-6 It can be alkyl, -CF3 or -CF2H.

[0091] Preferably, in a compound selected from the compound of formula 1 of the present invention, pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof, R4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 Heterocyclyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 Heterocyclyl, or the above -N(R5)(R6) is C 2-9 It may be a heterocyclyl.

[0092] According to another embodiment of the present invention, the compound represented by the above chemical formula 1 may be represented by the following chemical formula 2:

[0093] [Chemical Formula 2]

[0094]

[0095] In the above chemical formula 2,

[0096] L1 is a direct bond, -C(O)-, -O- or -NH-;

[0097] n is an integer from 0 to 2;

[0098] Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, except when both Z1 and Z2 are hydrogen;

[0099] R 4a is hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is a heterocyclyl;

[0100] is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein the morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

[0101] According to another embodiment of the present invention, the compound represented by the above chemical formula 1 may be represented by the following chemical formula 3:

[0102] [Chemical Formula 3]

[0103]

[0104] In the above chemical formula 3,

[0105] L3 is a direct bond or -C(O)-;

[0106] n is an integer from 0 to 2;

[0107] Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, except in the case where both Z1 and Z2 are hydrogen;

[0108] R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl,

[0109] or the above -N(R 5a )(R 5b ) is R 5a Wow R 5b are connected to each other -N(R 5a )(R 5b ) forming a ring with the nitrogen atom in it 2-9 It is a heterocyclyl;

[0110] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

[0111] According to another embodiment of the present invention, the compound represented by the above chemical formula 2 may be represented by the following chemical formula 4:

[0112] [Chemical Formula 4]

[0113]

[0114] In the above chemical formula 4,

[0115] L4 is a direct bond, -C(O)- or -O-;

[0116] n is an integer from 0 to 2;

[0117] Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, except in the case where both Z1 and Z2 are hydrogen;

[0118] is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, wherein the morpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl may be unsubstituted or substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

[0119] According to another embodiment of the present invention, the compound represented by the above chemical formula 3 may be represented by the following chemical formula 5:

[0120] [Chemical Formula 5]

[0121]

[0122] In the above chemical formula 5,

[0123] L5 is a direct bond or -C(O)-;

[0124] n is an integer from 0 to 2;

[0125] Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, except in the case where both Z1 and Z2 are hydrogen;

[0126] is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein said morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

[0127] In addition, preferred examples of the compound of the above chemical formula 1 according to the present invention are as follows, but are not limited thereto:

[0128] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0129] (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone;

[0130] (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R, 5S)-3,5-dimethylpiperazin-1-yl)methanone;

[0131] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone;

[0132] (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;

[0133] (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

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

[0135] (6-methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone;

[0136] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone;

[0137] (R)-2,2,2-Trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide;

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

[0139] (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl) ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone;

[0140] (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0141] (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl) ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0142] (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino) quinazolin-7-yl)(morpholino)methanone;

[0143] (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0144] (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0145] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone;

[0146] (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

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

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

[0149] (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile;

[0150] (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0151] (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0152] (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

[0153] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone;

[0154] (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone;

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

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

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

[0158] (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone;

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

[0160] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone;

[0161] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine;

[0162] (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine;

[0163] (R)-N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine;

[0164] (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine;

[0165] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine;

[0166] (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine;

[0167] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0168] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone;

[0169] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone;

[0170] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0171] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone;

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

[0173] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone;

[0174] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone;

[0175] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone;

[0176] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine;

[0177] (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0178] (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0179] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone;

[0180] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone;

[0181] (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0182] (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone;

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

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

[0185] (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;

[0186] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone;

[0187] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone;

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

[0189] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone;

[0190] (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;

[0191] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone;

[0192] (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone;

[0193] (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;

[0194] (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone;

[0195] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone; and

[0196] (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.

[0197]

[0198] In the present invention, the method for preparing the compound of the above chemical formula 1 is not particularly limited, but for example, it can be synthesized by the preparation method of the following reaction scheme 1 or reaction scheme 2:

[0199]

[0200] [Reaction Formula 1]

[0201]

[0202] In the above reaction formula 1 , R1, R2, R3, R4, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0203]

[0204] [Step 1]

[0205] 2-Bromoterephthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5 to 5 °C and refluxed for 4 to 6 minutes. After mixing sulfuric acid and nitric acid, they were slowly added dropwise to the reaction mixture at 0 to 5 °C. After the addition was complete, the mixture was refluxed at 95 to 110 °C for 1 to 3 hours. After the reaction was complete, 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 mixture. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solution was concentrated under reduced pressure to obtain the title compound.

[0206] [Step 2]

[0207] B (1 equivalent), sodium acetate (2.2 equivalents), sodium hydroxide (3 equivalents), and copper (0.01 equivalent) prepared in the above [Step-1] were dissolved in distilled water and refluxed under microwave at 110-130°C for 1.5-3 hours. After the reaction was completed, the solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with water. The filtered aqueous layer was acidified with 6N hydrochloric acid until the pH reached 1-2. The acidified aqueous solution was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure to obtain the title compound.

[0208] [Step 3]

[0209] C (1 equivalent) and sulfuric acid (1 equivalent) obtained in the above [Step-2] were dissolved in methanol and stirred under reflux at 65-75°C for 60-70 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted three times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0210] [Step 4]

[0211] D (1 equivalent), methyl iodide (8 equivalents), and potassium carbonate (8 equivalents) obtained in the above [Step-3] were dissolved in acetone and stirred under reflux at 50-70°C for 16-24 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in distilled water and ethyl acetate, extracted three times with ethyl acetate, and 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 obtained residue was purified by MPLC to obtain the title compound.

[0212] [Step 5]

[0213] E (1 equivalent) prepared in the above [Step-4] was dissolved in ethyl acetate:ethanol, and Pd / C was added. The reaction solution was stirred at 45-55°C under hydrogen gas for 16-24 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the resulting residue was purified by MPLC to obtain the title compound.

[0214] [Step 6]

[0215] F (1 equivalent) obtained in the above [Step-5] was dissolved in tetrahydrofuran, and 4% potassium hydroxide was slowly added dropwise. The mixture was stirred at 65-75°C for 2-4 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic layer, and the obtained aqueous layer was acidified with 1 N hydrochloric acid until the pH reached 1-2 to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 50-60°C to obtain the title compound.

[0216] [Step 7]

[0217] G (1 equivalent), acetamidine hydrochloride (2 equivalents), and sodium acetate (2 equivalents) obtained in the above [Step-6] were dissolved in 2-methoxyethanol, and the mixture was stirred under reflux at 140 to 160 °C for 12 to 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, distilled water was added dropwise, and the mixture was stirred at 0 to 5 °C for 0.5 to 1 hour to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 50 to 60 °C to obtain the title compound.

[0218] [Step 8]

[0219] H (1 equivalent), amine (1.5 equivalents), HATU (3 equivalents), and DIPEA (5 equivalents) obtained in the above [Step-7] were dissolved in DMF, and the mixture was refluxed and stirred at room temperature for 2 to 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethyl acetate to obtain the title compound.

[0220] [Step 9]

[0221] I (1 equivalent) obtained in the above [Step-8] was dissolved in phosphoryl chloride and refluxed at 105-114°C for 1-2.5 hours. After completion of the reaction, the mixture was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound.

[0222] [Step 10]

[0223] J (1 equivalent), aniline (1.1 equivalent), and DIPEA (4 equivalent) prepared in the above [Step-9] were dissolved in DMF, and the mixture was refluxed and stirred at 95-110°C for 12-15 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0224]

[0225] [Reaction Formula 2]

[0226]

[0227] In the above reaction formula 2 , R1, R2, R3, R4, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0228]

[0229] [Step 1]

[0230] Methyl 3-methoxy-4-methylbenzoate (1 equivalent) was mixed with acetic acid and water, and bromine (1.1 equivalent) was added dropwise. After the addition was complete, the mixture was refluxed and stirred at 50-60°C for 1-2 hours. After the reaction was complete, the mixture was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. The aqueous solution was extracted with a hexane / ether solution, and the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered solution was concentrated under reduced pressure to obtain the title compound.

[0231] [Step 2]

[0232] B (1 equivalent), N-bromosuccinimide (0.9 equivalent), and azobisisobutyronitrile (0.2 equivalent) obtained in the above [Step-1] were dissolved in chloroform and stirred under reflux at 65-70°C for 1.5-3 hours. After the reaction was completed, the mixture was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. After extraction with ethyl acetate, the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by MPLC to obtain the title compound.

[0233] [Step 3]

[0234] C (1 equivalent), amine (1.1 equivalent), and potassium carbonate (2 equivalent) obtained in the above [Step-2] were dissolved in acetonitrile and stirred at 20-30°C for 17-20 hours. After the reaction was completed, the mixture was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. The mixture was extracted with ethyl acetate, and 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 obtained residue was purified by MPLC to obtain the title compound.

[0235] [Step 4]

[0236] D (1 equivalent), tert-butyl carbamate (1.1 equivalent), xanthos (0.2 equivalent), Pd2(dba)3dba (0.1 equivalent), and cesium carbonate (3 equivalent) obtained in the above [Step-3] were dissolved in 1,4-dioxane and stirred at 100-120°C for 1-3 hours. After completion of the reaction, it was cooled to room temperature, filtered through a filter filled with Celite, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC to obtain the title compound.

[0237] [Step 5]

[0238] E (1 equivalent) obtained in the above [Step-4] was dissolved in acetonitrile, and a 4N dioxane hydrogen chloride solution was added dropwise. The mixture was stirred under reflux at 70-90°C for 1-3 hours. After the reaction was completed, it was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to obtain the title compound.

[0239] [Step 6]

[0240] F (1 equivalent), aniline (1.5 equivalents), PyBOP (1.5 equivalents), and DBU (2.5 equivalents) obtained in the above [Step-5] were dissolved in acetonitrile and stirred at 75-85°C for 4-6 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0241]

[0242] In addition, the method for preparing the compound of the above chemical formula 1 in the present invention is not particularly limited, but for example, it can be synthesized by the preparation method of the following reaction scheme 3:

[0243]

[0244] [Reaction Formula 3]

[0245]

[0246] In the above reaction formula 3 , R1, R2, R3, R5, R6, m and is as defined in the above chemical formula 1, but is not limited thereto.

[0247]

[0248] [Step 1]

[0249] 2-Bromoterephthalic acid (1 equivalent) was slowly added dropwise to sulfuric acid at -5 to 5 °C and refluxed for 4 to 6 minutes. After mixing sulfuric acid and nitric acid, they were slowly added dropwise to the reaction mixture at 0 to 5 °C. After the addition was complete, the mixture was refluxed at 95 to 110 °C for 1 to 3 hours. After the reaction was complete, 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 mixture. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting solution was concentrated under reduced pressure to obtain the title compound.

[0250] [Step 2]

[0251] B (1 equivalent) and sulfuric acid (1 equivalent) obtained in the above [Step-1] were dissolved in methanol and stirred under reflux at 65-75°C for 60-70 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted three times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure to obtain the title compound.

[0252] [Step 3]

[0253] C (1 equivalent), amine (5 equivalents), and DIPEA (10 equivalents) obtained in the above [Step-2] were dissolved in DMF and refluxed at 95-105°C for 1-2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and added dropwise to distilled water. The resulting solution was filtered under reduced pressure to obtain the title compound.

[0254] [Step 4]

[0255] D (1 equivalent) and zinc dust (3.5 equivalents) obtained in the above [Step-3] were dissolved in a dioxane:distilled water mixture and stirred under reflux at 25-30°C for 0.5-1 hour. After stirring, the reaction solution was cooled to 0-5°C, and ammonium chloride (5 equivalents) was added dropwise. After the addition, the solution was stirred under reflux at 25-30°C for 1-3 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. This was dissolved in distilled water and ethyl acetate, extracted three times with ethyl acetate, and the 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 obtained residue was purified by column chromatography to obtain the title compound.

[0256] [Step 5]

[0257] E (1 equivalent) prepared in the above [Step-4] and acetonitrile (8 equivalents) were dissolved in a 4N hydrochloric acid solution dissolved in dioxane, and the reaction solution was stirred at 85-95°C for 2.5-3.5 hours using a sealed tube. After the reaction was completed, the reaction solution was filtered through a filter and washed with hexane. The filtered solid was neutralized with an aqueous sodium bicarbonate solution and then filtered under reduced pressure to obtain the title compound.

[0258] [Step 6]

[0259] F (1 equivalent) obtained in the above [Step-5] was dissolved in phosphoryl chloride and stirred at 110-130°C for 2-4 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic layer, and the resulting residue was dissolved in dichloromethane and neutralized with an aqueous sodium bicarbonate solution at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain the title compound.

[0260] [Step 7]

[0261] G (1 equivalent), aniline (1.3 equivalents), and DIPEA (3 equivalents) obtained in the above [Step-6] were dissolved in DMF, and the mixture was refluxed and stirred at 85-100°C for 12-15 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound.

[0262] [Step 8]

[0263] The H (1 equivalent) obtained in the above [Step-7] was dissolved in a mixed solution of tetrahydrofuran:methanol:water, sodium hydroxide (5 equivalents) was added, and the mixture was refluxed at 25-30°C for 1-3 hours. After the reaction was completed, a 2N HCl aqueous solution was added dropwise to adjust the pH to 5-6, and then washed with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound without further purification. To the obtained title compound, amine (1.1 equivalents), HATU (1.3 equivalents), and DIPEA (3 equivalents) were dissolved in DMF, and the mixture was refluxed at 25-30°C for 1-3 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the title compound.

[0264] Although the manufacturing method of the above chemical formula 1 has been described with specific examples, specific reaction conditions, such as the amount of reaction solvent, base, and reactant, are not limited to those described in this specification, and cannot be interpreted as limiting the scope of the present invention in any way.

[0265] The pharmaceutical composition of the present invention is also useful for preventing or treating various diseases related thereto, as the compound of chemical formula 1 contained therein inhibits SOS1 binding to RAS family proteins and / or RAC1.

[0266] In one embodiment, the compound of the present invention has almost no inhibitory effect on cytochrome P450 enzyme (CYP) subtypes, thereby reducing side effects such as drug-drug interactions that may occur due to decreased activity of P450 enzyme (CYP) subtypes, and is thus useful even when administering multiple drugs in combination. In a specific embodiment, the compound of the present invention has a structure represented by Chemical Formula 2 or Chemical Formula 3, and has almost no inhibitory effect on cytochrome P450 enzyme subtypes. In a more specific embodiment, the compound of the present invention has a structure represented by Chemical Formula 4 or Chemical Formula 5, and has excellent activity maintenance against cytochrome P450 enzyme subtypes. For example, inhibition of cytochrome P450 enzyme (CYP) subtype activity by the compound of Chemical Formula 4 or 5 of the present invention is IC 50 The value can be at least 20 μM or more.

[0267] According to another embodiment of the present invention, a preventive or therapeutic pharmaceutical composition comprising the compound of the above chemical formula 1 and a pharmaceutically acceptable salt thereof as an active ingredient is provided.

[0268] According to another embodiment of the present invention, a pharmaceutical preparation comprising the above-described pharmaceutical composition is provided.

[0269] The pharmaceutical preparation of the present invention may be in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions, or in parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration such as injections, and preferably in oral dosage forms.

[0270] In addition, the above pharmaceutical preparation may be formulated according to a conventional method by adding, in addition to the active ingredient, a conventional non-toxic pharmaceutically acceptable additive, for example, at least one selected from the group consisting of a carrier, an adjuvant, and an excipient.

[0271] Excipients that can be used in the pharmaceutical preparation of the present invention include, but are not limited to, sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc. For example, excipients that can be used include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0272] When the pharmaceutical preparation of the present invention is in an oral dosage form, examples of 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.

[0273] When the pharmaceutical preparation of the present invention is in the form of an injection, the carrier may include, but is not limited to, water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, etc.

[0274] For use of the compounds according to the present invention as medicaments, the latter are prepared in the form of pharmaceutical preparations, which contain, in addition to the active ingredients for oral or parenteral administration, suitable pharmaceutically organic or inorganic inert carrier substances, such as water, gelatin, gum arabic, lactose, starch, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, such as tablets, dragees, suppositories or capsules, or in liquid form, such as solutions, suspensions or emulsions. In addition, they optionally contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers; salts or buffers for altering the osmotic pressure.

[0275] For parenteral administration, injectable solutions or suspensions are particularly preferred.

[0276] As carrier systems, surfactants, for example, bile salts or animal or plant phospholipids, or mixtures thereof, and liposomes or components thereof may also be used.

[0277] For oral administration, tablets, dragees, or capsules containing talc and / or a hydrocarbon vehicle or binder, such as lactose, corn starch, or potato starch, are particularly suitable. Liquid forms, such as juices with added sweeteners, are also suitable.

[0278] In addition, the dosage for the human body of the compound of the above chemical formula 1 according to the present invention is preferably in the range of 0.1 mg / day to 2,000 mg / day, based on an adult patient weighing 70 kg. The compound according to the present invention may be administered once or several times a day in divided doses. However, the above-mentioned dosage may vary depending on the patient's health condition, age, weight, and sex, as well as the dosage form and disease severity, and therefore, the scope of the present invention is not limited to the dosage presented above.

[0279] According to another embodiment of the present invention, a compound selected from the compound of the chemical formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof is provided for use in the prevention or treatment of cancer or tumor.

[0280] According to another embodiment of the present invention, a method for preventing or treating cancer is provided, comprising administering to a subject a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate, and solvate thereof, or a pharmacologically acceptable salt thereof. Preferably, the subject refers to, but is not limited to, an individual or a patient.

[0281] According to another embodiment of the present invention, there is provided a method of treating cancer in a subject requiring administration of an inhibitor of the compound and a standard-of-care formulation, comprising administering a therapeutically effective amount of a standard-of-care formulation comprising a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0282] According to another embodiment of the present invention, a method for treating cancer in a subject requiring administration of a composition is provided, comprising administering a therapeutically effective amount of a composition comprising a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0283] According to another embodiment of the present invention, a method for inhibiting SOS1 binding to a RAS family protein and / or RAC1 in a sample or cell is provided, comprising administering to the sample a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0284] According to another embodiment of the present invention, a method for inhibiting tyrosine kinase in a sample or cell is provided, comprising administering to the sample a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0285] According to another embodiment of the present invention, a method for preventing or treating cancer in a subject is provided, comprising administering to the subject a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0286] According to another embodiment of the present invention, a method for preventing or treating cancer is provided by inhibiting binding of SOS1 protein to RAS family protein and / or RAC1 in a sample or cell, comprising administering to the sample a compound selected from the compound of formula 1 of the present invention, a pharmaceutically acceptable salt, optical isomer, diastereomer, hydrate and solvate thereof, or a pharmacologically acceptable salt thereof.

[0287]

[0288] Hereinafter, the present invention will be described in more detail with the following examples and experimental examples. However, these examples and experimental examples are intended only to aid understanding of the present invention and are not intended to limit the scope of the present invention in any way.

[0289]

[0290] Example 1: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0291]

[0292] [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0293]

[0294] 2-Bromoterephthalic acid (13.8 g, 56.32 mmol) was slowly added dropwise to 78 mL of sulfuric acid at 0 °C and stirred for 5 minutes. 7.5 mL of sulfuric acid and 17.5 mL of nitric acid were mixed and slowly added dropwise to the reaction solution at 0 °C. After the addition was complete, the mixture was refluxed and stirred at 100 °C for 2 hours. After the reaction was complete, it was cooled to room temperature and stirred at room temperature for 12 hours. Upon completion of the reaction, the reaction solution was slowly added dropwise to ice water. The aqueous solution was extracted three times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered solution was concentrated under reduced pressure to obtain 16 g of the title compound without further purification.

[0295] 1 H-NMR (300 MHz, DMSO-d6): δ8.34 (s, 1H), 8.17 (s, 1H).

[0296]

[0297] [Step 2] Preparation of 2-hydroxy-5-nitroterephthalic acid

[0298]

[0299] 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 the above [Step-1] were dissolved in 60 mL of distilled water and refluxed under a microwave at 120°C for 2 hours. After the reaction was completed, the solution was cooled to room temperature, filtered through a filter filled with Celite, and washed with water. The filtered aqueous layer was acidified with 6N hydrochloric acid until the pH reached 1-2. The acidified aqueous solution was extracted three times with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated under reduced pressure to obtain 7 g of the title compound in a yield of 85%.

[0300] 1 H-NMR (300 MHz, DMSO-d6): δ8.42 (s, 1H), 7.15 (s, 1H).

[0301]

[0302] [Step 3] Preparation of dimethyl 2-hydroxy-5-nitroterephthalate

[0303]

[0304] 2-Hydroxy-5-nitroterephthalic acid (7 g, 30.82 mmol) and sulfuric acid (35 mL, 653.04 mmol) obtained in the above [Step-2] were dissolved in 330 mL of methanol and refluxed at 70°C for 65 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was extracted three times with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure to obtain 7.9 g of the title compound without further purification.

[0305] 1H-NMR (300 MHz, DMSO-d6): δ8.43 (s, 1H), 6.85 (s, 1H), 3.83 (s, 6H).

[0306]

[0307] [Step 4] Preparation of dimethyl 2-methoxy-5-nitroterephthalate

[0308]

[0309] Dimethyl 2-hydroxy-5-nitroterephthalate (7.9 g, 30.82 mmol), methyl iodide (15.3 mL, 246.56 mmol), and potassium carbonate (34 g, 246.56 mmol) obtained in the above [Step-3] were dissolved in 310 mL of acetone and stirred under reflux at 60 °C for 21 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in distilled water and ethyl acetate (1:1 vol / vol), extracted three times with ethyl acetate, and 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 obtained residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 6.1 g of the title compound in 73% yield.

[0310] 1 H-NMR (300 MHz, CDCl3): δ8.57 (s, 1H), 7.15 (s, 1H), 4.05 (s, 3H), 3.98 (s, 3H), 3.96 (s, 3H).

[0311]

[0312] [Step 5] Preparation of dimethyl 2-amino-5-methoxyterephthalate

[0313]

[0314] Dimethyl 2-methoxy-5-nitroterephthalate (6.1 g, 22.50 mmol) prepared in the above [Step-4] was dissolved in 122 mL (1:4, vol / vol) of ethyl acetate:ethanol, and Pd / C (600 mg, 10 wt%) was added. The reaction solution was stirred at 50°C under hydrogen gas for 20 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 5 g of the title compound in a yield of 93%.

[0315] 1 H-NMR (300 MHz, CDCl3): δ7.38 (s, 1H), 7.05 (s, 1H), 5.50 (s, 2H), 3.86 (s, 6H), 3.80 (s, 3H).

[0316]

[0317] [Step 6] Preparation of 2-amino-5-methoxyterephthalic acid

[0318]

[0319] Dimethyl 2-amino-5-methoxyterephthalate (5 g, 20.93 mmol) obtained in the above [Step-5] was dissolved in 115 mL of tetrahydrofuran, and 115 mL of 4% potassium hydroxide was slowly added dropwise. The mixture was stirred at 70°C for 3 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic layer, and the obtained aqueous layer was acidified with 1 N hydrochloric acid until the pH reached 1-2 to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 55°C to obtain 4.3 g of the title compound in a 98% yield.

[0320] 1H-NMR (300 MHz, DMSO-d6): δ7.30 (s, 1H), 7.01 (s, 1H), 3.70 (s, 3H).

[0321]

[0322] [Step-7] Preparation of 6-methoxy-2-methyl-4-oxo-1,4-dihydroquinazoline-7-carboxylic acid

[0323]

[0324] 2-Amino-5-methoxyterephthalic acid (4.3 g, 20.51 mmol), acetamide hydrochloride (3.86 g, 41.02 mmol), and sodium acetate (3.38 g, 40.77 mmol) obtained in the above [Step-6] were dissolved in 86 mL of 2-methoxyethanol, and the mixture was stirred under reflux at 150 °C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, distilled water was added dropwise, and the mixture was stirred at 0 °C for 0.5 hours to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with distilled water. The filtered solid was dried in an oven dryer at 55 °C to obtain 3.3 g of the title compound in a yield of 69%.

[0325] 1 H-NMR (300 MHz, DMSO-d6): δ13.19 (s, 1H), 12.26 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 3.90 (s, 3H), 2.34 (s, 3H).

[0326]

[0327] [Step-8] Preparation of 6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1H)-one

[0328]

[0329] 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 the above [Step-7] were dissolved in 4.5 mL of DMF, and the mixture was refluxed and stirred at room temperature for 2.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature to obtain a solid product. The obtained solid was filtered under reduced pressure, and the filtered solid was washed with ethyl acetate to obtain 255 mg of the title compound in a yield of 66%.

[0330] 1 H-NMR (300 MHz, DMSO-d6): δ12.24 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 3.90 (s, 3H), 3.68 (m, 4H), 3.52 (m, 2H), 3.11 (m, 2H), 2.51 (s, 3H).

[0331]

[0332] [Step-9] Preparation of (4-chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholine)methanone

[0333]

[0334] 6-Methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4(1H)-one (255 mg, 0.84 mmol) obtained in the above [Step-8] was dissolved in 14 mL of phosphoryl chloride and refluxed at 110°C for 2 hours. After completion of the reaction, it was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 25:1 to 10:1 (v / v)) to obtain 221 mg of the title compound in a yield of 82%.

[0335] 1H-NMR (300 MHz, DMSO-d6): δ7.86 (s, 1H), 7.52 (s, 1H), 4.01 (s, 3H), 3.67 (m, 4H), 3.50 (m, 2H), 3.14 (m, 2H), 2.50 (s, 3H).

[0336]

[0337] [Step-10] Preparation of (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0338]

[0339] (4-Chloro-6-methoxy-2-methylquinazolin-7-yl)(morpholine)methanone (70 mg, 0.22 mmol) prepared in the above [Step-9], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (57 mg, 0.24 mmol) synthesized by the method presented in WO2018115380, and DIPEA (0.15 mL, 0.88 mmol) were dissolved in 1 mL of DMF, and the mixture was stirred under reflux at 100 °C for 13 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to obtain 60 mg of the title compound in 56% yield.

[0340] 1 H-NMR (300 MHz, DMSO-d6): δ8.29 (d, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 6.90 (d, 2H), 6.71 (s, 1H), 5.62 (m, 1H), 5.57 (s, 2H), 3.94 (s, 3H), 3.50 (m, 4H), 3.37 (m, 2H), 3.11 (m, 2H), 2.50 (s, 3H), 1.58 (m, 3H).

[0341] MS (ESI+, m / z): 490.2 [M+H] +

[0342]

[0343] Example 2: (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0344]

[0345] [Step 1] Preparation of (4-((1-(4-bromothiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0346]

[0347] The procedure of Example 1 was repeated except that 1-(4-bromothiophen-2-yl)ethan-1-amine (100 mg, 0.47 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10] and DMAc was used instead of DMF, to obtain 156 mg of the title compound in a yield of 68%.

[0348] 1 H-NMR (300 MHz, DMSO-d6): δ8.40 (d, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.10 (s, 1H), 5.90 (m, 1H), 3.91 (s, 3H), 3.65 (m, 4H), 3.48 (m, 2H), 3.11 (m, 2H), 2.49 (m, 3H), 1.72 (m, 3H).

[0349]

[0350] [Step 2] Preparation of 2-(5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)thiophen-3-yl)benzaldehyde

[0351]

[0352] (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(PPh3)4 (40 mg, 0.03 mmol), and potassium carbonate (177 mg, 1.28 mmol) prepared in the above [Step-1] were dissolved in 3 mL of dioxane:water (5:1), and stirred at 100°C for 5 hours. After completion of the reaction, it was cooled to room temperature, filtered through a filter filled with Celite, and washed with dichloromethane. Water was added dropwise to the combined organic layer, which was then extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 100:1 to 10:1 (v / v)) to obtain 143 mg of the title compound in 88% yield.

[0353] 1 H-NMR (300 MHz, DMSO-d6): δ10.08 (s, 1H), 8.40 (m, 1H), 7.90 (d, 1H), 7.87 (s, 1H), 7.73 (m, 1H), 7.70 (m, 3H), 7.51 (s, 1H), 7.32 (s, 1H), 6.00 (m, 1H), 4.09 (s, 3H), 3.65 (m, 4H), 3.50 (m, 2H), 3.11 (m, 2H), 2.49 (m, 3H), 1.79 (m, 3H).

[0354]

[0355] [Step 3] Preparation of (6-methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0356]

[0357] 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] were dissolved in 2 mL of dichloroethane, and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 50:1 to 7:1 (v / v)) to obtain 80 mg of the title compound in 56% yield.

[0358] 1 H-NMR (300 MHz, DMSO-d6): δ8.45 (m, 1H), 7.81 (s, 1H), 7.48 (m, 3H), 7.29 (m, 4H), 6.00 (m, 1H), 4.09 (m, 3H), 3.65 (m, 4H), 3.58 (m, 2H), 3.50 (m, 2H), 3.11 (m, 2H), 2.51 (m, 3H), 2.23 (s, 3H), 1.94 (m, 1H), 1.71 (m, 3H).

[0359] MS (ESI+, m / z): 532.2 [M+H] +

[0360]

[0361] 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

[0362]

[0363] The procedure of Example 1 was repeated except that cis-2,6-dimethylpiperazine (270 mg, 2.34 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 14 mg of the title compound in a yield of 34%.

[0364] 1 H-NMR (300 MHz, DMSO-d6): δ8.28 (d, 1H), 7.84 (m, 1H), 7.36 (d, 1H), 6.93 (m, 2H), 6.72 (s, 1H), 5.62 (m, 3H), 4.41 (m, 1H), 3.92 (s, 3H), 3.07 (m, 1H), 2.68 (m, 3H), 2.40 (d, 3H), 2.28 (m, 3H), 1.60 (m, 3H), 1.03 (d, 3H), 0.82 (m, 3H).

[0365] MS (ESI+, m / z): 517.3 [M+H] +

[0366]

[0367] Example 4: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone

[0368]

[0369] The procedure of Example 1 was repeated except that thiomorpholine (0.24 mL, 2.56 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 60 mg of the title compound in a yield of 56%.

[0370] 1H-NMR (300 MHz, DMSO-d6): δ8.27 (d, 1H), 7.85 (d, 1H), 7.41 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.59 (m, 3H), 3.88 (m, 5H), 3.36 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.38 (s, 3H), 1.58 (m, 3H).

[0371] MS (ESI+, m / z): 506.2 [M+H] +

[0372]

[0373] 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

[0374]

[0375] The procedure of Example 1 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (159 mg, 1.41 mmol) was used instead of morpholine in the above Example 1 [Step-8], to obtain 9.2 mg of the title compound in a 9% yield.

[0376] 1 H-NMR (300 MHz, CD3OD): δ7.82 (s, 1H), 7.52 (s, 1H), 7.00 (m, 2H), 6.83 (s, 1H), 5.66 (m, 1H), 4.02 (s, 3H), 3.94 (m, 2H), 3.84 (m, 2H), 3.66 (m, 2H), 3.18 (m, 4H), 2.49 (s, 3H), 1.67 (d,J= 6.9 Hz, 3H).

[0377] MS (ESI+, m / z): 516.2 [M+H] +

[0378]

[0379] Example 6: (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0380]

[0381]

[0382] The 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 the above Example 1 [Step-10], to obtain 8 mg of the title compound in a yield of 17%.

[0383] 1 H-NMR (300 MHz, DMSO-d6): δ8.40 (m, 1H), 7.89 (s, 1H), 7.68 (m, 1H), 7.66 (m, 1H), 7.50 (s, 1H), 7.40-7.06 (m, 2H), 5.82 (m, 1H), 3.97 (s, 3H), 3.50 (m, 4H), 3.42 (m, 2H), 3.29 (m, 2H), 2.33 (s, 3H), 1.64 (m, 3H).

[0384] MS (ESI+, m / z): 475.2 [M+H] +

[0385]

[0386] Example 7: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone

[0387]

[0388] The procedure of Example 1 was repeated except that azetidine (0.1 mL, 1.40 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 28 mg of the title compound in a 15% yield.

[0389] 1 H-NMR (300 MHz, DMSO-d6): δ8.28 (d, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 6.90 (d, 2H), 6.71 (s, 1H), 5.64 (m, 3H), 4.06 (m, 2H), 3.95 (s, 3H), 3.88 (m, 2H), 2.42 (s, 3H), 2.28 (m, 2H), 1.59 (d, 3H).

[0390] MS (ESI+, m / z): 460.2 [M+H] +

[0391]

[0392] Example 8: (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0393]

[0394] The procedure of Example 2 was repeated except that (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-8-yl)boronic acid (74 mg, 0.27 mmol) was used instead of (2-formylphenyl)boronic acid in the above Example 2 [Step-2], to obtain 30 mg of the title compound in a yield of 48%.

[0395] 1 H-NMR (300 MHz, CD3OD): δ7.77 (s, 1H), 7.54 (s, 1H), 7.13 (m, 5H), 6.00 (m, 1H), 4.13 (s, 3H), 3.82 (m, 4H), 3.61 (m, 2H), 3.32 (m, 2H), 3.13 (m, 2H), 2.87 (m, 4H), 2.57 (s, 3H), 1.83 (m, 3H).

[0396] MS (ESI+, m / z): 544.2 [M+H] +

[0397]

[0398] Example 9: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone

[0399]

[0400] The procedure of Example 1 was repeated except that piperazine (26 mg, 0.41 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 5 mg of the title compound in a yield of 9%.

[0401] 1 H-NMR (300 MHz, CD3OD): δ8.09 (s, 1H), 7.61 (s, 1H), 6.98 (m, 2H), 6.84 (s, 2H), 5.79 (m, 1H), 4.06 (m, 5H), 3.54 (m, 2H), 3.34 (m, 2H), 3.20 (m, 2H), 2.65 (s, 3H), 1.74 (d, 3H).

[0402] MS (ESI+, m / z): 489.2 [M+H] +

[0403]

[0404] Example 10: (R)-2,2,2-Trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide

[0405]

[0406]

[0407] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (30 mg, 0.061 mmol), trifluoroacetic anhydride (14 mg, 0.067 mmol), and DIPEA (10 mg, 0.078 mmol) obtained in the above Example 1 [Step-10] were dissolved in 1 mL of dichloromethane and stirred at room temperature for 3.5 hours. After the reaction was completed, an aqueous ammonium chloride solution was added dropwise to neutralize, the mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 50:1 to 10:1 (v / v)) to obtain 7 mg of the title compound in 20% yield.

[0408] 1 H-NMR (300 MHz, CD3OD): δ8.11-8.08 (d, 1H), 7.91-7.88 (d, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 5.74 (m, 1H), 4.86 (s, 6H), 4.03 (s, 3H), 3.79 (m, 4H), 3.63 (m, 2H), 3.32 (m, 2H), 2.47 (s, 3H), 1.76 (d, 3H).

[0409] MS (ESI+, m / z): 586.2 [M+H] +

[0410]

[0411] Example 11: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone

[0412]

[0413] The procedure of Example 1 was repeated except that 3-fluoroazetidine (258 mg, 1.07 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 30 mg of the title compound in a yield of 9%.

[0414] 1 H-NMR (300 MHz, CD3OD): δ8.03 (s, 1H), 7.64 (s, 1H), 7.00 (m, 2H), 6.85 (s, 1H), 5.78 (m, 1H), 5.34 (m, 1H), 4.51 (m, 1H), 4.28 (m, 3H), 4.08 (s, 3H), 2.63 (s, 3H), 1.74 (d, 3H)

[0415] MS (ESI+, m / z): 478.2 [M+H] +

[0416]

[0417] Example 12: (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone

[0418]

[0419] The procedure of Example 2 was repeated except that 2.0 M dimethylamine (0.16 ml, 0.32 mmol) was used instead of 2.0 M methylamine in [Step-3] of the above Example 2, to obtain 307 mg of the title compound in 8% yield.

[0420] 1 H-NMR (300 MHz, CD3OD): δ7.77 (s, 1H), 7.49 (m, 2H), 7.39 (m, 3H), 7.26 (s, 1H), 7.17 (s, 1H), 6.09 (m, 1H), 3.97 (m, 5H), 3.77 (m, 4H), 3.62 (m, 2H), 3.26 (m, 2H), 2.55 (s, 3H), 2.38 (s, 6H), 1.84 (d, 3H)

[0421] MS (ESI+, m / z): 546.2 [M+H] +

[0422]

[0423] Example 13: (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0424]

[0425] The procedure of Example 2 was repeated except that 2.0 M ammonia (0.22 ml, 0.45 mmol) was used instead of 2.0 M methylamine in [Step-3] of the above Example 2, to obtain 15 mg of the title compound in a 13% yield.

[0426] 1 H-NMR (300 MHz, CD3OD): δ7.78 (s, 1H), 7.52 (m, 2H), 7.30 (m, 5H), 6.10 (m, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.76 (m, 4H), 3.62 (m, 2H), 3.26 (m, 2H), 2.56 (s, 3H), 1.82 (d, 3H)

[0427] MS (ESI+, m / z): 518.2 [M+H] +

[0428]

[0429] Example 14: (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl) ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0430]

[0431] The procedure of Example 2 was repeated except that 2-(hydroxymethyl)phenylboronic acid (0.14 ml, 0.92 mmol) was used instead of (2-formylphenyl)boronic acid in [Step-2] of the above Example 2, to obtain 88 mg of the title compound in a 20% yield.

[0432] 1H-NMR (300 MHz, CD3OD): δ7.76 (s, 1H), 7.51 (m, 2H), 7.31 (m, 5H), 6.10 (m, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.76 (m, 4H), 3.60 (m, 2H), 3.27 (m, 2H), 2.55 (s, 3H), 1.24 (d, 3H)

[0433] MS (ESI+, m / z): 519.2 [M+H] +

[0434]

[0435] Example 15: (R)-(6-Methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone

[0436]

[0437] The procedure of Example 1 was repeated except that (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (33 mg, 0.16 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of the above Example 1, to obtain 20 mg of the title compound in a yield of 27%.

[0438] 1 H-NMR (300 MHz, DMSO-d6): δ8.38 (d, 1H), 7.85 (s, 2H), 7.78 (d, 1H), 7.60 (d, 2H), 7.41 (s, 1H), 5.74 (m, 1H), 3.96 (s, 3H), 3.65 (m, 4H), 3.49 (m, 2H), 3.12 (m, 2H), 2.37 (s, 3H), 1.67 (m, 3H).

[0439] MS (ESI+, m / z): 475.2 [M+H] +

[0440]

[0441] Example 16: (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0442]

[0443] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-4-methyl-5-(trifluoromethyl)aniline hydrochloride (83 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of the above Example 1, to obtain 15 mg of the title compound in a yield of 13%.

[0444] 1 H-NMR (300 MHz, DMSO-d6): δ8.36 (d, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 6.92 (d, 2H), 6.79 (s, 1H), 5.68 (m, 1H), 5.25 (s, 2H), 3.96 (s, 3H), 3.65 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 2.38 (d, 6H), 1.55 (m, 3H).

[0445] MS (ESI+, m / z): 504.2 [M+H] +

[0446]

[0447] Example 17: (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0448]

[0449] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-fluoroaniline hydrochloride (46 mg, 0.24 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 24 mg of the title compound in a 25% yield.

[0450] 1 H-NMR (300 MHz, CD3OD): δ8.00 (s, 1H), 7.53 (s, 1H), 6.58 (s, 1H), 6.44 (m, 1H), 6.31 (m, 1H), 5.73 (m, 1H), 4.04 (s, 3H), 3.76 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.61 (s, 3H), 1.69 (d, 3H)

[0451] MS (ESI+, m / z): 440.2 [M+H] +

[0452]

[0453] Example 18: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0454]

[0455] The procedure of Example 1 was repeated except that thiomorpholine 1,1-dioxide (30 mg, 0.21 mmol) was used instead of morpholine in the above Example 1 [Step-8], to obtain 23 mg of the title compound in a 30% yield.

[0456] 1 H-NMR (300 MHz, CD3OD): δ7.85 (s, 1H), 7.58 (s, 1H), 7.01 (m, 2H), 6.83 (s, 1H), 5.67 (m, 1H), 4.26 (m, 2H), 4.03 (s, 3H), 3.68 (m, 2H), 3.24 (m, 2H), 3.13 (m, 2H), 2.50 (s, 3H), 1.67 (d,J= 6.9 Hz, 3H).

[0457] MS (ESI+, m / z): 538.1 [M+H] +

[0458]

[0459] Example 19: (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0460]

[0461] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-2-methoxyaniline hydrochloride (49 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of the above Example 1, to obtain 30 mg of the title compound in a yield of 31%.

[0462] 1 H-NMR (300 MHz, DMSO-d6): δ8.24 (m, 1H), 7.92 (s, 1H), 7.38 (s, 1H), 6.78 (m, 1H), 6.67 (m, 1H), 6.57 (m, 1H), 5.92 (m, 1H), 4.92 (m, 2H), 3.97 (s, 3H), 3.90 (d, 3H), 3.65 (m, 4H), 3.51 (m, 2H), 3.13 (m, 2H), 2.34 (s, 3H), 1.52 (m, 3H).

[0463] MS (ESI+, m / z): 452.2 [M+H] +

[0464]

[0465] Example 20: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone

[0466]

[0467] The procedure of Example 1 was repeated except that thiazolidine (0.06 mL, 0.70 mmol) was used instead of morpholine in [Step-8] of the above Example 1, to obtain 18 mg of the title compound in a yield of 56%.

[0468] 1H-NMR (300 MHz, DMSO-d6): δ8.31 (d, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 6.90 (d, 2H), 6.72 (s, 1H), 5.63 (m, 3H), 4.64 (s, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.86 (m, 1H), 3.45 (m, 1H), 3.12 (m, 1H), 2.99 (m, 1H), 2.39 (s, 3H), 1.60 (d, 3H).

[0469] MS (ESI+, m / z): 492.2 [M+H] +

[0470]

[0471] Example 21: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0472]

[0473] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (45 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of the above Example 1, to obtain 15 mg of the title compound in a yield of 16%.

[0474] 1 H-NMR (300 MHz, DMSO-d6): δ8.20 (m, 1H), 7.87 (s, 1H), 7.39 (s, 1H), 6.63 (m, 2H), 6.48 (m, 1H), 5.60 (m, 1H), 4.92 (m, 2H), 3.94 (d, 3H), 3.65 (s, 4H), 3.54 (m, 2H), 3.12 (m, 2H), 2.40 (d, 3H), 2.20 (d, 3H), 1.55 (m, 3H).

[0475] MS (ESI+, m / z): 436.2 [M+H] +

[0476]

[0477] Example 22: (R)-3-Amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile

[0478]

[0479] The procedure of Example 1 was repeated except that (R)-3-amino-5-(1-aminoethyl)benzonitrile hydrochloride (65 mg, 0.33 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 6 mg of the title compound in a 6% yield.

[0480] 1 H-NMR (300 MHz, CD3OD): δ7.80 (s, 1H), 7.49 (s, 1H), 7.02 (m, 2H), 6.80 (s, 1H), 5.58 (m, 1H), 4.01 (s, 3H), 3.76 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.47 (s, 3H), 1.64 (d, 3H)

[0481] MS (ESI+, m / z): 447.2 [M+H] +

[0482]

[0483] Example 23: (R)-(4-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0484]

[0485]

[0486] The 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 the above Example 1 [Step-10], to obtain 35 mg of the title compound in a yield of 31%.

[0487] 1 H-NMR (300 MHz, DMSO-d6): δ8.29 (m, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.27 (m, 1H), 7.09 (s, 1H), 5.63 (m, 1H), 3.95 (s, 3H), 3.64 (m, 4H), 3.48 (m, 2H), 3.32 (m, 2H), 2.95 (m, 2H), 2.36 (s, 3H), 2.09 (m, 2H), 1.58 (m, 3H)

[0488] MS (ESI+, m / z): 447.2 [M+H] +

[0489]

[0490] Example 24: (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0491]

[0492]

[0493] The 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 the above Example 1 [Step-10], to obtain 23 mg of the title compound in a 20% yield.

[0494] 1H-NMR (300 MHz, DMSO-d6): δ8.18 (d, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 6.41 (s, 2H), 6.10 (s, 1H), 5.55 (m, 1H), 4.89 (s, 2H), 3.95 (s, 3H), 3.65 (m, 4H), 3.50 (m, 2H), 3.38 (m, 2H), 3.11 (s, 2H), 2.39 (s, 3H), 1.83 (m, 1H), 1.53 (m, 3H), 0.83 (m, 2H), 0.55 (m, 2H)

[0495] MS (ESI+, m / z): 462.2 [M+H] +

[0496]

[0497] Example 25: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0498]

[0499] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-4-fluoro-5-trifluoromethyl)aniline hydrochloride (62 mg, 0.24 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 40 mg of the title compound in a yield of 36%.

[0500] 1 H-NMR (300 MHz, CD3OD): δ7.84 (m, 1H), 7.47 (s, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 5.72 (m, 1H), 4.00 (s, 3H), 3.78 (m, 4H), 3.57 (m, 2H), 3.22 (m, 2H), 2.39 (m, 3H), 1.64 (d,J= 7.4 Hz, 3H).

[0501] MS (ESI+, m / z): 508.1 [M+H] +

[0502]

[0503] Example 26: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone

[0504]

[0505] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (58 mg, 0.31 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-10] of the above Example 1, to obtain 33 mg of the title compound in a yield of 31%.

[0506] 1 H-NMR (300 MHz, DMSO-d6): δ8.30 (m, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.09 (m, 1H), 6.79 (d, 1H), 6.63 (m, 1H), 5.78 (m, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.66 (s, 4H), 3.54 (m, 2H), 3.13 (m, 2H), 2.35 (s, 3H), 1.60 (m, 3H).

[0507] MS (ESI+, m / z): 490.2 [M+H] +

[0508]

[0509] Example 27: (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone

[0510]

[0511] The procedure of Example 1 was repeated except that (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (1.11 g, 4.6 mmol) was used instead of methyl iodide in the above Example 1 [Step-4], to obtain 25 mg of the title compound in 18% yield.

[0512] 1 H-NMR (300 MHz, CD3OD): δ7.79 (m, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.01 (m, 1H), 6.83 (s, 1H), 5.67 (m, 1H), 5.25 (m, 1H), 3.94 (m, 4H), 3.81 (m, 4H), 3.62 (m, 2H), 3.34 (m, 2H), 2.49 (s, 3H), 2.38 (m, 2H), 1.68 (d,J= 5.4 Hz, 3H).

[0513] MS (ESI+, m / z): 546.2 [M+H] +

[0514]

[0515] Example 28: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0516]

[0517] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(furan-3-yl)aniline hydrochloride (62 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 10 mg of the title compound in a yield of 9%.

[0518] 1H-NMR (300 MHz, CD3OD): δ8.04 (s, 1H), 7.80 (s, 1H), 7.51 (m, 2H), 6.97 (s, 1H), 6.83 (s, 1H), 6.74 (m, 2H), 5.80 (m, 1H), 4.04 (s, 3H), 3.78 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.64 (s, 3H), 1.75 (d, 3H)

[0519] MS (ESI+, m / z): 488.2 [M+H] +

[0520]

[0521] Example 29: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0522]

[0523] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)aniline hydrochloride (58 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 10 mg of the title compound in a 10% yield.

[0524] 1 H-NMR (300 MHz, CD3OD): δ7.82 (s, 1H), 7.49 (s, 1H), 6.91 (s, 2H), 6.58 (s, 1H), 6.39 (m, 1H), 5.68 (m, 1H), 4.00 (s, 3H), 3.76 (m, 4H), 3.60 (m, 2H), 3.27 (m, 2H), 2.49 (s, 3H), 1.67 (d, 3H)

[0525] MS (ESI+, m / z): 472.2 [M+H] +

[0526]

[0527] Example 30: (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0528]

[0529] The procedure of Example 1 was repeated except that (R)-3-(1-aminoethyl)-5-(thiazol-5-yl)aniline hydrochloride (67 mg, 0.26 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 1 [Step-10], to obtain 4 mg of the title compound in a 4% yield.

[0530] 1 H-NMR (300 MHz, CD3OD): δ8.89 (s, 1H), 8.06 (d, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 7.06 (s, 1H), 6.87 (s, 1H), 6.84 (m, 1H), 5.65 (m, 1H), 4.00 (s, 3H), 3.78 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.48 (s, 3H), 1.69 (d, 3H)

[0531] MS (ESI+, m / z): 505.2 [M+H] +

[0532]

[0533] Example 31: (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone

[0534]

[0535] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone (50 mg, 0.10 mmol) obtained in Example 1 [Step-10] was dissolved in 1 mL of dichloromethane, and then acetaldehyde (5.4 mg, 0.12 mmol) and 1.0 M titanium tetrachloride dichloromethane solution (0.01 mL, 0.01 mmol) were added to the reaction solution, followed by sodium cyanobromine hydride (26 mg, 0.41 mmol) and stirring at room temperature overnight. After completion of the reaction, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 20:1 (v / v)) to obtain 16 mg of the title compound in 31% yield.

[0536] 1 H-NMR (300 MHz, CD3OD): δ7.82 (d, 1H), 7.51 (s, 1H), 6.98 (d, 2H), 6.71 (s, 1H), 5.68 (m, 1H), 4.02 (s, 3H), 3.77 (m, 4H), 3.63 (m, 2H), 3.35 (m, 2H), 3.28 (m, 2H), 2.49 (s, 3H), 1.68 (d,J= 6.9 Hz, 3H), 1.25 (m, 3H).

[0537] MS (ESI+, m / z): 518.2 [M+H] +

[0538]

[0539] Example 32: Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone

[0540]

[0541] The procedure of Example 1 was repeated except that 2-methoxyethyl 4-methylbenzenesulfonate (3.2 g, 14.11 mmol) was used instead of methyl iodide in [Step-4] of Example 1, to obtain 7 mg of the title compound in a 6% yield.

[0542] 1 H-NMR (300 MHz, DMSO-d6): δ8.31 (m, 1H), 7.86 (s, 1H), 7.41 (s, 1H), 6.89 (m, 2H), 6.71 (s, 1H), 5.57 (m, 3H), 4.28 (m, 2H), 3.94-3.50 (m, 8H), 3.37 (m, 3H), 3.16 (m, 2H), 2.39 (s, 3H), 1.59 (m, 3H).

[0543] MS (ESI+, m / z): 534.2 [M+H] +

[0544]

[0545] Example 33: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone

[0546]

[0547] The procedure of Example 1 was repeated except that fluoroacetonitrile (7.1 mL, 125 mmol) was used instead of acetonitrile in the above Example 1 [Step-7], to obtain 32 mg of the title compound in a yield of 34%.

[0548] 1 H-NMR (300 MHz, CD3OD): δ7.92 (s, 1H), 7.68 (s, 1H), 7.00 (m, 2H), 6.83 (s, 1H), 5.68 (m, 1H), 5.51 (m, 1H), 5.39 (m, 1H), 4.01 (s, 3H), 3.79 (m, 4H), 3.63 (m, 2H), 3.23 (m, 2H), 1.69 (d,J= 7.2 Hz, 3H).

[0549] MS (ESI+, m / z): 508.2 [M+H] +

[0550]

[0551] Example 34: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine

[0552]

[0553] [Step 1] Preparation of methyl 2-bromo-5-methoxy-methylbenzoate

[0554]

[0555] Methyl 3-methoxy-4-methylbenzoate (5 g, 27.74 mmol) was mixed with 40 mL of acetic acid and 40 mL of water, and bromine (1.5 mL, 30.52 mmol) was added dropwise. After the addition was complete, the mixture was refluxed at 60 °C for 1 hour. After the reaction was complete, it was cooled to room temperature and aqueous sodium bicarbonate solution was added dropwise. The aqueous solution was extracted three times with a hexane / ether (8:3) solution, and the organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain 6.92 g of the title compound in a yield of 96%.

[0556] 1 H-NMR (300 MHz, CDCl3): δ7.39 (s, 1H), 7.26 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 2.21 (s, 3H).

[0557]

[0558] [Step 2] Preparation of methyl 2-bromo-4-(bromomethyl)-5-methoxybenzoate

[0559]

[0560] Methyl 2-bromo-5-methoxy-methylbenzoate (6.92 g, 26.70 mmol), N-bromosuccinimide (4.28 g, 24.60 mmol), and azobicisobutyronitrile (853 mg, 5.19 mmol) obtained in the above [Step-1] were dissolved in 130 mL of chloroform and stirred under reflux at 70 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and aqueous sodium bicarbonate solution was added dropwise. The mixture was extracted three times with ethyl acetate, and the 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 obtained residue 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 in 66% yield.

[0561] 1 H-NMR (300 MHz, CDCl3): δ7.59 (s, 1H), 7.30 (s, 1H), 4.45 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H).

[0562]

[0563] [Step-3] Preparation of methyl 2-bromo-5-methoxy-4-(morpholinomethyl)benzoate

[0564]

[0565] 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 the above [Step-2] were dissolved in 20 mL of acetonitrile and stirred at room temperature for 18 hours. After the reaction was completed, it was cooled to room temperature and an aqueous sodium bicarbonate solution was added dropwise. After the mixture was extracted three 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 obtained residue was purified by MPLC (ethyl acetate: hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 1.0 g of the title compound in a yield of 82%.

[0566] 1 H-NMR (300 MHz, CDCl3): δ7.68 (s, 1H), 7.28 (s, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.73 (m, 4H), 3.51 (m, 2H), 2.49 (m, 4H).

[0567]

[0568] [Step-4] Preparation of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinomethyl)benzoate

[0569]

[0570] 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), Pd2(dba)3dba (266 mg, 0.29 mmol), and cesium carbonate (2.83 g, 8.71 mmol) obtained in the above [Step-3] were dissolved in 25 mL of 1,4-dioxane and stirred at 110 °C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through a filter filled with Celite, and washed with ethyl acetate. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 953 mg of the title compound in 86% yield.

[0571] 1 H-NMR (300 MHz, CDCl3): δ8.39 (s, 1H), 7.41 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H), 3.73 (m, 4H), 3.56 (s, 2H), 2.51 (m, 4H), 1.52 (s, 9H).

[0572]

[0573] [Step 5] Preparation of 6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-ol

[0574]

[0575] Methyl 2-((tert-butoxycarbonyl)amino)-5-methoxy-4-(morpholinomethyl)benzoate (950 mg, 2.49 mmol) obtained in the above [Step-4] was dissolved in 10 mL of acetonitrile, and 10 mL of 4N hydrogen chloride dioxane solution was added dropwise. The mixture was stirred under reflux at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to obtain 680 mg of the title compound in a 94% yield.

[0576] 1 H-NMR (300 MHz, CD3OD): δ7.70 (s, 1H), 7.59 (s, 1H), 3.95 (s, 3H), 3.73 (m, 4H), 3.67 (s, 2H), 2.55 (m, 4H), 2.43 (s, 3H).

[0577]

[0578] [Step-6] Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine

[0579]

[0580] 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 the above [Step-5] were dissolved in 3 mL of acetonitrile and stirred at 80 °C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 23:1 (v / v)) to obtain 14 mg of the title compound in a yield of 8%.

[0581] 1 H-NMR (300 MHz, DMSO-d6): δ8.11 (d, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 6.85 (m, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 3.92 (s, 3H), 3.61 (m, 4H), 3.57(s, 2H), 2.44 (m, 4H), 2.36 (s, 3H), 1.56 (d, 3H)

[0582] MS (ESI+, m / z): 476.2 [M+H] +

[0583]

[0584] Example 35: (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine

[0585]

[0586] The procedure of Example 39 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (125 mg, 0.51 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 39 [Step-6], to obtain 9 mg of the title compound in a 5% yield.

[0587] 1 H-NMR (300 MHz, DMSO-d6): δ8.11 (d, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.06 (t, 1H), 6.74 (m, 1H), 6.58 (m, 1H), 5.72 (m, 3H), 5.16 (s, 2H), 3.94 (s, 3H), 3.60 (m, 4H), 3.56 (s, 2H), 2.42 (m, 4H), 2.31 (s, 3H), 1.55 (d, 3H)

[0588] MS (ESI+, m / z): 476.2 [M+H] +

[0589]

[0590] Example 36: (R)-N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine

[0591]

[0592] [Step 1] Preparation of methyl 4-hydroxy-5-methoxy-2-nitrobenzoate

[0593]

[0594] 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 under hydrogen gas for 20 hours. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with methanol. The filtered organic layer was concentrated under reduced pressure, and the obtained residue was purified by MPLC (ethyl acetate:hexane = 1:5 (v / v) to 1:1 (v / v)) to obtain 7 g of the title compound in a 96% yield.

[0595] 1 H-NMR (300 MHz, CD3OD): δ7.29 (s, 1H), 6.24 (s, 1H), 6.84 (m, 1H), 4.87 (bs, 2H), 3.91 (s, 3H), 3.81 (s, 3H).

[0596]

[0597] [Step 2] Preparation of 7-hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one

[0598]

[0599] Methyl 4-hydroxy-5-methoxy-2-mitrobenzoate (7.0 g, 35.5 mmol) obtained in the above [Step-1] was dissolved in a 4N dioxane hydrogen chloride solution (71 mL, 284 mmol) and acetonitrile (20 mL, 355 mmol), and the mixture was refluxed and stirred at 70°C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, 30 mL of dichloromethane was added, and the mixture was stirred for 0.5 hours to obtain a solid product. The obtained solid was filtered under reduced pressure and dried in an oven dryer at 55°C to obtain 9 g of the title compound in a yield of 82%.

[0600] 1H-NMR (300 MHz, DMSO-d6): δ11.2 (s, 1H), 9.38 (s, 1H), 8.24 (s, 1H), 7.49 (s, 1H), 6.86 (s, 1H), 3.85 (s, 3H), 3.79 (s, 3H).

[0601]

[0602] [Step-3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4(1H)-one

[0603]

[0604] 7-Hydroxy-6-methoxy-2-methylquinazolin-4(1H)-one (1.8 g, 8.7 mmol) obtained in the above [Step-2] was dissolved in 20 mL of DMF, and tetrahydro-2H-pyran-4-yl methanesulfonate (1.7 g, 9.5 mmol) and cesium carbonate (3.4 g, 10.4 mmol) were added. The mixture was stirred at 100°C for 15 hours. After completion of the reaction, water was added, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 10 mL of acetone was added, stirred, and the precipitated crystals were filtered to obtain 250 mg of the title compound in a 10% yield.

[0605] 1 H-NMR (300 MHz, CD3OD): δ7.84 (s, 1H), 7.58 (s, 1H), 4.77 (m, 1H), 4.13 (m, 2H), 3.96 (s, 3H), 3.64 (m, 2H), 2.44 (s, 3H), 2.22 (m, 2H), 2.09 (m, 2H).

[0606]

[0607] [Step-4] Preparation of 4-chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline

[0608]

[0609] 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] was dissolved in 14 mL of phosphoryl chloride and refluxed at 110°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was used in the next step without further purification.

[0610]

[0611] [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

[0612]

[0613] 4-Chloro-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline (100 mg, 0.33 mmol) prepared in the above [Step-4] was dissolved in 1 mL of DMF, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (92 mg, 0.36 mmol) and DIPEA (0.17 mL, 0.97 mmol) were added, and the mixture was stirred at 100 °C for 13 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 23:1 (v / v)) to obtain 21 mg of the title compound in a 13% yield.

[0614] 1H-NMR (300 MHz, CD3OD): δ7.67 (s, 1H), 7.06 (s, 1H), 6.99 (m, 2H), 6.82 (s, 1H), 5.64 (m, 1H), 4.74 (m, 1H), 4.12 (m, 5H), 3.66 (m, 2H), 2.46 (s, 3H), 2.16 (m, 2H), 1.86 (m, 2H), 1.67 (d, 3H).

[0615] MS (ESI+, m / z): 477.2 [M+H] +

[0616]

[0617] 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

[0618]

[0619] The procedure of Example 44 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline (69 mg, 0.28 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 44 [Step-5], to obtain 5.7 mg of the title compound in a yield of 4.6%.

[0620] 1 H-NMR (300 MHz, CD3OD): δ7.73 (s, 1H), 7.09 (s, 1H), 6.79 (m, 3H), 5.81 (m, 1H), 4.59 (m, 1H), 3.99 (m, 5H), 3.66 (m, 2H), 2.42 (s, 3H), 2.17 (m, 2H), 1.73 (m, 2H), 1.62 (d, 3H).

[0621] MS (ESI+, m / z): 477.2 [M+H] +

[0622]

[0623] 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

[0624]

[0625] The procedure of 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 the above Example 44 [Step-3], to obtain 15 mg of the title compound in a yield of 3.5%.

[0626] 1 H-NMR (300 MHz, CD3OD): δ7.46 (s, 1H), 7.00 (s, 3H), 6.83 (s, 1H), 5.67 (q, 1H), 4.08~4.10 (m, 7H), 3.73 (m, 2H), 3.50 (t, 2h\H), 2.54 (s, 3H), 1.89(m, 2H), 1.68(d, 3H), 1.57(m, 2H).

[0627] MS (ESI+, m / z): 491.2 [M+H] +

[0628]

[0629] Example 39: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine

[0630]

[0631] The procedure of 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 the above Example 44 [Step-3], to obtain 20 mg of the title compound in a 15% yield.

[0632] 1H-NMR (300 MHz, DMSO-d6): δ8.00 (d, 1H), 7.71 (s, 1H), 7.10 (s, 1H), 6.89 (d, 2H), 6.70 (s, 1H), 5.59 (m, 3H), 4.76 (m, 2H), 4.47 (m, 2H), 4.34 (m, 2H), 3.90 (s, 3H), 3.50 (m, 1H), 2.36 (s, 3H), 1.57 (d, 3H).

[0633] MS (ESI+, m / z): 463.2 [M+H] +

[0634]

[0635] Example 40: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0636]

[0637] [Step 1] Preparation of 2-bromo-5-nitroterephthalic acid

[0638]

[0639] 2-Bromoterephthalic acid (75 g, 306.12 mmol) was dissolved in 490 mL of sulfuric acid, and 98 mL of nitric acid was slowly added dropwise at 0°C. After the addition was complete, the mixture was refluxed and stirred at room temperature for 17 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water and stirred at room temperature for 1 hour. After stirring, the mixture was filtered under reduced pressure, and the obtained solid was washed with distilled water to obtain 61 g of the title compound in a 69% yield.

[0640] 1 H-NMR (300 MHz, DMSO-d6): δ8.34 (s, 1H), 8.17 (s, 1H).

[0641]

[0642] [Step 2] Preparation of dimethyl 2-bromo-5-nitroterephthalate

[0643]

[0644] 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 at 0°C. After the addition was complete, the mixture was stirred under reflux at 90°C for 17 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. Then, 600 mL of distilled water was added dropwise at 0°C and stirred at room temperature for 0.5 hours. After stirring, the mixture was filtered under reduced pressure to obtain 61 g of the title compound in a yield of 91%.

[0645] 1 H-NMR (300 MHz, DMSO-d6): δ8.47 (s, 1H), 8.28 (s, 1H), 3.93-3.89 (m, 6H).

[0646]

[0647] [Step 3] Preparation of dimethyl 2-(methylamino)-5-nitroterephthalate

[0648]

[0649] Dimethyl 2-bromo-5-nitroterephthalate (60 g, 188.63 mmol), methylamine hydrochloride (63.6 g, 941.94 mmol), and DIPEA (492 mL, 2829.48 mmol) prepared in the above [Step-2] were dissolved in 900 mL of DMF and stirred under reflux at 100 °C for 1 hour. After completion of the reaction, the solution was cooled to 0 °C, 1.8 L of distilled water was added dropwise, and the mixture was 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 in a 96% yield.

[0650] 1 H-NMR (300 MHz, DMSO-d6): δ8.59 (s, 2H), 6.95 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.01-2.99 (d, 3H).

[0651]

[0652] [Step 4] Preparation of dimethyl 2-amino-5-(methylamino) terephthalate

[0653]

[0654] Dimethyl 2-(methylamino)-5-nitroterephthalate (45.5 g, 169.63 mmol) and zinc dust (39.4 g, 593.71 mmol) obtained in the above [Step-3] were dissolved in 460 mL of dioxane:distilled water (4:1) and stirred under reflux at room temperature for 0.5 h. After stirring, the reaction solution was cooled to 0 °C and ammonium chloride (45.4 g, 848.76 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred under reflux at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. The obtained organic layer was added dropwise with distilled water (1:1 vol / vol), extracted three times with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, the organic layer was 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 31 g of the title compound in a 77% yield.

[0655] 1 H-NMR (300 MHz, DMSO-d6): δ7.39 (s, 1H), 7.02 (s, 1H), 6.55 (m, 1H), 5.88 (s, 2H), 3.83-3.81 (m, 6H), 2.78-2.76 (d, 3H).

[0656]

[0657] [Step 5] Preparation of methyl 4-hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate

[0658]

[0659] Dimethyl 2-amino-5-(methylamino) terephthalate (31 g, 130.12 mmol) and acetonitrile (68 mL, 1301.20 mmol) obtained in the above [Step-4] were dissolved in 260 mL of 4N hydrochloric acid dissolved in dioxane, and the mixture was refluxed at 90 °C for 3 hours using a sealed tube. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with hexane. The filtered solid was neutralized with aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to obtain 30 g of the title compound in a yield of 93.2%.

[0660] 1 H-NMR (300 MHz, DMSO-d6): δ12.03 (m, 1H), 8.02 (s, 1H), 7.41 (m, 1H), 7.16 (s, 1H), 3.87 (s, 3H), 2.91 (d, 3H), 2.28 (s, 3H).

[0661]

[0662] [Step-6] Preparation of methyl 4-chloro-2-methyl-6-(methylamino)quinazoline-7-carboxylate

[0663]

[0664] Methyl 4-hydroxy-2-methyl-6-(methylamino)quinazoline-7-carboxylate (6.1 g, 24.69 mmol) obtained in the above [Step-5] was dissolved in 150 mL of phosphoryl chloride and stirred under reflux at 120 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane and neutralized with sodium bicarbonate aqueous solution at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, the organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: ethyl acetate = 45:55 (v / v)) to obtain 1.6 g of the title compound in a yield of 24%.

[0665] 1 H-NMR (300 MHz, DMSO-d6): δ8.36 (s, 1H), 7.57 (m, 1H), 6.92 (s, 1H), 3.93 (s, 3H), 2.94 (d, 3H), 2.66 (s, 3H).

[0666]

[0667] [Step 7] Preparation of methyl (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylate

[0668]

[0669] Methyl 4-chloro-2-methyl-6-(methylamino)quinazoline-7-carboxylate (600 mg, 2.26 mmol) prepared in the above [Step-6], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (705 mg, 2.93 mmol) synthesized by the method presented in WO2018115380, and DIPEA (1.21 mL, 6.78 mmol) were dissolved in 30 mL of DMF, and the mixture was stirred under reflux at 90 °C for 13 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 23:1 (v / v)) to obtain 280 mg of the title compound in 29% yield.

[0670] 1 H-NMR (300 MHz, CDCl3): δ8.46 (s, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 6.83 (s, 1H), 6.47 (s, 1H), 5.62 (m, 1H), 3.93 (s, 3H), 2.93 (s, 3H), 2.55 (s, 3H).

[0671]

[0672] [Step 8] (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0673]

[0674] (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylate (280 mg, 0.64 mmol) obtained in the above [Step-7] was dissolved in 20 mL of tetrahydrofuran:methanol:water = 2:1:1, sodium hydroxide (129 mg. 3.23 mmol) was added, and the mixture was refluxed and stirred at room temperature for 2 hours. After the reaction was completed, 2 N HCl aqueous solution was added dropwise to adjust the pH to 5-6, and then washed with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to synthesize (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazoline-7-carboxylic acid without any additional purification. The obtained title compound was dissolved in 5 mL of DMF with morpholine (0.62 mL, 0.72 mmol), HATU (272 mg, 0.18 mmol), and DIPEA (0.26 mL, 1.43 mmol), and the mixture was refluxed at room temperature for 2.5 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 20:1 (v / v)) to obtain 30 mg of the title compound in a 20% yield.

[0675] 1 H-NMR (300 MHz, CD3OD): δ7.38 (s, 1H), 7.28 (s, 1H), 6.99 (m, 2H), 6.82 (s, 1H), 5.67 (m, 1H), 3.73 (m, 8H), 2.96 (s, 3H), 2.46 (s, 3H), 1.67 (d,J= 7.2 Hz, 3H).

[0676] MS (ESI+, m / z): 489.2 [M+H] +

[0677]

[0678] Example 41: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0679]

[0680] The procedure of Example 49 was repeated except that dimethylamine hydrochloride (2.3 g, 28 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 40 mg of the title compound in a yield of 12%.

[0681] 1 H-NMR (300 MHz, DMSO-d6): δ7.77 (d, 1H), 7.38 (s, 1H), 6.90 (d, 2H), 6.74 (s, 1H), 5.68 (m, 3H), 3.77 (m, 6H), 3.11 (m, 2H), 2.87 (d, 6H), 2.47 (s, 3H), 1.63 (m, 3H).

[0682] MS (ESI+, m / z): 503.2 [M+H] +

[0683]

[0684] Example 42: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone

[0685]

[0686] The procedure of Example 49 was repeated except that pyrrolidine (2.0 g, 28 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 60 mg of the title compound in a 19% yield.

[0687] 1 H-NMR (300 MHz, DMSO-d6): δ8.17 (d, 1H), 7.34 (m, 2H), 6.90 (d, 2H), 6.70 (s, 1H), 5.65 (m, 3H), 3.76 (m, 6H), 3.28 (m, 6H), 2.35 (d, 3H), 1.98 (m, 4H), 1.58 (m, 3H).

[0688] MS (ESI+, m / z): 529.3 [M+H] +

[0689]

[0690] Example 43: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0691]

[0692] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], to obtain 24 mg of the title compound in a yield of 38%.

[0693] 1 H-NMR (300 MHz, CD3OD): δ7.38 (s, 1H), 7.32 (s, 1H), 7.09 (m, 2H), 5.78 (m, 1H), 3.67 (m, 8H), 2.98 (s, 3H), 2.42 (s, 3H), 1.67 (d,J= 7.2 Hz, 3H).

[0694] MS (ESI+, m / z): 489.2 [M+H] +

[0695]

[0696] Example 44: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0697]

[0698] The procedure of Example 49 was repeated except that 2-methoxyethane-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 12 mg of the title compound in 11% yield.

[0699] 1 H-NMR (300 MHz, CD3OD): δ7.39 (m, 2H), 6.99 (m, 1H), 6.83 (s, 1H), 5.65 (m, 1H), 3.76 (m, 8H), 3.68 (m, 4H), 3.66 (s, 3H), 2.52 (s, 3H), 1.66 (d,J= 6.9 Hz, 3H)

[0700] MS (ESI+, m / z): 533.2 [M+H] +

[0701]

[0702] Example 45: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0703]

[0704] The procedure of Example 49 was repeated except that cyclopentanamine (4.7 g, 47.2 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 22 mg of the title compound in a 6% yield.

[0705] 1H-NMR (300 MHz, CD3OD): δ7.44 (s, 1H), 7.38 (s, 1H), 6.99 (m, 2H), 6.84 (m, 1H), 5.73 (m, 1H), 4.08 (m, 1H), 3.67 (m, 8H), 2.52 (s, 3H), 1.81 (m, 4H), 1.73 (m, 3H), 1.53 (m, 4H).

[0706] MS (ESI+, m / z): 543.2 [M+H] +

[0707]

[0708] Example 46: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0709]

[0710] The procedure of Example 49 was repeated except that 2.0 M ethylamine (23 mL, 47 mmol) dissolved in tetrahydrofuran was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 120 mg of the title compound in a yield of 53%.

[0711] 1 H-NMR (300 MHz, DMSO-d6): δ8.74 (s, 1H), 7.37 (d, 2H), 6.89 (d, 2H), 6.73 (s, 1H), 5.76 (m, 4H), 3.65 (m, 6H), 3.33 (m, 4H), 2.43 (s, 3H), 1.62 (d, 3H), 1.26 (m, 3H).

[0712] MS (ESI+, m / z): 503.2 [M+H] +

[0713]

[0714] Example 47: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0715]

[0716] The procedure of Example 49 was repeated except that isopropylamine (3.86 mL, 47.1 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 3 mg of the title compound in a 1% yield.

[0717] 1 H-NMR (300 MHz, CD3OD): δ7.36 (m, 2H), 6.98 (m, 2H), 6.80 (s, 1H), 5.64 (m, 1H), 3.92 (m, 1H), 3.69 (m, 8H), 2.42 (s, 3H), 1.64 (d, 3H), 1.27 (m, 6H).

[0718] MS (ESI+, m / z): 517.2 [M+H] +

[0719]

[0720] Example 48: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone

[0721]

[0722] The procedure of Example 49 was repeated except that 4-aminotetrahydropyran hydrochloride (3.89 g, 28.29 mmol) was used instead of methylamine hydrochloride in the above Example 49 [Step-3], to obtain 130 mg of the title compound in a yield of 56%.

[0723] 1H-NMR (300 MHz, DMSO-d6): δ7.42 (s, 1H), 7.34 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 5.68 (p, 1H), 5.57(br, 2H), 5.15(d, 1H), 3.90 (d, 2H), 3.82-3.48 (br, 10H), 2.41 (s, 3H), 1.92(d, 2H), 1.62 (d, 3H), 1.57-1.48(m, 2H).

[0724] MS (ESI+, m / z): 559.2 [M+H] +

[0725]

[0726] Example 49: (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine

[0727]

[0728] [Step-1] Preparation of ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate

[0729]

[0730] Methyl 2-amino-4-methylbenzoate (6.2 g, 34.5 mmol), di-tert-butyl dicarbonate (20 mL, 86.2 mmol), triethylamine (12 mL, 86.2 mmol), and 4-dimethylaminopyridine (4.2 g, 34.5 mmol) were dissolved in 100 mL of tetrahydrofuran and refluxed at room temperature for 15 hours. After the reaction was completed, water was added dropwise, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1 (v / v)) to obtain 4.7 g of the title compound in a 49% yield.

[0731] 1H-NMR (300 MHz, CDCl3): δ10.35 (s, 1H), 8.30 (s, 1H), 7.93 (d, 1H), 6.84 (m, 1H), 4.41 (m, 2H), 2.40 (s, 3H), 1.55 (s, 9H), 1.44 (m, 3H).

[0732]

[0733] [Step 2] Preparation of ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate

[0734]

[0735] Ethyl 2-(tert-butoxycarbonyl)amino)-4-methylbenzoate (4.7 g, 16.8 mmol), N-bromosuccinimide (3.0 g, 16.8 mmol), and azobicisobutyronitrile (0.55 g, 3.3 mmol) prepared in the above [Step-1] were dissolved in 100 mL of chloroform and stirred under reflux 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, which was then carried out to the next reaction without further purification.

[0736]

[0737] [Step-3] Preparation of ethyl 2-((tert-butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate

[0738]

[0739] Ethyl 4-(bromomethyl)-2-((tert-butoxycarbonyl)amino)benzoate (4.3 g, 11.9 mmol), morpholine (2.0 mL, 23.8 mmol), and potassium carbonate (6.6 g, 47.6 mmol) prepared in the above [Step-2] were dissolved in 40 mL of acetonitrile and stirred under reflux at room temperature for 1 hour. After the reaction was completed, water was added dropwise, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: ethyl acetate = 5:1 (v / v)) to obtain 2.1 g of the title compound in a yield of 34%.

[0740] 1 H-NMR (300 MHz, CDCl3): δ10.34 (s, 1H), 8.39 (d, 1H), 8.00 (d, 1H), 7.08 (m, 1H), 4.42 (m, 2H), 3.75 (m, 4H), 3.54 (m, 2H), 2.49 (m, 4H), 1.55 (s, 9H), 1.45 (m, 3H).

[0741]

[0742] [Step-4] Preparation of 2-methyl-7-(morpholinomethyl)quinazolin-4-ol

[0743]

[0744] Ethyl 2-((tert-butoxycarbonyl)amino)-4-(morpholinomethyl)benzoate (2.1 g, 5.73 mmol) prepared in the above [Step-3] and acetonitrile (21 mL, 402.5 mmol) were dissolved in 21 mL of 4N hydrochloric acid dissolved in dioxane, and the mixture was refluxed and stirred at 90 °C for 3 hours using a sealed tube. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and washed with hexane. The filtered solid was neutralized with aqueous sodium bicarbonate solution, filtered under reduced pressure, and washed with distilled water to obtain 1.2 g of the title compound in a yield of 81%.

[0745] 1 H-NMR (300 MHz, DMSO-d6): δ12.17 (m, 1H), 8.04 (d, 1H), 7.49 (s, 1H), 7.42 (m, 1H), 3.61 (m, 6H), 2.52 (m, 4H), 2.39 (m, 3H).

[0746]

[0747] [Step 5] Preparation of 2-methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol

[0748]

[0749] 2-Methyl-7-(morpholinomethyl)quinazolin-4-ol (1.2 g, 4.62 mmol) obtained in the above [Step-4] was dissolved in 12 mL of sulfuric acid, and 2.4 mL of nitric acid was slowly added dropwise at 0 °C. The mixture was stirred under reflux at 70 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane and neutralized with sodium hydroxide aqueous solution at low temperature. The organic layer was washed with distilled water and dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, and the organic layer was concentrated under reduced pressure to obtain 1.2 g of the title compound in an 85% yield.

[0750] 1 H-NMR (300 MHz, DMSO-d6): δ12.57 (m, 1H), 8.49 (s, 1H), 7.79 (s, 1H), 3.86 (s, 2H), 3.55 (m, 4H), 2.52 (m, 3H), 2.39 (m, 4H).

[0751]

[0752] [Step-6] Preparation of 6-amino-2-methyl-7-(morpholinomethyl)quinazolin-4-ol

[0753]

[0754] 2-Methyl-7-(morpholinomethyl)-6-nitroquinazolin-4-ol (450 mg, 1.47 mmol) and zinc dust (340 mg, 5.14 mmol) obtained in the above [Step-5] were dissolved in 5 mL of dioxane:distilled water (4:1) and refluxed at room temperature for 0.5 h. After stirring, the reaction solution was cooled to 0 °C and ammonium chloride (400 mg, 7.35 mmol) was slowly added dropwise. After the addition was completed, the mixture was refluxed and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with ethyl acetate. Distilled water was added to the obtained organic layer (1:1 (v / v)), extracted three times with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered under reduced pressure, the organic layer was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (dichloromethane: methanol = 10:1 (v / v)) to obtain 330 mg of the title compound in 81% yield.

[0755] 1 H-NMR (300 MHz, DMSO-d6): δ11.76 (m, 1H), 7.26 (d, 2H), 5.62 (s, 2H), 3.60 (m, 6H), 2.38 (m, 4H), 2.26 (s, 3H).

[0756]

[0757] [Step-7] Preparation of 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-ol

[0758]

[0759] 6-Amino-2-methyl-7-(morpholinomethyl)quinazolin-4-ol (155 mg, 0.56 mmol), methyl iodide (70 mg, 0.50 mmol), and calcium carbonate (84 mg, 0.84 mmol) obtained in the above [Step-6] were dissolved in 2 mL of dimethylformamide and stirred under reflux at 50 °C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 13:1 (v / v)) to obtain 30 mg of the title compound in an 18% yield.

[0760] 1 H-NMR (300 MHz, CDCl3): δ9.75 (s, 1H), 7.38 (s, 1H), 7.27 (s, 1H), 6.41 (d, 1H), 3.73 (m, 6H), 2.98 (d, 3H), 2.50 (s, 3H), 2.47 (m, 4H).

[0761]

[0762] [Step-8] Preparation of 2-methyl-6-(methylamino)-7-(morpholinomethyl)quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate

[0763]

[0764] 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 the above [Step-7] were dissolved in 2 mL of dichloromethane and stirred under reflux at room temperature for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 15:1 (v / v)) to obtain 25 mg of the title compound in a yield of 43%.

[0765]

[0766] [Step-9] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 Preparation of ,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine

[0767]

[0768] 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 the above [Step-8] were dissolved in 2 mL of DMF, and the mixture was stirred under reflux at 90 °C for 22 hours. After the reaction was completed, water was added dropwise. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 15:1 (v / v)) to obtain 3 mg of the title compound in a 14% yield.

[0769] 1 H-NMR (300 MHz, CDCl3): δ7.52 (s, 1H), 7.11 (s, 1H), 7.00 (m, 1H), 6.82 (s, 1H), 6.49 (m, 2H), 5.71 (m, 1H), 3.89 (s, 2H), 3.71 (m, 6H), 2.97 (s, 3H), 2.59 (s, 3H), 2.44 (m, 4H), 1.71 (d, 3H).

[0770] MS (ESI+, m / z): 475.2 [M+H] +

[0771]

[0772] Example 50: (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0773]

[0774] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-4-fluoro-5-(trifluoromethyl)aniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], to obtain 23 mg of the title compound in a 15% yield.

[0775] 1 H-NMR (300 MHz, CD3OD): δ 7.38 (s, 1H), 7.32 (s, 1H), 7.09 (m, 2H), 6.95 (m, 1H), 6.81 (m, 1H), 5.75 (m, 1H), 3.68 (m, 8H), 2.98 (s, 3H), 2.41 (s, 3H), 1.68 (d, J = 6.9 Hz, 3H).

[0776] MS (ESI+, m / z): 507.2 [M+H] +

[0777]

[0778] Example 51: (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0779]

[0780] The 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 the above Example 49 [Step-7], to obtain 70 mg of the title compound in a yield of 41%.

[0781] 1 H-NMR (300 MHz, DMSO-d6): δ 9.15 (d, 1H), 7.34 (d, 2H), 7.03-6.66 (m, 3H), 6.62 (s, 1H), 5.81 (d, 1H), 5.73 (m, 1H), 5.45 (d, 2H), 3.68-3.51(m, 6H), 3.32(s, 2H), 2.88 (d, 3H), 2.48 (s, 3H), 1.62 (d, 3H).

[0782] MS (ESI+, m / z): 471.2 [M+H] +

[0783]

[0784] Example 52: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0785]

[0786] The procedure of Example 49 was repeated except that 2.0 M ethylamine (23 mL, 47 mmol) dissolved in tetrahydrofuran was used instead of methylamine hydrochloride in Example 49 [Step-3] and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (230 mg, 0.96 mmol) in Example 49 [Step-7], to obtain 55 mg of the title compound in a yield of 41%.

[0787] 1H-NMR (300 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.41 (d, 2H), 7.27-6.90 (m, 1H), 6.76 (d, 1H), 6.63 (m, 1H), 5.81 (m, 1H), 5.36 (s, 1H), 5.27 (d, 2H), 3.64(s, 6H), 3.32(m, 4H), 2.37 (s, 3H), 1.60 (d, 3H), 1.28 (m, 3H).

[0788] MS (ESI+, m / z): 503.2 [M+H] +

[0789]

[0790] Example 53: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone

[0791]

[0792] The procedure of Example 49 was repeated except that thiazolidine (24 mg, 0.26 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 16 mg of the title compound in a 14% yield.

[0793] 1 H-NMR (300 MHz, DMSO-d6): δ8.10 (d, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 6.90 (d, 2H), 6.70 (s, 1H), 5.61-5.53 (m, 4H), 4.55 (m, 2H), 3.72 (m, 2H), 3.04 (m, 2H), 2.87 (m, 3H), 2.34 (s, 3H), 1.58 (d, 3H).

[0794] MS (ESI+, m / z): 491.2 [M+H] +

[0795]

[0796] Example 54: (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0797]

[0798] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(furan-3-yl)aniline hydrochloride (233 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], to obtain 15 mg of the title compound in a yield of 32%.

[0799] 1 H-NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 6.75 (s, 1H), 6.72 (s, 1H), 5.67 (m, 1H), 3.66 (m, 8H), 2.96 (s, 3H), 2.46 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H).

[0800] MS (ESI+, m / z): 487.2 [M+H] +

[0801]

[0802] Example 55: (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone

[0803]

[0804] The procedure of Example 49 was repeated except that isopropylamine (2.7 mL, 31.4 mmol) was used instead of methylamine hydrochloride in [Step-3] of the above Example 49 and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (224 mg, 0.92 mmol) in [Step-7], to obtain 20 mg of the title compound in a yield of 23%.

[0805] 1 H-NMR (300 MHz, DMSO-d6): δ 8.03 (d, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.07 (t, 1H), 6.73 (m, 1H), 6.58 (m, 1H), 5.71 (m, 1H), 5.17 (s, 2H), 4.80 (m, 1H), 3.94 (m, 1H), 3.72 (m, 8H), 2.28 (s, 3H), 1.55 (d, 3H), 1.23 (m, 6H).

[0806] MS (ESI+, m / z): 517.2 [M+H] +

[0807]

[0808] Example 56: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone

[0809]

[0810] The procedure of Example 49 was repeated except that 2-methoxyethane-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Example 49 [Step-3] and (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in [Step-7], to obtain 35 mg of the title compound in a yield of 30%.

[0811] 1 H-NMR (300 MHz, DMSO-d6): δ 8.06 (d, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 7.07 (t, 1H), 6.74 (m, 1H), 6.59 (m, 1H), 5.72 (m, 1H), 5.21 (m, 3H), 3.60 (m, 8H), 3.42 (m, 4H), 3.31 (s, 3H), 2.29 (s, 3H), 1.55 (d, 3H).

[0812] MS (ESI+, m / z): 533.2 [M+H] +

[0813]

[0814] Example 57: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone

[0815]

[0816] The procedure of Example 49 was repeated except that 1-methylpiperazine (0.03 mL, 0.25 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 20 mg of the title compound in a 16% yield.

[0817] 1H-NMR (300 MHz, DMSO-d6): δ 8.32 (s, 1H), 7.26 (d, 2H), 6.90 (d, 2H), 6.71 (s, 1H), 5.64-5.46 (m, 4H), 3.74 (m, 4H), 2.87 (d, 3H), 2.38-2.26 (m, 10H), 1.60 (d, 3H).

[0818] MS (ESI+, m / z): 502.2 [M+H] +

[0819]

[0820] 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

[0821]

[0822]

[0823]

[0824] The procedure of Example 49 was repeated except that hexahydro-1H-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in Example 49 [Step-8], to obtain 38 mg of the title compound in a yield of 31%.

[0825] 1 H-NMR (300 MHz, DMSO-d6): δ 9.12 (m, 1H), 7.36 (d, 2H), 6.90 (d, 2H), 6.74 (s, 1H), 5.88-5.60 (m, 4H), 3.80-3.45 (m, 8H), 2.92 (m, 5H), 2.48 (s, 3H), 1.60 (d, 3H).

[0826] MS (ESI+, m / z): 515.2 [M+H] +

[0827]

[0828] Example 59: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0829]

[0830] The procedure of Example 49 was repeated except that thiomorpholino 1,1-dioxide (35 mg, 0.26 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 5 mg of the title compound in a 4% yield.

[0831] 1 H-NMR (300 MHz, CD3OD): δ 7.42 (s, 1H), 7.27 (s, 1H), 6.99 (m, 2H), 6.80 (m, 1H), 5.64 (m, 1H), 3.22 (m, 8H), 2.94 (s, 3H), 2.44 (s, 3H), 1.65 (d, 3H).

[0832] MS (ESI+, m / z): 537.2 [M+H] +

[0833]

[0834] Example 60: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone

[0835]

[0836] The procedure of Example 49 was repeated except that thiomorpholine (0.03 mL, 0.26 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 22 mg of the title compound in 18% yield.

[0837] 1H-NMR (300 MHz, DMSO-d6): δ8.07 (d, 1H), 7.25 (s, 1H), 7.19 (s, 1H), 6.90 (d, 2H), 6.70 (s, 1H), 5.60-5.53 (m, 3H), 5.36 (m, 1H), 3.89 (m, 2H), 3.50 (m, 2H), 2.85 (m, 3H), 2.73 (m, 2H), 2.53 (m, 2H), 2.34 (s, 3H), 1.55 (d, 3H).

[0838] MS (ESI+, m / z): 505.2 [M+H] +

[0839]

[0840] Example 61: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone

[0841]

[0842] The procedure of Example 49 was repeated except that piperazine (100 mg, 0.50 mmol) was used instead of morpholine in Example 49 [Step-8], to obtain 30 mg of the title compound in a yield of 13%.

[0843] 1 H-NMR (300 MHz, DMSO-d6): δ8.06 (d, 1H), 7.21 (d, 2H), 6.90 (d, 2H), 6.70 (s, 1H), 5.64-5.33 (m, 4H), 3.61 (m, 2H), 3.18 (m, 2H), 2.86 (d, 3H), 2.78-2.55 (m, 4H), 2.34 (s, 3H), 1.58(d, 3H).

[0844] MS (ESI+, m / z): 488.2 [M+H] +

[0845]

[0846] Example 62: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone

[0847]

[0848] The procedure of Example 49 was repeated except that azetidine hydrochloride (24 mg, 0.26 mmol) was used instead of morpholine in the above Example 49 [Step-8], to obtain 12 mg of the title compound in 11% yield.

[0849] 1 H-NMR (300 MHz, DMSO-d6): δ8.16 (m, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.88 (m, 2H), 6.69 (s, 1H), 6.35 (m, 1H), 5.56 (m, 3H), 4.12 (m, 2H), 4.04 (m, 2H) 2.87 (m, 3H), 2.34 (s, 3H), 2.22 (m, 2H), 1.56 (d, 3H).

[0850] MS (ESI+, m / z): 459.2 [M+H] +

[0851]

[0852] 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

[0853]

[0854] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (230 mg, 0.96 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7] and that hexahydro-1H-furo[3,4-c]pyrrole (30 mg, 0.25 mmol) was used instead of morpholine in the above Example 49 [Step-8], thereby obtaining 40 mg of the title compound in a yield of 32%.

[0855] 1 H-NMR (300 MHz, DMSO-d6): δ9.56 (m, 1H), 7.44 (d, 2H), 7.27-6.91 (m, 1H), 6.80 (d, 1H), 6.67 (m, 1H), 6.06-5.32 (m, 4H), 3.80-3.43 (m, 8H), 2.91 (m, 5H), 2.50 (s, 3H), 1.65 (d, 3H).

[0856] MS (ESI+, m / z): 515.2 [M+H] +

[0857]

[0858] Example 64: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0859]

[0860] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7] and that thiomorpholino 1,1-dioxide (35 mg, 0.26 mmol) was used instead of morpholine in [Step-8], thereby obtaining 8 mg of the title compound in a 6% yield.

[0861] 1 H-NMR (300 MHz, DMSO-d6): δ8.09 (m, 1H), 7.41 (s, 1H), 7.26 (t, 1H), 6.75 (m, 2H), 6.59 (m, 1H), 5.72 (m, 1H), 5.19 (m, 2H), 4.07 (m, 2H), 3.58 (m, 2H), 3.31 (m, 2H), 3.19 (m, 2H), 2.87 (m, 3H), 2.29 (s, 3H), 1.55 (d, 3H).

[0862] MS (ESI+, m / z): 537.2 [M+H] +

[0863]

[0864] Example 65: (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone

[0865]

[0866] The procedure of Example 49 was repeated except that (R)-3-(1-aminoethyl)-5-methylaniline hydrochloride (165 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride in the above Example 49 [Step-7], to obtain 3.5 mg of the title compound in a 10% yield.

[0867] 1 H-NMR (300 MHz, CD3OD): δ 7.37 (s, 1H), 7.28 (s, 1H), 6.66 (m, 2H), 6.47 (s, 1H), 5.65 (m, 1H), 3.98 (m, 8H), 2.96 (s, 3H), 2.48 (s, 3H), 2.24 (s, 3H), 1.66 (s, 3H).

[0868] MS (ESI+, m / z): 435.2 [M+H] +

[0869]

[0870] 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

[0871]

[0872] The procedure of Example 49 was repeated except that 2-methoxyethylamine (4.1 mL, 47.15 mmol) was used instead of methylamine hydrochloride in Example 49 [Step-3], (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (190 mg, 0.76 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride in Example 49 [Step-7], and hexahydro-1H-furo[3,4-c]pyrrole (22 mg, 0.18 mmol) was used instead of morpholine in Example 49 [Step-8], to obtain 40 mg of the title compound in a yield of 36%.

[0873] 1 H-NMR (300 MHz, DMSO-d6): δ8.63 (m, 1H), 7.46 (d, 2H), 7.09-6.91 (m, 1H), 6.76 (d, 1H), 6.63 (m, 1H), 5.78-5.24 (m, 4H), 4.11-3.32 (m, 15H), 2.91 (m, 2H), 2.37 (s, 3H), 1.60 (d, 3H).

[0874] MS (ESI+, m / z): 559.2 [M+H] +

[0875]

[0876] Example 67: (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0877]

[0878] The procedure of Example 49 was repeated except that 2-methoxyethane-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in [Step-3] of the above Example 49, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline hydrochloride (235 mg, 0.98 mmol) was used instead of (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline hydrochloride in [Step-7], and thiomorpholino 1,1-dioxide (29 mg, 0.21 mmol) was used instead of morpholine in [Step-8], to obtain 2 mg of the title compound in a yield of 2%.

[0879] 1 H-NMR (300 MHz, CD3OD): δ 7.40 (s, 1H), 7.38 (s, 1H), 6.88 (t, 1H), 6.85 (m, 1H), 6.77 (m, 1H), 5.77 (m, 1H), 4.59 (m, 4H), 3.69 (m, 6H), 3.48 (m, 2H), 3.42 (s, 3H), 2.39 (s, 3H), 1.65 (d, 3H).

[0880] MS (ESI+, m / z): 581.2 [M+H] +

[0881]

[0882] Example 68: (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone

[0883]

[0884] The procedure of Example 49 was repeated except that 2-methoxyethane-1-amine (3.5 g, 47.2 mmol) was used instead of methylamine hydrochloride in Example 49 [Step-3] and thiomorpholino 1,1-dioxide (55 mg, 0.40 mmol) was used instead of morpholine in [Step-8], to obtain 18 mg of the title compound in 8% yield.

[0885] 1 H-NMR (300 MHz, DMSO-d6): δ8.07 (m, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.87 (m, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 5.31 (m, 1H), 3.59 (m, 2H), 3.41 (m, 4H), 3.29 (m, 9H), 2.33 (s, 3H), 1.55 (d, 3H).

[0886] MS (ESI+, m / z): 581.2 [M+H] +

[0887]

[0888] 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

[0889]

[0890] [Step-1] Preparation of methyl 5-methoxy-2-nitro-4((tetrahydro-2H-pyran-4-yl)amino) benzoate

[0891]

[0892] Methyl-bromo-5-methoxy-2-nitrobenzoate (800 mg, 2.75 mmol), 4-aminotetrahydropyran hydrochloride (455 mg, 3.30 mmol), Pd2(OAc)2 (43 mg, 0.19 mmol), (±) BINAP (120 mg, 0.19 mmol), and cesium carbonate (3.14 g, 9.64 mmol) were dissolved in 16 mL of 1,4-dioxane and stirred at 100 °C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate: hexane = 1:1 (v / v)) to obtain 970 mg of the title compound in a yield of 91%.

[0893] 1 H-NMR (300 MHz, CDCl3): δ7.07 (s, 1H), 6.89 (s, 1H), 4.69 (m, 1H), 4.01 (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.54 (m, 2H), 2.03 (m, 2H), 1.54 (m, 2H).

[0894]

[0895] [Step-2] Preparation of methyl 2-amino-5-methoxy-4((tetrahydro-2H-pyran-4-yl) amino) benzoate

[0896]

[0897] Methyl 5-methoxy-2-nitro-4((tetrahydro-2H-pyran-4-yl)amino) benzoate (970 mg, 3.12 mmol) and iron (715 mg, 10.94 mmol) obtained in the above [Step-1] were dissolved in 10 mL of 1,4-dioxane:distilled water (4:1) and the mixture was cooled to 0°C. Ammonium chloride (836 mg, 15.62 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was filtered through a filter filled with Celite and washed with dichloromethane. Water was added dropwise to the filtrate, which was then extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by MPLC (ethyl acetate:hexane = 1:1 (v / v)) to obtain 850 mg of the title compound in 97% yield.

[0898] 1 H-NMR (300 MHz, CDCl3): δ6.88 (s, 1H), 5.53 (s, 1H), 5.24 (s, 2H), 3.35 (m, 1H), 3.72 (m, 2H), 3.54 (m, 6H), 3.26 (m, 2H), 1.74 (m, 2H), 1.26 (m, 2H).

[0899]

[0900] [Step-3] Preparation of 6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol

[0901]

[0902] Methyl 2-amino-5-methoxy-4((tetrahydro-2H-pyran-4-yl)amino)benzoate (850 mg, 3.03 mmol) obtained in the above [Step-2] was dissolved in 3 mL of acetonitrile, and 6 mL of a 4N hydrochloric acid solution dissolved in dioxane was added dropwise. The mixture was stirred under reflux at 80°C for 2 hours. After the reaction was completed, it was cooled to room temperature and neutralized by dropwise addition of an aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was solidified with ethyl acetate and filtered under reduced pressure. The filtered solid was dried to obtain 830 mg of the title compound in a 95% yield.

[0903] 1 H-NMR (300 MHz, DMSO-d6): δ7.23 (s, 1H), 6.62 (s, 1H), 5.52 (m, 1H), 3.85 (m, 5H), 3.63 (m, 1H), 3.49 (m, 1H), 2.25 (s, 3H), 1.89 (m, 2H), 1.54 (m, 2H).

[0904]

[0905] [Step-4] Preparation of 4-chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl)quinazolin-7-amine

[0906]

[0907] 6-Methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-4-ol (200 mg, 0.69 mmol) obtained in the above [Step-3] was dissolved in 2 mL of phosphoryl chloride and refluxed at 100 °C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and neutralized by dropwise addition of aqueous sodium bicarbonate solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then subjected to the next step without further purification.

[0908]

[0909] [Step-5] (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 Preparation of -(tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine

[0910]

[0911] 4-Chloro-6-methoxy-2-methyl-N-(tetrahydro-2H-pyran-4-yl) quinazolin-7-amine (130 mg, 0.42 mmol) prepared in the above [Step-4] was dissolved in 2 mL of DMF, (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline (163 mg, 0.67 mmol) and DIPEA (0.23 mL, 1.26 mmol) were added, and the mixture was stirred at 90 °C for 13 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added dropwise, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane: methanol = 23:1 (v / v)) to obtain 2 mg of the title compound in a 1% yield.

[0912] 1 H-NMR (300 MHz, CD3OD): δ7.52 (s, 1H), 6.96 (m, 2H), 6.80 (m, 1H), 6.61 (s, 1H), 5.63 (m, 1H), 3.98 (m, 5H), 3.68 (m, 1H), 3.58 (m, 2H), 2.44 (s, 3H), 2.04 (m, 2H), 1.67 (m, 5H).

[0913] MS (ESI+, m / z): 476.2 [M+H] +

[0914]

[0915] Compound number Structure name MS [M+H] + 1 H-NMR spectrum (300 MHz) 1 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 490.2 1 H-NMR (300 MHz, DMSO-d6): δ8.29 (d, 1H), 7.85 (s, 1H), 7.40 (s, 1H), 6.90 (d, 2H), 6.71 (s, 1H), 5.62 (m, 1H), 5.57 (s, 2H), 3.94 (s, 3H), 3.50 (m, 4H), 3.37 (m, 2H), 3.11 (m, 2H), 2.50 (s, 3H), 1.58 (m, 3H).2 (6-Methoxy-2-methyl-4-((1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone 532.2 1 H-NMR (300 MHz, DMSO-d6): δ8.45 (m, 1H), 7.81 (s, 1H), 7.48 (m, 3H), 7.29 (m, 4H), 6.00 (m, 1H), 4.09 (m, 3H), 3.65 (m, 4H), 3.58 (m, 2H), 3.50 (m, 2H), 3.11 (m, 2H), 2.51 (m, 3H), 2.23 (s, 3H), 1.94 (m, 1H), 1.71 (m, 3H).3 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)((3R, 5S)-3,5-dimethylpiperazin-1-yl)methanone 517.3 1 H-NMR (300 MHz, DMSO-d6): δ8.28 (d, 1H), 7.84 (m, 1H), 7.36 (d, 1H), 6.93 (m, 2H), 6.72 (s, 1H), 5.62 (m, 3H), 4.41 (m, 1H), 3.92 (s, 3H), 3.07 (m, 1H), 2.68 (m, 3H), 2.40 (d, 3H), 2.28 (m, 3H), 1.60 (m, 3H), 1.03 (d, 3H), 0.82 (m, 3H).4 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiomorpholino)methanone 506.2 1 H-NMR (300 MHz, DMSO-d6): δ8.27 (d, 1H), 7.85 (d, 1H), 7.41 (s, 1H), 6.88 (m, 2H), 6.71 (s, 1H), 5.59 (m, 3H), 3.88 (m, 5H), 3.36 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.38 (s, 3H), 1.58 (m, 3H).5 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone 516.2 1 H-NMR (300 MHz, CD3OD): δ7.82 (s, 1H), 7.52 (s, 1H), 7.00 (m, 2H), 6.83 (s, 1H), 5.66 (m, 1H), 4.02 (s, 3H), 3.94 (m, 2H), 3.84 (m, 2H), 3.66 (m, 2H), 3.18 (m, 4H), 2.49 (s, 3H), 1.67 (d,J= 6.9 Hz, 3H).6 (R)-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 475.2 1 H-NMR (300 MHz, DMSO-d6): δ8.40 (m, 1H), 7.89 (s, 1H), 7.68 (m, 1H), 7.66 (m, 1H), 7.50 (s, 1H), 7.40-7.06 (m, 2H), 5.82 (m, 1H), 3.97 (s, 3H), 3.50 (m, 4H), 3.42 (m, 2H), 3.29 (m, 2H), 2.33 (s, 3H), 1.64 (m, 3H).7 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(azetidin-1-yl)methanone 460.2 1 H-NMR (300 MHz, DMSO-d6): δ8.28 (d, 1H), 7.83 (s, 1H), 7.43 (s, 1H), 6.90 (d, 2H), 6.71 (s, 1H), 5.64 (m, 3H), 4.06 (m, 2H), 3.95 (s, 3H), 3.88 (m, 2H), 2.42 (s, 3H), 2.28 (m, 2H), 1.59 (d, 3H).8 (6-Methoxy-2-methyl-4-((1-(4-(1,2,3,4-tetrahydroisoquinolin-8-yl)thiophen-2-yl)ethyl)amino)quinazolin-7-yl)(morpholino)methanone 544.2 1 H-NMR (300 MHz, CD3OD): δ7.77 (s, 1H), 7.54 (s, 1H), 7.13 (m, 5H), 6.00 (m, 1H), 4.13 (s, 3H), 3.82 (m, 4H), 3.61 (m, 2H), 3.32 (m, 2H), 3.13 (m, 2H), 2.87 (m, 4H), 2.57 (s, 3H), 1.83 (m, 3H).9 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(piperazin-1-yl)methanone 489.2 1 H-NMR (300 MHz, CD3OD): δ8.09 (s, 1H), 7.61 (s, 1H), 6.98 (m, 2H), 6.84 (s, 2H), 5.79 (m, 1H), 4.06 (m, 5H), 3.54 (m, 2H), 3.34 (m, 2H), 3.20 (m, 2H), 2.65 (s, 3H), 1.74 (d, 3H).10 (R)-2,2,2-Trifluoro-N-(3-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenylacetamide 586.2 1H-NMR (300 MHz, CD3OD): δ8.11-8.08 (d, 1H), 7.91-7.88 (d, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 5.74 (m, 1H), 4.86 (s, 6H), 4.03 (s, 3H), 3.79 (m, 4H), 3.63 (m, 2H), 3.32 (m, 2H), 2.47 (s, 3H), 1.76 (d, 3H).11 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(3-fluoroazetidin-1-yl)methanone 478.2 1 H-NMR (300 MHz, CD3OD): δ8.03 (s, 1H), 7.64 (s, 1H), 7.00 (m, 2H), 6.85 (s, 1H), 5.78 (m, 1H), 5.34 (m, 1H), 4.51 (m, 1H), 4.28 (m, 3H), 4.08 (s, 3H), 2.63 (s, 3H), 1.74 (d, 3H).12 (4-((1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methoxyquinazolin-7-yl)(morpholino)methanone 546.2 1 H-NMR (300 MHz, CD3OD): δ7.77 (s, 1H), 7.49 (m, 2H), 7.39 (m, 3H), 7.26 (s, 1H), 7.17 (s, 1H), 6.09 (m, 1H), 3.97 (m, 5H), 3.77 (m, 4H), 3.62 (m, 2H), 3.26 (m, 2H), 2.55 (s, 3H), 2.38 (s, 6H), 1.84 (d, 3H).13 (4-((1-(4-(2-((aminomethyl)phenyl)thiophen-2-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 518.2 1H-NMR (300 MHz, CD3OD): δ7.78 (s, 1H), 7.52 (m, 2H), 7.30 (m, 5H), 6.10 (m, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.76 (m, 4H), 3.62 (m, 2H), 3.26 (m, 2H), 2.56 (s, 3H), 1.82 (d, 3H).14 (4-((1-(4-(2-((hydroxymethyl)phenyl)thiophen-2-yl) ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 519.2 1 H-NMR (300 MHz, CD3OD): δ7.76 (s, 1H), 7.51 (m, 2H), 7.31 (m, 5H), 6.10 (m, 1H), 4.57 (s, 2H), 3.98 (s, 3H), 3.76 (m, 4H), 3.60 (m, 2H), 3.27 (m, 2H), 2.55 (s, 3H), 1.24 (d, 3H).15 (R)-(6-methoxy-2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino) quinazolin-7-yl)(morpholino)methanone 475.2 1 H-NMR (300 MHz, DMSO-d6): δ8.38 (d, 1H), 7.85 (s, 2H), 7.78 (d, 1H), 7.60 (d, 2H), 7.41 (s, 1H), 5.74 (m, 1H), 3.96 (s, 3H), 3.65 (m, 4H), 3.49 (m, 2H), 3.12 (m, 2H), 2.37 (s, 3H), 1.67 (m, 3H).16 (R)-(4-((1-(5-amino-2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 504.2 1H-NMR (300 MHz, DMSO-d6): δ8.36 (d, 1H), 7.91 (s, 1H), 7.39 (s, 1H), 6.92 (d, 2H), 6.79 (s, 1H), 5.68 (m, 1H), 5.25 (s, 2H), 3.96 (s, 3H), 3.65 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 2.38 (d, 6H), 1.55 (m, 3H).17 (R)-(4-((1-(3-amino-5-(fluorophenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 440.2 1 H-NMR (300 MHz, CD3OD): δ8.00 (s, 1H), 7.53 (s, 1H), 6.58 (s, 1H), 6.44 (m, 1H), 6.31 (m, 1H), 5.73 (m, 1H), 4.04 (s, 3H), 3.76 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.61 (s, 3H), 1.69 (d, 3H).18 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone 538.1 1 H-NMR (300 MHz, CD3OD): δ7.85 (s, 1H), 7.58 (s, 1H), 7.01 (m, 2H), 6.83 (s, 1H), 5.67 (m, 1H), 4.26 (m, 2H), 4.03 (s, 3H), 3.68 (m, 2H), 3.24 (m, 2H), 3.13 (m, 2H), 2.50 (s, 3H), 1.67 (d,J= 6.9 Hz, 3H).19 (R)-(4-((1-(3-amino-2-methoxyphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 452.2 1H-NMR (300 MHz, DMSO-d6): δ8.24 (m, 1H), 7.92 (s, 1H), 7.38 (s, 1H), 6.78 (m, 1H), 6.67 (m, 1H), 6.57 (m, 1H), 5.92 (m, 1H), 4.92 (m, 2H), 3.97 (s, 3H), 3.90 (d, 3H), 3.65 (m, 4H), 3.51 (m, 2H), 3.13 (m, 2H), 2.34 (s, 3H), 1.52 (m, 3H).20 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(thiazolidin-3-yl)methanone 492.2 1 H-NMR (300 MHz, DMSO-d6): δ8.31 (d, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 6.90 (d, 2H), 6.72 (s, 1H), 5.63 (m, 3H), 4.64 (s, 1H), 4.22 (s, 1H), 3.95 (s, 3H), 3.86 (m, 1H), 3.45 (m, 1H), 3.12 (m, 1H), 2.99 (m, 1H), 2.39 (s, 3H), 1.60 (d, 3H).21 (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 436.2 1 H-NMR (300 MHz, DMSO-d6): δ8.20 (m, 1H), 7.87 (s, 1H), 7.39 (s, 1H), 6.63 (m, 2H), 6.48 (m, 1H), 5.60 (m, 1H), 4.92 (m, 2H), 3.94 (d, 3H), 3.65 (s, 4H), 3.54 (m, 2H), 3.12 (m, 2H), 2.40 (d, 3H), 2.20 (d, 3H), 1.55 (m, 3H).22 (R)-3-amino-5-(1-((6-methoxy-2-methyl-7-(morpholine-4-carbonyl)quinazolin-4-yl)amino)ethyl)benzonitrile 447.2 1H-NMR (300 MHz, CD3OD): δ7.80 (s, 1H), 7.49 (s, 1H), 7.02 (m, 2H), 6.80 (s, 1H), 5.58 (m, 1H), 4.01 (s, 3H), 3.76 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.47 (s, 3H), 1.64 (d, 3H)23 (R)-(4-((1-(2,3-dihydro-1H-indene-4-yl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 447.2 1 H-NMR (300 MHz, DMSO-d6): δ8.29 (m, 1H), 7.86 (s, 1H), 7.37 (s, 1H), 7.27 (m, 1H), 7.09 (s, 1H), 5.63 (m, 1H), 3.95 (s, 3H), 3.64 (m, 4H), 3.48 (m, 2H), 3.32 (m, 2H), 2.95 (m, 2H), 2.36 (s, 3H), 2.09 (m, 2H), 1.58 (m, 3H)24 (R)-(4-((1-(3-amino-5-cyclopropylphenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 462.2 1 H-NMR (300 MHz, DMSO-d6): δ8.18 (d, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 6.41 (s, 2H), 6.10 (s, 1H), 5.55 (m, 1H), 4.89 (s, 2H), 3.95 (s, 3H), 3.65 (m, 4H), 3.50 (m, 2H), 3.38 (m, 2H), 3.11 (s, 2H), 2.39 (s, 3H), 1.83 (m, 1H), 1.53 (m, 3H), 0.83 (m, 2H), 0.55 (m, 2H)25 (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 508.1 1H-NMR (300 MHz, CD3OD): δ7.84 (m, 1H), 7.47 (s, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 5.72 (m, 1H), 4.00 (s, 3H), 3.78 (m, 4H), 3.57 (m, 2H), 3.22 (m, 2H), 2.39 (m, 3H), 1.64 (d,J= 7.4 Hz, 3H).26 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-methoxy 2-methylquinazolin-7-yl)(morpholino)methanone 490.2 1 H-NMR (300 MHz, DMSO-d6): δ8.30 (m, 1H), 7.92 (s, 1H), 7.41 (s, 1H), 7.09 (m, 1H), 6.79 (d, 1H), 6.63 (m, 1H), 5.78 (m, 1H), 5.20 (s, 2H), 3.97 (s, 3H), 3.66 (s, 4H), 3.54 (m, 2H), 3.13 (m, 2H), 2.35 (s, 3H), 1.60 (m, 3H).27 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-7-yl)(morpholino)methanone 546.2 1 H-NMR (300 MHz, CD3OD): δ7.79 (m, 1H), 7.58 (s, 1H), 7.52 (s, 1H), 7.01 (m, 1H), 6.83 (s, 1H), 5.67 (m, 1H), 5.25 (m, 1H), 3.94 (m, 4H), 3.81 (m, 4H), 3.62 (m, 2H), 3.34 (m, 2H), 2.49 (s, 3H), 2.38 (m, 2H), 1.68 (d,J= 5.4 Hz, 3H).28 (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 488.2 1H-NMR (300 MHz, CD3OD): δ8.04 (s, 1H), 7.80 (s, 1H), 7.51 (m, 2H), 6.97 (s, 1H), 6.83 (s, 1H), 6.74 (m, 2H), 5.80 (m, 1H), 4.04 (s, 3H), 3.78 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.64 (s, 3H), 1.75 (d, 3H)29 (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 472.2 1 H-NMR (300 MHz, CD3OD): δ7.82 (s, 1H), 7.49 (s, 1H), 6.91 (s, 2H), 6.58 (s, 1H), 6.39 (m, 1H), 5.68 (m, 1H), 4.00 (s, 3H), 3.76 (m, 4H), 3.60 (m, 2H), 3.27 (m, 2H), 2.49 (s, 3H), 1.67 (d, 3H)30 (R)-(4-((1-(3-amino-5-(thiazol-5-yl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 505.2 1 H-NMR (300 MHz, CD3OD): δ8.89 (s, 1H), 8.06 (d, 1H), 7.81 (s, 1H), 7.49 (s, 1H), 7.06 (s, 1H), 6.87 (s, 1H), 6.84 (m, 1H), 5.65 (m, 1H), 4.00 (s, 3H), 3.78 (m, 4H), 3.61 (m, 2H), 3.27 (m, 2H), 2.48 (s, 3H), 1.69 (d, 3H)31 (R)-(4-((1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-6-methoxy-2-methylquinazolin-7-yl)(morpholino)methanone 518.2 1H-NMR (300 MHz, CD3OD): δ7.82 (d, 1H), 7.51 (s, 1H), 6.98 (d, 2H), 6.71 (s, 1H), 5.68 (m, 1H), 4.02 (s, 3H), 3.77 (m, 4H), 3.63 (m, 2H), 3.35 (m, 2H), 3.28 (m, 2H), 2.49 (s, 3H), 1.68 (d,J= 6.9 Hz, 3H), 1.25 (m, 3H).32 Methyl (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(2-methoxyethoxy)-2-methylquinazolin-7-yl)(morpholino)methanone 534.2 1 H-NMR (300 MHz, DMSO-d6): δ8.31 (m, 1H), 7.86 (s, 1H), 7.41 (s, 1H), 6.89 (m, 2H), 6.71 (s, 1H), 5.57 (m, 3H), 4.28 (m, 2H), 3.94-3.50 (m, 8H), 3.37 (m, 3H), 3.16 (m, 2H), 2.39 (s, 3H), 1.59 (m, 3H).33 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(fluoromethyl)-6-methoxyquinazolin-7-yl)(morpholino)methanone 508.2 1 H-NMR (300 MHz, CD3OD): δ7.92 (s, 1H), 7.68 (s, 1H), 7.00 (m, 2H), 6.83 (s, 1H), 5.68 (m, 1H), 5.51 (m, 1H), 5.39 (m, 1H), 4.01 (s, 3H), 3.79 (m, 4H), 3.63 (m, 2H), 3.23 (m, 2H), 1.69 (d,J= 7.2 Hz, 3H).34 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine 476.2 1H-NMR (300 MHz, DMSO-d6): δ8.11 (d, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 6.85 (m, 2H), 6.69 (s, 1H), 5.57 (m, 3H), 3.92 (s, 3H), 3.61 (m, 4H), 3.57(s, 2H), 2.44 (m, 4H), 2.36 (s, 3H), 1.56 (d, 3H)35 (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-(morpholinomethyl)quinazolin-4-amine 476.2 1 H-NMR (300 MHz, DMSO-d6): δ8.11 (d, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.06 (t, 1H), 6.74 (m, 1H), 6.58 (m, 1H), 5.72 (m, 3H), 5.16 (s, 2H), 3.94 (s, 3H), 3.60 (m, 4H), 3.56 (s, 2H), 2.42 (m, 4H), 2.31 (s, 3H), 1.55 (d, 3H)36 (R)-N-(1-(3-amino-5-trifluoromethylphenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine 477.2 1 H-NMR (300 MHz, CD3OD): δ7.67 (s, 1H), 7.06 (s, 1H), 6.99 (m, 2H), 6.82 (s, 1H), 5.64 (m, 1H), 4.74 (m, 1H), 4.12 (m, 5H), 3.66 (m, 2H), 2.46 (s, 3H), 2.16 (m, 2H), 1.86 (m, 2H), 1.67 (d, 3H)37 (R)-N-(1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-4-amine 477.2 1H-NMR (300 MHz, CD3OD): δ7.73 (s, 1H), 7.09 (s, 1H), 6.79 (m, 3H), 5.81 (m, 1H), 4.59 (m, 1H), 3.99 (m, 5H), 3.66 (m, 2H), 2.42 (s, 3H), 2.17 (m, 2H), 1.73 (m, 2H), 1.62 (d, 3H)38 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)quinazolin-4-amine 491.2 1 H-NMR (300 MHz, CD3OD): δ7.46 (s, 1H), 7.00 (s, 3H), 6.83 (s, 1H), 5.67 (q, 1H), 4.08~4.10 (m, 7H), 3.73 (m, 2H), 3.50 (t, 2h\H), 2.54 (s, 3H), 1.89(m, 2H), 1.68(d, 3H), 1.57(m, 2H)39 (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-7-(oxetan-3-ylmethoxy)quinazolin-4-amine 463.2 1 H-NMR (300 MHz, DMSO-d6): δ8.00 (d, 1H), 7.71 (s, 1H), 7.10 (s, 1H), 6.89 (d, 2H), 6.70 (s, 1H), 5.59 (m, 3H), 4.76 (m, 2H), 4.47 (m, 2H), 4.34 (m, 2H), 3.90 (s, 3H), 3.50 (m, 1H), 2.36 (s, 3H), 1.57 (d, 3H)40 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 489.2 [M+H] + 1H-NMR (300 MHz, CD3OD): δ7.38 (s, 1H), 7.28 (s, 1H), 6.99 (m, 2H), 6.82 (s, 1H), 5.67 (m, 1H), 3.73 (m, 8H), 2.96 (s, 3H), 2.46 (s, 3H), 1.67 (d,J= 7.2 Hz, 3H).41 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(dimethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone 503.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ7.77 (d, 1H), 7.38 (s, 1H), 6.90 (d, 2H), 6.74 (s, 1H), 5.68 (m, 3H), 3.77 (m, 6H), 3.11 (m, 2H), 2.87 (d, 6H), 2.47 (s, 3H), 1.63 (m, 3H).42 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(pyrrolidin-1-yl)quinazolin-7-yl)(morpholino)methanone 529.3 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.17 (d, 1H), 7.34 (m, 2H), 6.90 (d, 2H), 6.70 (s, 1H), 5.65 (m, 3H), 3.76 (m, 6H), 3.28 (m, 6H), 2.35 (d, 3H), 1.98 (m, 4H), 1.58 (m, 3H).43 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 489.2 [M+H] + 1H-NMR (300 MHz, CD3OD): δ7.38 (s, 1H), 7.32 (s, 1H), 7.09 (m, 2H), 5.78 (m, 1H), 3.67 (m, 8H), 2.98 (s, 3H), 2.42 (s, 3H), 1.67 (d,J= 7.2 Hz, 3H).44 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone 533.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ7.39 (m, 2H), 6.99 (m, 1H), 6.83 (s, 1H), 5.65 (m, 1H), 3.76 (m, 8H), 3.68 (m, 4H), 3.66 (s, 3H), 2.52 (s, 3H), 1.66 (d,J= 6.9 Hz, 3H).45 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(cyclopentylamino)-2-methylquinazolin-7-yl)(morpholino)methanone 543.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ7.44 (s, 1H), 7.38 (s, 1H), 6.99 (m, 2H), 6.84 (m, 1H), 5.73 (m, 1H), 4.08 (m, 1H), 3.67 (m, 8H), 2.52 (s, 3H), 1.81 (m, 4H), 1.73 (m, 3H), 1.53 (m, 4H).46 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone 503.2 [M+H] + 1H-NMR (300 MHz, DMSO-d6): δ8.74 (s, 1H), 7.37 (d, 2H), 6.89 (d, 2H), 6.73 (s, 1H), 5.76 (m, 4H), 3.65 (m, 6H), 3.33 (m, 4H), 2.43 (s, 3H), 1.62 (d, 3H), 1.26 (m, 3H).47 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-yl)(morpholino)methanone 517.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ7.36 (m, 2H), 6.98 (m, 2H), 6.80 (s, 1H), 5.64 (m, 1H), 3.92 (m, 1H), 3.69 (m, 8H), 2.42 (s, 3H), 1.64 (d, 3H), 1.27 (m, 6H).48 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)quinazolin-7-yl)(morpholino)methanone 559.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ7.42 (s, 1H), 7.34 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.42 (s, 1H), 5.68 (p, 1H), 5.57(br, 2H), 5.15(d, 1H), 3.90 (d, 2H), 3.82-3.48 (br, 10H), 2.41 (s, 3H), 1.92(d, 2H), 1.62 (d, 3H), 1.57-1.48(m, 2H).49 (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 ,2-dimethyl-7-(morpholinomethyl)quinazoline-4,6-diamine 475.2 [M+H] + 1H-NMR (300 MHz, CDCl3): δ7.52 (s, 1H), 7.11 (s, 1H), 7.00 (m, 1H), 6.82 (s, 1H), 6.49 (m, 2H), 5.71 (m, 1H), 3.89 (s, 2H), 3.71 (m, 6H), 2.97 (s, 3H), 2.59 (s, 3H), 2.44 (m, 4H), 1.71 (d, 3H).50 (R)-(4-((1-(5-amino-2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 507.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.38 (s, 1H), 7.32 (s, 1H), 7.09 (m, 2H), 6.95 (m, 1H), 6.81 (m, 1H), 5.75 (m, 1H), 3.68 (m, 8H), 2.98 (s, 3H), 2.41 (s, 3H), 1.68 (d, J = 6.9 Hz, 3H).51 (R)-(4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 471.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 9.15 (d, 1H), 7.34 (d, 2H), 7.03-6.66 (m, 3H), 6.62 (s, 1H), 5.81 (d, 1H), 5.73 (m, 1H), 5.45 (d, 2H), 3.68-3.51(m, 6H), 3.32(s, 2H), 2.88 (d, 3H), 2.48 (s, 3H), 1.62 (d, 3H).52 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(ethylamino)-2-methylquinazolin-7-yl)(morpholino)methanone 503.2 [M+H] + 1H-NMR (300 MHz, DMSO-d6): δ 8.53 (s, 1H), 7.41 (d, 2H), 7.27-6.90 (m, 1H), 6.76 (d, 1H), 6.63 (m, 1H), 5.81 (m, 1H), 5.36 (s, 1H), 5.27 (d, 2H), 3.64(s, 6H), 3.32(m, 4H), 2.37 (s, 3H), 1.60 (d, 3H), 1.28 (m, 3H).53 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiazolidin-3-yl)methanone 491.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.10 (d, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 6.90 (d, 2H), 6.70 (s, 1H), 5.61-5.53 (m, 4H), 4.55 (m, 2H), 3.72 (m, 2H), 3.04 (m, 2H), 2.87 (m, 3H), 2.34 (s, 3H), 1.58 (d, 3H).54 (R)-(4-((1-(3-amino-5-(furan-3-yl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 487.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.80 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 6.75 (s, 1H), 6.72 (s, 1H), 5.67 (m, 1H), 3.66 (m, 8H), 2.96 (s, 3H), 2.46 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H).55 (R)-4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(isopropylamino)-2-methylquinazolin-7-(yl)(morpholino)methanone 517.2 [M+H]+ 1 H-NMR (300 MHz, DMSO-d6): δ 8.03 (d, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 7.07 (t, 1H), 6.73 (m, 1H), 6.58 (m, 1H), 5.71 (m, 1H), 5.17 (s, 2H), 4.80 (m, 1H), 3.94 (m, 1H), 3.72 (m, 8H), 2.28 (s, 3H), 1.55 (d, 3H), 1.23 (m, 6H).56 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(morpholino)methanone 533.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 8.06 (d, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 7.07 (t, 1H), 6.74 (m, 1H), 6.59 (m, 1H), 5.72 (m, 1H), 5.21 (m, 3H), 3.60 (m, 8H), 3.42 (m, 4H), 3.31 (s, 3H), 2.29 (s, 3H), 1.55 (d, 3H).57 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(4-methylpiperazin-1-yl)methanone 502.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 8.32 (s, 1H), 7.26 (d, 2H), 6.90 (d, 2H), 6.71 (s, 1H), 5.64-5.46 (m, 4H), 3.74 (m, 4H), 2.87 (d, 3H), 2.38-2.26 (m, 10H), 1.60 (d, 3H).58 (4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone 515.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ 9.12 (m, 1H), 7.36 (d, 2H), 6.90 (d, 2H), 6.74 (s, 1H), 5.88-5.60 (m, 4H), 3.80-3.45 (m, 8H), 2.92 (m, 5H), 2.48 (s, 3H), 1.60 (d, 3H).59 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone 537.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.42 (s, 1H), 7.27 (s, 1H), 6.99 (m, 2H), 6.80 (m, 1H), 5.64 (m, 1H), 3.22 (m, 8H), 2.94 (s, 3H), 2.44 (s, 3H), 1.65 (d, 3H).60 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(thiomorpholino)methanone 505.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.07 (d, 1H), 7.25 (s, 1H), 7.19 (s, 1H), 6.90 (d, 2H), 6.70 (s, 1H), 5.60-5.53 (m, 3H), 5.36 (m, 1H), 3.89 (m, 2H), 3.50 (m, 2H), 2.85 (m, 3H), 2.73 (m, 2H), 2.53 (m, 2H), 2.34 (s, 3H), 1.55 (d, 3H).61 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(piperazin-1-yl)methanone 488.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.06 (d, 1H), 7.21 (d, 2H), 6.90 (d, 2H), 6.70 (s, 1H), 5.64-5.33 (m, 4H), 3.61 (m, 2H), 3.18 (m, 2H), 2.86 (d, 3H), 2.78-2.55 (m, 4H), 2.34 (s, 3H), 1.58(d, 3H).62 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(azetidin-1-yl)methanone 459.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.16 (m, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.88 (m, 2H), 6.69 (s, 1H), 6.35 (m, 1H), 5.56 (m, 3H), 4.12 (m, 2H), 4.04 (m, 2H) 2.87 (m, 3H), 2.34 (s, 3H), 2.22 (m, 2H), 1.56 (d, 3H).63 (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone 515.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ9.56 (m, 1H), 7.44 (d, 2H), 7.27-6.91 (m, 1H), 6.80 (d, 1H), 6.67 (m, 1H), 6.06-5.32 (m, 4H), 3.80-3.43 (m, 8H), 2.91 (m, 5H), 2.50 (s, 3H), 1.65 (d, 3H).64 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(1,1-dioxothiomorpholino)methanone 537.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.09 (m, 1H), 7.41 (s, 1H), 7.26 (t, 1H), 6.75 (m, 2H), 6.59 (m, 1H), 5.72 (m, 1H), 5.19 (m, 2H), 4.07 (m, 2H), 3.58 (m, 2H), 3.31 (m, 2H), 3.19 (m, 2H), 2.87 (m, 3H), 2.29 (s, 3H), 1.55 (d, 3H).65 (R)-(4-((1-(3-amino-5-methylphenyl)ethyl)amino)-2-methyl-6-(methylamino)quinazolin-7-yl)(morpholino)methanone 435.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.37 (s, 1H), 7.28 (s, 1H), 6.66 (m, 2H), 6.47 (s, 1H), 5.65 (m, 1H), 3.98 (m, 8H), 2.96 (s, 3H), 2.48 (s, 3H), 2.24 (s, 3H), 1.66 (s, 3H).66 (4-(((R)-1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone 559.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.63 (m, 1H), 7.46 (d, 2H), 7.09-6.91 (m, 1H), 6.76 (d, 1H), 6.63 (m, 1H), 5.78-5.24 (m, 4H), 4.11-3.32 (m, 15H), 2.91 (m, 2H), 2.37 (s, 3H), 1.60 (d, 3H).67 (R)-(4-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone 581.2 [M+H] + 1 H-NMR (300 MHz, CD3OD): δ 7.40 (s, 1H), 7.38 (s, 1H), 6.88 (t, 1H), 6.85 (m, 1H), 6.77 (m, 1H), 5.77 (m, 1H), 4.59 (m, 4H), 3.69 (m, 6H), 3.48 (m, 2H), 3.42 (s, 3H), 2.39 (s, 3H), 1.65 (d, 3H).68 (R)-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-methoxyethyl)amino)-2-methylquinazolin-7-yl)(1,1-dioxothiomorpholino)methanone 581.2 [M+H] + 1 H-NMR (300 MHz, DMSO-d6): δ8.07 (m, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 6.87 (m, 2H), 6.69 (s, 1H), 5.56 (m, 3H), 5.31 (m, 1H), 3.59 (m, 2H), 3.41 (m, 4H), 3.29 (m, 9H), 2.33 (s, 3H), 1.55 (d, 3H).69 (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-2-methyl-N 7 -(Tetrahydro-2H-pyran-4-yl)quinazoline-4,7-diamine 476.2 1 H-NMR (300 MHz, CD3OD): δ 7.52 (s, 1H), 6.96 (m, 2H), 6.80 (m, 1H), 6.61 (s, 1H), 5.63 (m, 1H), 3.98 (m, 5H), 3.68 (m, 1H), 3.58 (m, 2H), 2.44 (s, 3H), 2.04 (m, 2H), 1.67 (m, 5H).

[0916]

[0917] Experimental Example 1: Testing the GTP displacement inhibition ability of SOS1.

[0918] To confirm whether the aforementioned compounds inhibit the substitution function of SOS1 binding to KRAS G12C, a homogenous time-resolved fluorescence (HTRF) assay was performed using GST-KRAS G12C (#MSC-11-538) and SOS1-Strep (#MSC-11-502) purchased from Reaction Biology Corp. (USA, MA). The activity of the SOS1 enzyme was measured by measuring the amount of GTP bound to the KRAS G12C protein using the principle of time-resolved fluorescence energy transfer (TR-FRET). Based on the principle that Terbium bound to the antibody that binds to GST of the GST-KRAS G12C protein acts as a donor for fluorescence resonance energy transfer (FRET), and GTP bound to the KRAS G12C protein is labeled with the fluorescent agent DY-647P1 and acts as an acceptor for FRET, the more GTP is bound to the KRAS G12C protein by the substitution reaction of SOS1 according to this test, the higher the HTRF or FRET signal can be measured.

[0919] In brief, the glutathione S-transferase (GST)-tagged KRAS G12C protein (amino acid residues 2-169), streptavidin-tagged SOS1 protein (amino acid residues 564-1049, which is the catalytic domain), anti-GST antibody (#61GSTKLA) purchased from CISBIO, nucleic acid (#NU-820-647P1) purchased from Jena Bioscience, and compounds were mixed in a buffer solution composed of 10 mM HEPES pH7.4, 150 mM NaCl, 5 mM MgCl2, and 1 mM dithiothreitol (DTT), added to a 384-well plate, and after reaction at room temperature, the FRET signal was measured using a Perkin Elmer Envision microplate reader. At this time, the excitation signal was measured at 320 nm and the emission signal was measured at 615 / 665 nm. The fluorescence measurement value when the SOS1 protein was not included was calculated as the background signal value and was subtracted from all measured HTRF values, and the fluorescence measurement value when the synthesized compound was not included was measured as the non-inhibitory value (Control value) and this value was selected as the reference point of 100%. The fluorescence of the example compounds was measured at concentration values ​​of 1.6, 8, 40, 200, and 1,000 nM (5 points, 5-fold), and the 50% activity inhibition value (IC 50 ) was calculated using GraphPad Prism. The results of the inhibitory ability of the example compounds to inhibit KRAS G12C-SOS1 binding are shown in Table 2 below.

[0920] IC 50 If the value is 50 nM or less, it is indicated as +++, if it is more than 50 nM but less than 100 nM, it is indicated as ++, and if it is more than 100 nM, it is indicated as +.

[0921]

[0922] Synthetic compound IC 50 (nM) Synthetic compound IC 50 (nM) Synthetic compound IC 50 (nM) Example 1+++ Example 24++ Example 47++ Example 2++ Example 25++ Example 48+ Example 3+ Example 26++ Example 49++ Example 4++ Example 27++ Example 50+++ Example 5+ Example 28+++ Example 51+++ Example 6++ Example 29+++ Example 52++ Example 7+ Example 30++ Example 53++ Example 8+ Example 31++ Example 54++ Example 9+++ Example 32+ Example 55++ Example 10+ Example 33+ Example 56+++ Example 11+ Example 34+ Example 57++ Example 12++Example 35++Example 58++Example 13++Example 36++Example 59++Example 14+Example 37+Example 60++Example 15+Example 38+Example 61+++Example 16++Example 39+Example 62++Example 17+++Example 40+++Example 63+++Example 18+++Example 41++Example 64++Example 19+Example 42+Example 65++Example 20+++Example 43+++Example 66Example 21++Example 44++Example 67Example 22+Example 45++Example 68+++Example 23++Example 46++Example 69+

Claims

1. A compound selected from the compounds of the following chemical formula 1, pharmaceutically acceptable salts, optical isomers, diastereomers, hydrates and solvates thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is hydrogen or C 1-4 It is alkyl; R2 is hydrogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 2-6 Alkenyl or C 2-6 It is alkyne; R3 is R 3a or -L2- and; Each R 3a are independently halogen, hydroxy, cyano, amino, amine, nitro, oxo(=O), C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, Halo C 1-6 Alkyl, Amino C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy-C 1-4 Alkyl, -CF2H, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b And, R a class R b are each independently Hydrogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, -CF2H and C 3-8 Selected from the group consisting of carbocyclyl; r is an integer between 0 and 1; m is an integer from 0 to 5; L2 is a direct bond, -O-(CH2) p or -CH=CH-(CH2) q and; p is an integer from 0 to 3; q is an integer from 0 to 2; class are each independently C 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl, and at this time, C of 6-10 Aryl, C 4-10 Heteroaryl, C 3-10 Carbocyclyl, C 2-10 Heterocyclyl or C 9-12 Bicyclic heterocyclyl is unsubstituted or substituted with one or more R 3a can be replaced with; X1 is -O(R4) or -N(R5)(R6); R4 is hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 Bridged heterocyclyl, which is halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkyne, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR c R d , -C(O)OR c , -OR c or -NR c R d may be substituted or unsubstituted, where R c and R d are each independently hydrogen or C 1-6 It is alkyl; R5 and R6 is each independently hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16 Bridged carbocyclyl or C 6-14 It is a bridged heterocyclyl, and at this time, the above C 1-6 Alkyl, hydroxy C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 8-16 Spirocarbocyclyl, C 6-14 Heterospirocarbocyclyl, C 8-16 Fused carbocyclyl, C 6-14 Fused heterocyclyl, C 8-16Bridged carbocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR e R f , -C(O)OR e , -OR e and -NR e R f may be substituted with one or more functional groups selected from the group consisting of , where R e and R f are each independently hydrogen or C 1-6 It is alkyl, Or the above -N(R5)(R6) is R5 and C in which R6 is connected to each other to form a ring with the nitrogen atom in -N(R5)(R6) 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl, wherein the C 2-9 Heterocyclyl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl, C 6-14 Bridged heterocyclyl or C 4-10 Heteroaryl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), cyano, haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, -S(O)-C 1-4 Alkyl, -S(O)2-C1-4 Alkyl, -C(O)-NR g R h , -C(O)OR g , -OR g and -NR g R h may be substituted with one or more functional groups selected from the group consisting of , wherein R g class R h are each independently Hydrogen, C 1-6 Alkyl, hydroxy-C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, HaloC 1-6 Alkoxy or C 3-8 It is carbocyclyl; L1 is a direct bond, -C(O)-, -O- or -NH- and; n is an integer from 0 to 2; is C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 It is a bridged heterocyclyl, and at this time, the above C 3-10 Carbocyclyl, C 2-9 Heterocyclyl, C 6-10 Aryl, C 4-10 Heteroaryl, C 6-14 Heterospirocarbocyclyl, C 6-14 Fused heterocyclyl or C 6-14 Bridged heterocyclyl is unsubstituted or substituted with halogen, hydroxy, nitro, oxo (=O), haloC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, -S(O)-C 1-4Alkyl, -S(O)2-C 1-4 Alkyl, -C(O)-NR i R j , -C(O)OR i , -OR i and -NR i R j may be substituted with one or more functional groups selected from the group consisting of , wherein R i and R j are each independently hydrogen or C 1-6 It's alkyl.

2. In paragraph 1, class are each independently C 6-10 Aryl or C 4-10 A heteroaryl compound.

3. In paragraph 1, R 3a are each independently halogen, hydroxy, cyano, amino, amine, nitro, C 1-6 Alkyl, HaloC 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkoxy, -CF2H, C 6-10 Aryl, C 3-6 Cyclyl, -(CH2) r -C 2-6 Heterocyclyl, -(CH2) r -NH(CO)-R a or -(CH2) r -NR a R b And, here R a and R b are each independently hydrogen, C 1-6 A compound which is alkyl, -CF3 or -CF2H.

4. In paragraph 1, R4 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9is heterocyclyl; R5 and R6 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkyne, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 Heterocyclyl, or -N(R5)(R6) is C 2-9 A heterocyclyl compound.

5. In paragraph 1, The compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 2: [Chemical formula 2] In the above chemical formula 2, L1 is a direct bond, -C(O)-, -O- or -NH-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; R 4a is hydrogen, C 1-6 Alkyl, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl; is morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein morpholinyl, dioxothiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

6. In paragraph 1, The compound represented by the above chemical formula 1 is a compound represented by the following chemical formula 3: [Chemical Formula 3] In the above chemical formula 3, L3 is a direct bond or -C(O)-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; R 5a and R 5b are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Carbocyclyl or C 2-9 It is heterocyclyl, or the above -N(R 5a )(R 5b ) is R 5a Wow R 5b are connected to each other -N(R 5a )(R 5b ) forming a ring with the nitrogen atom in C 2-9 It is heterocyclyl; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl, wherein morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, hexahydro-1H-furo[3,4-c]pyrrolyl, oxetanyl or azetidinyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

7. In paragraph 5, The compound represented by the above chemical formula 2 is a compound represented by the following chemical formula 4: [Chemical Formula 4] In the above chemical formula 4, L4 is a direct bond, -C(O)- or -O-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; is morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl, wherein morpholinyl, piperazinyl, thiazolidinyl or tetrahydropyranyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

8. In paragraph 6, The compound represented by the above chemical formula 3 is a compound represented by the following chemical formula 5: [Chemical Formula 5] In the above chemical formula 5, L5 is a direct bond or -C(O)-; n is an integer from 0 to 2; Z1 and Z2 are each independently hydrogen, -F, -CF2H, -CF3, -CH3 or -NH2, excluding the case where both Z1 and Z2 are hydrogen; is morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl, wherein morpholinyl, dioxothiomorpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl or hexahydro-1H-furo[3,4-c]pyrrolyl is unsubstituted or may be substituted with one or more functional groups selected from the group consisting of halogen or -CH3.

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

10. A preventive or therapeutic pharmaceutical composition containing a compound described in any one of claims 1 to 9 or a pharmacologically acceptable salt thereof as an active ingredient.

11. In paragraph 10, The pharmaceutical composition is a pharmaceutical composition for use in treating cancer or tumors that can be treated by inhibiting the binding of SOS1 to RAS family proteins and / or RAC1.

12. A pharmaceutical preparation comprising the pharmaceutical composition of clause 10.

13. In paragraph 12, A pharmaceutical preparation characterized in that the pharmaceutical preparation is in the form of a tablet, pill, powder, capsule, syrup or emulsion.

14. In paragraph 12, A pharmaceutical preparation characterized in that the above pharmaceutical preparation additionally comprises at least one selected from the group consisting of pharmaceutically acceptable carriers, adjuvants and excipients.

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

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

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

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

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