Quinazoline derivatives, salts thereof and pharmaceutical compositions comprising them as active ingredients

Abstract

The present application relates to quinazoline derivatives, salts thereof, and pharmaceutical compositions comprising the same as an effective ingredient, which can exhibit a preventive or therapeutic effect on cancer by inhibiting MASTL activity, and in particular, can exhibit an effective anticancer effect in cancer in which MASTL is overexpressed, such as breast cancer.

Description

Technical Field

[0001] This invention relates to quinazoline derivatives, their salts, and pharmaceutical compositions containing them as active ingredients that inhibit MASTL activity. Background Technology

[0002] Compared to normal cells, cancer cells have problems regulating mitotic kinases or checkpoints, resulting in abnormal proliferation due to an inability to regulate the cell cycle. Therefore, targeting the cell cycle of cancer cells is becoming a strategy for anti-cancer therapy. However, mitotic inhibitors can cause side effects when they also affect the mitosis of normal cells, making it particularly important to target factors overexpressed in cancer cells.

[0003] Microtubule-associated serine / threonine kinase-like (MASTL), also known as Greatwall kinase (GWL), belongs to the AGC family of serine / threonine protein kinases. MASTL regulates the cell cycle and is associated with various cancers, including breast cancer, gastric cancer, colon cancer, and liver cancer.

[0004] When MASTL is overexpressed in cancer, cancer cell proliferation and migration increase. In particular, MASTL overexpression is known to occur in breast cancer, and knockout of MASTL is known to inhibit breast cancer cell proliferation. To date, most research on MASTL has been related to breast cancer.

[0005] Breast cancer accounts for 31% of cancer deaths in women, making effective targeted therapy crucial. Inhibition of MASTL has proven effective not only against general breast cancer but also against triple-negative breast cancer (TNBC). Triple-negative breast cancer, accounting for 15% to 20% of all breast cancers, lacks the morphology of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor-2 (HER-2) receptors, which are essential for cell growth and characteristics. The challenge with triple-negative breast cancer lies in its limited effectiveness with hormone therapy or targeted anticancer agents specific to general breast cancer, coupled with rapid cancer cell growth and metastasis, leading to low survival rates. Therefore, the development of therapeutic agents is of paramount importance.

[0006] MASTL regulates mitosis by directly phosphorylating phosphoprotein 19 (ARPP19) through α-endosulfine (ENSA) and cAMP regulation. If MASTL, activated by cyclin-dependent kinases (CDKs) upon entering mitosis, phosphorylates ENSA and ARPP19, the activity of the tumor suppressor protein phosphatase 2A complex (PP2A-B55) decreases by more than 10-fold. Conversely, at the end of mitosis, MASTL is inactivated, and ARPP19 and ENSA are dephosphorylated, thereby reactivating PP2A.

[0007] Protein phosphatase 2A (PP2A), a major serine-threonine phosphatase in mammals, is a tumor suppressor, and its activity is inhibited in most tumors. Mutations in the subunit genes of PP2A can induce breast cancer or breast cancer recurrence; therefore, the PP2A-B55 complex may play a role in inhibiting tumor growth in breast cancer. Furthermore, it is known that reduced MASTL activity induces apoptosis and decreases cell survival in breast cancer cell lines. It has been reported that increased PP2A activity when MASTL is inhibited can enhance the radiosensitivity of cancer cells. Therefore, MASTL inhibition can reduce tumor growth and metastasis in breast cancer by increasing PP2A activity, and when combined with radiotherapy, a good anti-cancer effect can be expected.

[0008] To date, reported MASTL inhibitors include AT13148, GKI-1, and MKI-1. AT13148, as a multi-AGC kinase inhibitor, has an IC50 value in MASTL. 50 The value was 5.9 μM. GKI-1 (Greatwall Kinase Inhibitor-1), a compound derived from studies based on the AT13148 and MASTL kinase domains, has an IC50 value of 5.9 μM in MASTL. 50 The value was 4.9 μM. Furthermore, it was confirmed that GKI-1 inhibits MASTL in vitro and reduces phosphorylated ENSA, thereby delaying mitosis. MKI-1 (MASTL Kinase Inhibitor-1), as a compound derived through in silico screening, had an IC50 of 9.9 μM in MASTL. 50 Furthermore, it exhibits anticancer activity and radiosensitivity by increasing the activity of PP2A in vitro and in vivo and destabilizing c-Myc.

[0009] The three compounds developed to date all exhibited activity at the μM level and low MASTL inhibition. Most of them showed comprehensive inhibition of the AGC kinase family. Therefore, there is a need to develop compounds that can selectively inhibit only MASTL.

[0010] For relevant literature, see Cory A. Ocasioet et al., “A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct” (Oncotarget 2016, 7 (44)). Summary of the Invention

[0011] Technical issues The object of this invention is to provide a compound that inhibits MASTL activity or a pharmaceutical composition containing such a compound as an active ingredient.

[0012] Technical solution To achieve the above objectives, the present invention provides a compound, its stereoisomer, its hydrate, its solvate, or its salt represented by the following chemical formula 1.

[0013] Chemical Formula 1

[0014] The compound, its stereoisomer, its hydrate, its solvate, or its salt is characterized by inhibiting the activity of MASTL.

[0015] Furthermore, in another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a compound represented by the chemical formula 1, its stereoisomer, its hydrate, its solvate, or its salt as an active ingredient.

[0016] The composition is characterized by inhibiting MASTL, and the cancers include stomach cancer, breast cancer, uterine cancer, colon cancer, lung cancer, colorectal cancer, pancreatic cancer, liver cancer, or prostate cancer.

[0017] Furthermore, in another aspect, the present invention provides a method for the prevention or treatment of cancer, comprising the step of administering the pharmaceutical composition for the prevention or treatment of cancer to a mammal other than a human.

[0018] Furthermore, in another aspect, the present invention provides a health-functional food composition for preventing or improving cancer, comprising a compound represented by the chemical formula 1, its stereoisomer, its hydrate, its solvate, or its salt as an active ingredient.

[0019] Furthermore, in another aspect, the present invention provides a proteolytic targeting chimeric compound (PROTAC) comprising a target protein ligand, a linker, and an E3 enzyme ligand, or a pharmaceutically acceptable salt thereof, wherein the target protein ligand is a compound represented by the chemical formula 1.

[0020] The effects of the invention The compounds according to the present invention, or compositions containing them as active ingredients, can exhibit anticancer effects by inhibiting the activity of MASTL, especially in breast cancer with MASTL overexpression. Detailed Implementation

[0021] Hereinafter, a detailed description will be provided with reference to embodiments of the present invention. In describing the present invention, detailed descriptions of related well-known structures or functions will be omitted where it is determined that such detailed descriptions may obscure the essence of the invention.

[0022] As used in this specification and the appended claims, unless otherwise stated, the following terms shall have the following meanings: Unless otherwise stated, the term "halogen" as used in this invention refers to fluorine (F), bromine (Br), chlorine (Cl), or iodine (I).

[0023] The term "alkyl" or "alkyl group" as used in this invention refers to an aliphatic hydrocarbon radical, and specifically to a radical containing a saturated aliphatic functional group, including straight-chain alkyl, branched alkyl, cycloalkyl (alicyclic) alkyl, alkyl-substituted cycloalkyl, and alkyl-substituted cycloalkyl groups. For example, C1-C6 alkyl groups, as aliphatic hydrocarbons having 1 to 6 carbon atoms, include all of the following: methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, etc. As an example, cycloalkyl may be used interchangeably with "cycloalkyl" in this specification, and as an example, may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, but are not limited thereto.

[0024] The term "alkenyl" as used in this invention refers to a group consisting of at least two carbon atoms forming at least one carbon-carbon double bond, including, but not limited to, straight-chain or branched chain groups.

[0025] Unless otherwise defined, the term "alkoxyl" or "alkoxy" as used in this invention refers to a free radical in which the hydrogen atom of the hydroxyl group is replaced by an alkyl group, such as C1-C6 alkoxyl, which includes all of the following: methoxyl, ethoxyl, propoxyl, n-butoxyl, n-pentoxyl, isopropoxyl, sec-butoxyl, tert-butoxyl, neopentoxyl, isopentoxyl, etc.

[0026] In this invention, "haloalkyl" can refer to a straight-chain or branched alkyl (hydrocarbon) having carbon atoms substituted with one or more halogens as defined in this application. Examples of said haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, which are independently substituted with one or more halogens (e.g., F, Cl, Br, or I).

[0027] In this invention, "heterocyclic group" can refer to a ring containing 1 to 5 heteroatoms selected from N, O, and S as cyclic atoms, and can be saturated or partially unsaturated. In the case of unsaturation, it can be called a heterocyclic alkene. Unless otherwise mentioned, heterocyclic alkyl groups can be monocyclic or polycyclic (such as spiro, bridged, or fused rings). Furthermore, "heterocyclic group of 3 to 12 atoms" can represent a heterocyclic group containing 3 to 12 cyclic atoms. As an example, this could include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, and thiomorpholine. orpholine), thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane, etc.Examples of saturated "heterocyclic groups" include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, and quinazoline. Quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine azopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole, benzocarbazole Benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran, etc.But it is not limited to this.

[0028] The term "aryl" or "arylene" as used in this invention refers to a monocyclic or polycyclic aromatic compound, including aromatic rings formed by the combination or reaction of adjacent substituents. Examples of aryl compounds include phenyl, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, terphenyl, tetraphenyl, pentphenyl, hexaphenyl, benzo[9,10]phenanthrene, pyrene, benzofluoranthene, chrysene, etc., but are not limited thereto.

[0029] The term "aliphatic ring" as used in this invention refers to an aliphatic hydrocarbon ring.

[0030] The term "aromatic ring" as used in this invention refers to an aromatic system consisting of hydrocarbons containing one or more rings, such as benzene and naphthalene.

[0031] Furthermore, the definitions described in this invention may be added to form chemically related combinations (e.g., "aralkyl", "alkylcarbonyl", "arylcarbonyl", etc.). When the term "alkyl" is used as a suffix in another term (such as "phenylalkyl" or "hydroxyalkyl"), it indicates an alkyl group substituted with a substituent selected from another explicitly named group. Thus, for example, "phenylalkyl" indicates an alkyl group having a phenyl substituent, and therefore includes benzyl, phenethyl, and biphenyl. "alkylaminoalkyl" indicates an alkyl group having an alkylamino substituent.

[0032] Hereinafter, a compound according to one aspect of the present invention and a pharmaceutical composition comprising the same will be described.

[0033] This invention provides a compound represented by the following chemical formula 1, its stereoisomer, its hydrate, its solvate, or its salt: Chemical Formula 1

[0034] In the chemical formula 1, L 1 It is a single bond; -NH-; or a C2~C bond containing at least one N. 30 heterocyclic group, Ar 1 Choose free hydrogen; C1~C 30 Alkyl groups; C1~C 30 Hydroxyalkyl; C6-C 30 aryl; C7-C 30 Aryl alkyl group; C2~C containing at least one N 30 The group consisting of heterocyclic groups; -S(=O)2-R'; and -C(=O)-NH-R', the Ar 1 Can be arbitrarily assigned to more than one R1 replace, Ring A is C6-C 30 aryl; -(CH2)n-aryl; or C2~C containing at least one N. 30 The heterocyclic group, wherein the A ring can optionally be composed of one or more R groups. 2 replace, n is an integer from 1 to 10. R' is C1~C 30 Alkyl groups; C3~C 30 cycloalkyl; C7-C 30 Aryl groups; C6-C 30 aryl; or C2~C 30 heterocyclic group, The R 1 The elements are independently selected from hydrogen, halogen, hydroxyl group, oxo group, -(CH2)n-cyano group, and C3~C. 30 Cycloalkyl groups; C1-C6 groups substituted with or unsubstituted with halogens. 30 Alkyl groups; C1~C 30 alkoxy group; -L'-C2~C 30 Heterocyclic groups; -L'-C(=O)-NH2; -L'-C(=O)OR a ;-L'-S(=O)2-R a ; and -S(=O)2-NR b R c The group formed The R 2 The elements are independently selected from hydrogen, halogen, hydroxyl group, amino group, oxo group, and C3~C. 30 cycloalkyl; C1~C 30 Alkyl groups; C2~C 30 alkenyl group; C1~C 30 alkoxy group; -NH-C(=O)OR d -S(=O)2-R d -S(=O)2-NR e R f ; and -O-C7~C 30 A group consisting of aralkyl groups, or multiple adjacent R groups. 2 They can combine with each other to form a ring. L' represents a single bond; or C1~C 10 alkylene, R a R b R c R d R e and R f Each of them is independently hydrogen; C1~C10 Alkyl groups; C3~C 30 Cycloalkyl groups; C6~C6 groups, substituted or unsubstituted with halogens. 12 aryl group; C2~C containing at least one N 30 Heterocyclic groups; or C1~C 10 Hydroxyalkyl groups. Furthermore, the present invention provides a compound of chemical formula 1 represented by the following chemical formulas 1-1, its stereoisomer, its hydrate, its solvate, or its salt: Chemical Formula 1-1

[0035] In the aforementioned chemical formula 1-1, Ring A is represented by any one of the following chemical formulas A-1 to A-5. Chemical Formula A-1 Chemical Formula A-2 Chemical Formula A-3 Chemical Formula A-4 Chemical Formula A-5

[0036] In the chemical formulas A-1 to A-5, * refers to the binding site. R 2 The content is the same as that defined in Chemical Formula 1. a is an integer from 0 to 3, b is an integer from 0 to 2, and c is an integer from 0 to 5. Furthermore, the present invention provides a compound of chemical formula 1 represented by the following chemical formula 2-1, its stereoisomer, its hydrate, its solvate, or its salt: Chemical formula 2-1

[0037] In the chemical formula 2-1, R 3 Each is independently selected from hydrogen; cyano group; C3~C 30 cycloalkyl; C1~C 30 alkoxy group; -L'-C2~C 30 Heterocyclic groups; -L''-C(=O)-NH2; -L''-C(=O)OR a ;-L'-S(=O)2-R a ; and -S(=O)2-NR b R c The group formed But excluding the aforementioned R 3 In the case where all atoms are hydrogen, L'' is C1~C 10 alkylene, d is an integer from 0 to 5. L', R a R b and R c This is identical to the content defined in Chemical Formula 1. Furthermore, the present invention provides a compound, its stereoisomer, its hydrate, its solvate, or its salt represented by any one of the following chemical formulas 2-2 to 2-6: Chemical Formula 2-2 Chemical Formula 2-3 Chemical Formula 2-4

[0038] Chemical formula 2-5 Chemical formula 2-6

[0039] {In the chemical formulas 2-2 to 2-6, R 1 The content is the same as that defined in Chemical Formula 1. e is an integer from 0 to 3, f is an integer from 0 to 5, g is an integer from 0 to 4, and h is an integer from 0 to 6. Furthermore, the present invention provides a compound, its stereoisomer, its hydrate, its solvate, or its salt represented by any one of the following chemical formulas 3-1 to 3-9: Chemical Formula 3-1 Chemical Formula 3-2 Chemical Formula 3-3

[0040] Chemical formula 3-4 Chemical formula 3-5 Chemical formula 3-6

[0041] Chemical formula 3-7 Chemical formula 3-8 Chemical formula 3-9

[0042] {In the chemical formulas 3-1 to 3-9, Ar' chooses freely from C1 to C. 30 Hydroxyalkyl; C6-C 30 aryl; C7-C 30 Aryl alkyl group; C2~C containing at least one N 30 The group consisting of heterocyclic groups; -S(=O)2-R'; and -C(=O)-NH-R', wherein the Ar' can optionally be surrounded by more than one R 1 replace, Ar 1 R 1And R' is the same as that defined in Chemical Formula 1.

[0043] Specifically, the chemical formula 1 can be represented by any of the following compounds, but is not limited thereto.

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] The compound, its stereoisomer, its hydrate, its solvate, or its salt according to the present invention is characterized by inhibiting the activity of MASTL.

[0086] Furthermore, in another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, comprising a compound, its stereoisomer, its hydrate, its solvate, or its salt as an active ingredient.

[0087] The composition has the effect of inhibiting MASTL.

[0088] In addition, the cancers mentioned may include, but are not limited to, stomach cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, pancreatic cancer, liver cancer, or prostate cancer.

[0089] Furthermore, in another aspect, the present invention provides a method for the prevention or treatment of cancer, comprising the step of administering a composition to a mammal other than a human.

[0090] Furthermore, in another aspect, the present invention provides a health-functional food composition for the prevention or improvement of cancer, comprising the compound, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient.

[0091] Proteolysis-targeting chimeras (PROTACs), as a type of targeted protein degradation (TPD) technology, are techniques that utilize intracellular protein degradation systems to specifically break down and eliminate pathogenic proteins. A PROTAC is a double-bonded molecule that binds to disease-causing proteins and induces the proteasome to break down these proteins, ultimately leading to selective proteolysis.

[0092] In other words, E3 enzymes (E3 ligases) can label target proteins with markers called ubiquitin, and the target proteins labeled with these ubiquitin markers are then broken down by the proteasome. If the target protein ligand of a PROTAC compound binds to the target protein, the E3 enzyme can be located at a distance very close to the target protein via the PROTAC compound, thereby providing an environment for the removal of the target protein by the proteasome.

[0093] PROTACs consist of a binder that binds to the target protein, a binder that binds to an E3 ubiquitin ligase, and a linker that acts as an intermediate connecting the two. By binding to both proteins, PROTACs deliver the target protein to the E3 ligase, inducing the target protein to be labeled (i.e., ubiquitinated) for subsequent degradation by the proteasome. Because the target protein is degraded through binding, it provides easy access to a wide range of diseases, and by degrading the target protein at its source, it can overcome the problem of resistance.

[0094] Ubiquitination involves a three-stage process of activation, conjugation, and ligation, performed by ubiquitin activator (E1), ubiquitin conjugator (E2), and ubiquitin ligase (E3). As a result of this sequential cascade, ubiquitin covalently binds to the target protein. Ubiquitinated proteins are ultimately broken down by the proteasome.

[0095] Since the core of PROTACs technology is the ability of E3 enzymes and target proteins to precisely mediate ubiquitination of target proteins through ligands, it is necessary to discover suitable E3 enzyme ligands and target protein ligands, as well as the technology for designing and synthesizing bifunctional compounds.

[0096] In another aspect, the present invention provides PROTACs compounds comprising a target protein ligand, a linker, and an E3 enzyme ligand, or a pharmaceutically acceptable salt thereof, wherein the target protein ligand is a compound represented by the chemical formula 1.

[0097] The compounds represented by Formula 1 according to the present invention can be used as target protein ligands in PROTACs compounds containing target protein ligands, linkers and E3 enzyme ligands or pharmaceutically acceptable salts thereof.

[0098] At this time, the target protein can preferably be the MASTL protein. PROTACs compounds bind to the MASTL protein and induce its degradation, thereby achieving the therapeutic effect of MASTL overexpression disease. As an example, it can be accompanied by the prevention or treatment of breast cancer.

[0099] In the PROTACs compounds according to the present invention, the compound of chemical formula 1 and the linker can be connected by covalent bonds.

[0100] In the PROTACs compounds according to the present invention, the linker is covalently linked to both the target protein ligand and the E3 enzyme ligand, thereby connecting the target protein ligand and the E3 enzyme ligand. Those skilled in the art will understand that at the sites where the linker, target protein ligand, and E3 enzyme ligand are covalently linked, some substituents may detach during the covalent bonding reaction.

[0101] Furthermore, in this invention, in addition to the compounds according to the invention, the pharmaceutical composition may also contain a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient.

[0102] In this invention, "pharmaceutical acceptable" means that when administered, it does not irritate the organism and does not inhibit the biological activity and properties of the administered compound, as is commonly used in the pharmaceutical field.

[0103] Specifically, the carrier is typically used in formulations and may be lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, or mineral oil, but is not limited to these. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavoring agents, and aromatizers may also be present in the composition.

[0104] The excipients include any and all solvents, inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils suitable for the desired specific dosage form. Excipients such as cocoa butter and suppository waxes, colorants, coating agents, sweeteners, flavorings and aromas may also be present in the composition.

[0105] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dicalcium phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.

[0106] Exemplary preservatives include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives.

[0107] Exemplary antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium iodide, sodium metabisulfite, sodium nitrite, sodium sulfite, and sodium thiosulfate.

[0108] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzyl chloride, benzyl alcohol, bromonitrobenzene glycol, cetrimonium bromide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerol, heexetidine, imidulazidrea, phenol, phenoxyethanol, phenethyl alcohol, nitric acid phenylmercury(II) salt, propylene glycol, and thimerosal.

[0109] Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0110] Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenethyl alcohol.

[0111] Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0112] Other preservatives include, but are not limited to, tocopherol, tocopheryl acetate, deferoxime mesylate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0113] Exemplary buffers include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluconate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dicalcium phosphate, phosphoric acid, tricalcium phosphate, hydroxycalcium phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium phosphate, monopotassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium phosphate, monosodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginate, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and combinations thereof.

[0114] The compositions of the present invention can be administered orally or non-orally. In the case of non-oral administration, they can be administered via intravenous injection, intra-articular injection, subcutaneous injection, intramuscular injection, intra-articular injection, intrasynovial injection, intrathecal injection, intrahepatic injection, intralesional injection, intracranial injection, or local non-oral administration. Specifically, the compositions of the present invention can be formulated into injectable preparations for intravenous administration, but are not limited thereto.

[0115] Furthermore, the compositions can be in various forms according to common methods, including but not limited to liquids, suspensions, pastes, powders, concentrates, granulated powders for mixing at appropriate concentrations, or solid forms. For example, the compositions of the present invention can be prepared as injections, transdermal formulations, intubation formulations, oral formulations, and rectal formulations.

[0116] The appropriate dosage of the composition of the present invention can be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, gender, pathological state, diet, administration time, route of administration, excretion rate and reaction sensitivity.

[0117] Furthermore, in this invention, the health-functional food composition can be readily used as a food with cancer prevention or improvement effects (e.g., a main ingredient, excipient, food additive, functional food, or beverage).

[0118] In addition, in this invention, besides the compounds according to the invention, the health functional food composition may also contain food science-acceptable food additives, and may further contain suitable carriers, excipients and diluents commonly used in the preparation of functional foods.

[0119] In this application, "food" refers to a natural or processed product containing one or more nutrients. Preferably, it refers to a product that has undergone a certain degree of processing and is in a state that is ready to be eaten. In a general sense, it includes all foods, food additives, functional foods, and beverages.

[0120] The term "functional food" refers to a food group in which physical, biochemical, and bioengineering methods are applied to food to add value, thereby enabling the corresponding food's function to act and be expressed for a specific purpose. Alternatively, it can refer to food designed and processed to fully express regulatory functions within an organism (involving biological defense rhythm regulation, disease prevention, and recovery inherent in the food composition). Specifically, it can be a health-promoting functional food. The functional food may contain food additives that are acceptable in food science, and may further contain appropriate carriers, excipients, and diluents commonly used in the preparation of functional foods.

[0121] The term "beverage" refers to any beverage consumed to quench thirst or for enjoyment of taste, including functional beverages. Aside from containing the indicated composition for cancer prevention and improvement as an essential ingredient, the beverage has no particular restrictions on other ingredients and may contain various flavorings or natural carbohydrates as additional ingredients, just like a typical beverage.

[0122] Foods that can be added to the health-functional food composition according to the present invention include, for example, various food categories, beverages, chewing gum, tea, vitamin complexes, functional foods, etc. Furthermore, in this invention, foods include special nutritional foods (e.g., formula foods, infant foods, etc.), meat products, fish products, tofu, freeze-dried products (muk), noodles (e.g., ramen, noodles, etc.), bread, health supplements, condiments (e.g., soy sauce, miso, chili sauce, mixed sauces, etc.), sauces, biscuits (e.g., snacks), candies, chocolates, chewing gum, ice cream, dairy products (e.g., fermented products, cheese, etc.), other processed foods, pickles, preserved foods (various types of pickles, miso soup, etc.), beverages (e.g., fruit drinks, vegetable drinks, bean drinks, fermented drinks, etc.), natural seasonings (e.g., ramen soup, etc.), but are not limited thereto. The aforementioned foods, beverages, or food additives can be prepared using conventional preparation methods.

[0123] Furthermore, in addition to the above description, foods containing the health-promoting functional food composition of the present invention that has the effect of preventing or improving cancer may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages, etc., and the ingredients may be used alone or in combination.

[0124] The following examples illustrate specific synthetic and experimental examples of the compounds represented by the chemical formula 1 of the present invention, but the present invention is not limited to the following examples.

[0125] [Synthesis example] The compounds represented by chemical formula 1-1 according to the present invention can be prepared according to the following reaction formula 1, but are not limited thereto.

[0126] <Reaction Formula 1>

[0127] {In reaction formula 1, ring A is the same as defined above.} 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine N -(5-cyclopropyl-1 H -pyrazol-3-yl)quinazolin-4-amine) (2a) At room temperature, MeCN (50 mL) and 5-cyclopropyl-1H-pyrazole-3-amine were added dropwise to a solution of 2,4-dichloro-quinazoline (4.00 g, 20.10 mmol) and DIPEA (2.63 mL, 15.07 mmol) in a round-bottom glass flask containing 50 mL of MeCN. H A mixed solution of pyrazol-3-amine (2.72 g, 22.11 mmol) and DIPEA (2.63 mL, 15.07 mmol) was prepared. After 24 hours, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and recovered, and washed successively with about 100 mL of cold MeCN and EtoAc. After drying, compound 2a was recovered as a white powder (4.18 g, 73% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.79 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 7.85 (t, J =7.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 6.50 (s, 1H), 4.04 (s, 1H), 3.31 (s, 1H), 1.96 (dt, J = 8.5, 3.6 Hz, 1H), 1.10-0.85 (m, 2H), 0.85-0.64 (m, 2H).

[0128] 2-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile ( ... H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile) (3a) Compound 2a (1.50 g, 5.25 mmol) was dissolved in tert-butanol (15 mL), and a solution of 4-aminobenzonitrile (1.04 g, 7.87 mmol) was added to tert-butanol (5 mL) and then added to the mixture. An aqueous solution of 37% HCl (0.100 mL) was added, and the reaction mixture was heated while stirring at 110 °C. The solvent was evaporated after 6 hours. The product was washed with MeOH and filtered to prepare a white solid, compound 3a (1.79 g, 89% yield). 1 H NMR (300 MHz, DMSO-d6) δ 11.52 (s, 1H), 10.58 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 7.7 Hz, 1H), 7.48-7.38 (m, 2H), 6.19 (s, 1H), 4.10 (s, 2H), 1.87(td, J = 8.5, 4.3 Hz, 1H), 1.07–0.81 (m, 2H), 0.72–0.48 (m, 2H). MS (ESI) m / z for C 22 H 19 N7[M + Calculated value: 381.4; Experimental value: 382.2 [M] + + H + ].

[0129] Synthesis example of 2-(4-((4-((1-isobutyl-3,5-dimethyl-1H-pyrazol-4-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3b) 1) 2-Chloro-N-(1-isobutyl-3,5-dimethyl-1H-pyrazol-4-yl)quinazoline-4-amine (2b) At room temperature, 2,4-dichloro-quinazoline (295 mg, 1.48 mmol) and DIPEA (0.263 mL, 1.51 mmol) were added to a stirred solution of 1-isobutyl-3,5-dimethyl-1H-pyrazole-4-amine (200 mg, 1.00 mmol) and MeCN (10 mL). After overnight incubation, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and washed with water. After drying, a white solid compound 2b (345 mg, 104% yield) was given.

[0130] 1 H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.92- 7.80 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 3.81 (d, J =7.3 Hz, 2H), 2.12 (s, 4H), 2.03 (s, 3H), 0.89 (d, J = 6.7 Hz, 6H).

[0131] 2) 3b Compound 2b (70 mg, 0.21 mmol) was dissolved in tert-butanol (2 mL), and a solution of 4-aminobenzyl cyanide (42 mg, 0.32 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After 4 hours, the product was filtered with ethyl acetate and washed to give a yellow solid, compound 3b (91 mg, 101% yield).

[0132] 1 H NMR (300 MHz, DMSO-d6) δ 12.91 (s, 1H), 10.83 (s, 1H), 10.62 (s,1H), 8.58 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.45 (d, J= 8.5 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 4.02(s, 2H), 3.84 (d, J = 7.3 Hz, 2H), 2.25-2.12 (m, 2H), 2.12 (s, 3H), 2.04 (s,3H), 0.88 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 161.45, 151.75, 143.06, 139.64, 137.05, 136.28, 135.23, 128.96, 127.43, 125.49, 125.19, 119.65, 118.00, 114.62, 110.67, 56.08, 31.77, 29.60, 22.26, 20.15, 12.19, 9.84. MS (ESI) m / z for C 25 H 27 N7[M + Calculated value: 425.5; Experimental value: 426.5 [M] + + H + ].

[0133] Synthetic example of 2-(4-((4-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3c) 1) 2-Chloro-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)quinazoline-4-amine (2c) At room temperature, a solution of 1,3,5-trimethyl-1H-pyrazole-4-amine (69 mg, 0.55 mmol) and DIPEA (0.066 mL, 0.38 mmol) dissolved in MeCN (2 mL) was added dropwise to a stirred solution of 2,4-dichloro-quinazoline (100 mg, 0.50 mmol), DIPEA (0.066 mL, 0.38 mmol), and MeCN (2 mL). After 4 hours, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and washed with water. After drying, a white solid compound 2c (109 mg, 75% yield) was given.

[0134] 1 H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.47 (d, J= 8.3 Hz, 1H),7.92-7.81 (m, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 3.71 (s, 3H), 2.11 (s, 3H), 2.00 (s, 3H).

[0135] 2) 3C Compound 2c (100 mg, 0.35 mmol) was dissolved in tert-butanol (1 mL), and a solution of 4-aminophenylacetonitrile (69 mg, 0.52 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.015 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the mixture was filtered with ethyl acetate and washed to give a white solid, compound 3c (133 mg, 100% yield).

[0136] 1 H NMR (300 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.64 (s, 1H), 8.60 (d, J =8.2 Hz, 1H), 8.00-7.82 (m, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 4.04 (s, 2H), 3.75 (s,3H), 2.06 (d, J = 6.0 Hz, 6H), 1.11 (s, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 161.36, 151.79, 142.50, 139.63, 136.94, 136.25, 135.51, 129.05, 127.76, 125.49, 125.24, 119.76, 118.02, 114.87, 110.73, 36.67, 31.78, 22.25, 11.90, 9.93. MS(ESI) m / z for C 22 H 21 N7[M +Calculated value: 383.5; Experimental value: 384.4 [M] + + H + ].

[0137] Synthesis example of 2-(4-((4-((3,5-dimethyl-1H-pyrazol-4-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3d) 1) 2-Chloro-N-(3,5-dimethyl-1H-pyrazol-4-yl)quinazolin-4-amine (2d) At room temperature, a solution of 3,5-dimethyl-1H-pyrazole-4-amine (61 mg, 0.55 mmol) dissolved in MeCN (2 mL) and DIPEA (0.066 mL, 0.38 mmol) was added dropwise to a stirred solution of 2,4-dichloroquinazoline (100 mg, 0.50 mmol), DIPEA (0.066 mL, 0.38 mmol), and MeCN (2 mL). After 2 hours, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and washed with water. After drying, a white solid compound 2d (114 mg, 83% yield) was given.

[0138] 1 H NMR (300 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.74 (s, 1H), 8.47 (d, J =8.2 Hz, 1H), 7.90-7.82 (m, 1H), 7.72-7.65 (m, 1H), 7.65-7.56 (m, 1H), 4.03(q, J = 7.1 Hz, 1H), 2.07 (s, 6H), 1.99 (s, 1H), 1.18 (t, J = 7.1 Hz, 1H).

[0139] 2) 3D Compound 2d (70 mg, 0.26 mmol) was dissolved in tert-butanol (2 mL), and a solution of 4-aminophenylacetonitrile (51 mg, 0.38 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After 3 hours, the mixture was filtered with ethyl acetate and washed to give a white solid, compound 3d (87 mg, 92% yield).

[0140] 1H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.78 (s, 1H), 10.60 (s,1H), 8.57 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.50-7.41 (m, 2H), 7.25 (d, J = 8.2 Hz, 2H), 4.03 (d, J =2.9 Hz, 3H), 2.09 (s, 6H), 1.99 (s, 1H), 1.18 (t, J = 7.1 Hz, 1H). 13 C NMR (101MHz, DMSO-d6) δ 170.81, 161.30, 151.80, 139.66, 137.07, 136.22, 129.06, 127.50, 127.50, 125.48, 125.20, 121.41, 119.71, 118.07, 114.56, 110.72, 60.23, 22.27, 21.24, 14.56, 11.01. MS (ESI) m / z for C 21 H 19 N7[M + Calculated value: 369.4; Experimental value: 370.4 [M] + + H + ].

[0141] Synthetic example of 2-(4-((4-((3-methyl-1H-pyrazol-4-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3e) 1) 2-Chloro-N-(3-methyl-1H-pyrazol-4-yl)quinazoline-4-amine (2e) At room temperature, a solution of 3-methyl-1H-pyrazole-4-amine (53.68 mg, 0.55 mmol) dissolved in MeCN (2 mL) and DIPEA (0.066 mL, 0.38 mmol) was added dropwise to a stirred solution of 2,4-dichloro-quinazoline (100 mg, 0.50 mmol), DIPEA (0.066 mL, 0.38 mmol), and MeCN (2 mL). After 1 hour, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and washed with water. After drying, a white solid compound 2e (95 mg, 73% yield) was given.

[0142] 1 H NMR (300 MHz, DMSO- d 6) δ 12.56 (s, 1H), 9.85 (s, 1H), 8.47 (d, J =8.3 Hz, 1H), 7.86 (t, J = 7.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 7.7Hz, 1H), 2.17 (s, 3H), 2.08 (s, 1H).

[0143] 2) 3e Compound 2e (70 mg, 0.27 mmol) was dissolved in tert-butanol (2 mL), and a solution of 4-aminophenylacetonitrile (53 mg, 0.40 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After 1.5 hours, the mixture was filtered with ethyl acetate and washed to give a yellow solid, compound 3e (47 mg, 49%).

[0144] 1 H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.36 (d, J = 20.3 Hz, 2H), 8.32 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.68 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.29 (t, J= 7.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 3.94 (s,2H), 2.18 (s, 3H), 1.06 (t, J = 7.0 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 159.88,156.42, 140.60, 133.69, 128.57, 128.51, 124.68, 123.74, 122.74, 119.99 (d, J =6.9 Hz), 119.79, 111.90, 49.08, 22.20 (d, J = 7.1 Hz). MS (ESI) m / z for C 20 H 17 N7[M + Calculated value: 355.4; Experimental value: 356.3 [M] + + H + ].

[0145] Synthetic example of 2-(4-((4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3f) 1) 2-Chloro-N-(1H-pyrazol-4-yl)quinazolin-4-amine (2f) At room temperature, a solution of 1H-pyrazole-4-amine (46 mg, 0.55 mmol) dissolved in MeCN (2 mL) and DIPEA (0.066 mL, 0.38 mmol) was added dropwise to a stirred solution of 2,4-dichloro-quinazoline (100 mg, 0.50 mmol), DIPEA (0.066 mL, 0.38 mmol), and MeCN (2 mL). After 1 hour, an equal volume of water was added, and the mixture was stirred at room temperature for 2 hours. The product was filtered and washed with water. After drying, a white solid compound 2f (102 mg, 83% yield) was given.

[0146] 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.52 (s, 1H), 8.47 (d, J =8.2 Hz, 1H), 8.02 (s, 2H), 7.92-7.78 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64(t, J= 7.3 Hz, 1H).

[0147] 2) 3f Compound 2f (70 mg, 0.29 mmol) was dissolved in tert-butanol (2 mL), and a solution of 4-aminophenylacetonitrile (56 mg, 0.43 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After 1 hour, the mixture was filtered and washed with ethyl acetate to give a yellow solid, compound 3f (110 mg, 113% yield).

[0148] 1 H NMR (300 MHz, DMSO-d6) δ 12.68 (s, 1H), 11.38 (s, 1H), 10.64 (s,1H), 8.63 (d, J = 8.2 Hz, 1H), 8.03 (s, 2H), 7.86 (t, J = 7.7 Hz, 1H), 7.66 (d, J =8.3 Hz, 1H), 7.59-7.49 (m, 3H), 7.47 (d, J = 8.3 Hz, 2H), 4.14 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 156.96, 152.68, 139.41, 136.19, 135.61, 129.53, 125.37, 125.20, 124.91, 120.41, 119.68, 118.07, 111.18, 67.42, 31.77, 22.54. MS (ESI) m / z for C 19 H 15 N7[M + Calculated value: 341.4; Experimental value: 342.3 [M] + + H + ].

[0149] Example of synthesis of 2-(4-((4-((2-(isopropylsulfonyl)phenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3g) 1) 2-Chloro-N-(2-(isopropylsulfonyl)phenyl)quinazoline-4-amine (2g) In a dry flask, sodium hydride (NaH) (30 mg, 1.26 mmol) was dissolved in anhydrous DMF (1 mL), and 2-(isopropylsulfonyl)aniline (100 mg, 0.50 mmol) was added while stirring at 0 °C. After 30 minutes, a solution of 2,4-dichloroquinazoline (110 mg, 0.55 mmol) dissolved in DMF (2 mL) was added to the reaction mixture, and the mixture was heated at room temperature for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and washed three times with ammonium chloride. The organic layer was dried with Na₂SO₄, and the solvent was removed under vacuum. The crude mixture was purified by column chromatography (EtOAc: hexane). The solvent was evaporated, and the solid was filtered through hexane to give 2 g (135 mg, 74% yield) of a bright green solid compound.

[0150] 1 H NMR (300 MHz, Chloroform- d ) δ 10.70 (s, 1H), 8.98 (dd, J = 8.5, 1.1Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 8.00-7.83 (m, 3H), 7.87-7.75 (m, 1H), 7.73-7.62 (m, 1H), 7.41-7.29 (m, 1H), 3.26 (p, J = 6.8 Hz, 1H), 1.33 (d, J = 6.8 Hz, 6H).

[0151] 2) 3g 2 g (100 mg, 0.28 mmol) of the compound was dissolved in tert-butanol (2 mL), and a solution of 4-aminophenylacetonitrile (55 mg, 0.42 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.015 mL of 37% HCl aqueous solution and stirring. After 2 hours, the mixture was filtered and washed with ethyl acetate to give 3 g (122 mg, 97% yield) of a yellow solid compound.

[0152] 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.49 (s, 1H), 8.50 (d, J =8.2 Hz, 1H), 8.02 (d, J= 7.9 Hz, 1H), 8.00-7.83 (m, 3H), 7.78-7.65 (m, 2H), 7.61 (t, J = 7.7 Hz, 1H), 7.37-7.22 (m, 2H), 7.20-7.08 (m, 2H), 3.97 (s, 2H), 3.47-3.39 (m, 1H), 1.02 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 161.95, 151.53, 136.80, 136.68, 136.54, 135.65, 131.93, 131.71, 129.00, 128.79, 127.75, 125.81, 125.24, 122.02, 119.66, 118.15, 110.69, 54.59, 22.23, 15.13. MS (ESI) m / z for C 25 H 23 N5O2S [M + Calculated value: 457.6; Experimental value: 458.5 [M] + + H + ].

[0153] Synthesis example of 4-((2-((4-(cyanomethyl)phenyl)amino)quinazolin-4-yl)amino)-N,N-dimethylbenzenesulfonamide (3h) 1) 4-((2-chloroquinazoline-4-yl)amino)-N,N-dimethylbenzenesulfonamide (2h) In a dry flask, sodium hydride (NaH) (44 mg, 5.53 mmol) was dissolved in anhydrous DMF (5 mL), and N,N-dimethyl-4-aminobenzenesulfonamide (221 mg, 1.11 mmol) was added while stirring at 5 °C. After 5 minutes, a solution of 2,4-dichloroquinazoline (200 mg, 1.01 mmol) dissolved in DMF (2 mL) was added dropwise to the reaction mixture, and the mixture was heated at room temperature for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and washed three times with ammonium chloride. The organic layer was dried with Na₂SO₄, and the solvent was removed under vacuum. The crude mixture was purified by column chromatography (25% EtOAc: hexane) to give compound 2h (160 mg, 44% yield).

[0154] 1 H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.64 (d,J = 8.3 Hz, 1H), 8.23-8.11 (m, 2H), 8.01-7.89 (m, 1H), 7.88-7.66 (m, 4H), 2.65 (s, 6H). MS(ESI) m / z for C 16 H 15 ClN4O2S [M + Calculated value: 362.1; Experimental value: 363.3 [M] + + H + ].

[0155] 2) 3h Compound 2h (88 mg, 0.24 mmol) was dissolved in tert-butanol (3 mL), and a solution of 4-aminophenylacetonitrile (48 mg, 0.36 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.015 mL of 37% HCl aqueous solution and stirring. After 16 hours, the solvent was evaporated, and the mixture was then dissolved in EtOAc and washed with water. The organic layer was dried with Na2SO4 and purified by column chromatography (2% DCM / MeOH) to give compound 3h (52 mg, 47% yield).

[0156] 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.39 (s, 1H), 8.45 (d, J = 8.2Hz, 1H), 8.34 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.82-7.67 (m, 3H), 7.62-7.52 (m, 1H), 7.41-7.29 (m, 1H), 7.27 (d, J = 8.5 Hz, 2H), 3.97 (s, 2H), 2.65 (s, 6H). MS (ESI) m / z for C 24 H 22 N6O2S [M + Calculated value: 458.2; Experimental value: 459.4 [M] + +H + ].

[0157] Synthetic example of 2-(4-((4-((6-chloropyridazin-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3i) 1) 2-Chloro-N-(6-chloropyridazin-3-yl)quinazoline-4-amine (2i) Sodium tert-butoxide (68 mg, 0.70 mmol) was added to a solution of 3-amino-6-chloropyridazine (70 mg, 0.54 mmol) dissolved in MeCN (5 mL) under nitrogen atmosphere at 0 °C. After a few minutes, 2,4-dichloroquinazoline (118 mg, 0.59 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated, the residue was dissolved in DMC and washed with water. The aqueous layer was extracted twice with DCM. The organic layer was dried over Na₂SO₄. The residue was purified by column chromatography (60% Hex / EA) to give a yellow solid, compound 2i (70 mg, 44% yield).

[0158] 1 H NMR (300 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.76 (d, J = 8.3 Hz, 1H), 8.54 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.81(d, J = 8.3 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H).

[0159] 2) 3i Compound 2i (60 mg, 0.21 mmol) was dissolved in tert-butanol (2 mL), and a solution of 4-aminophenylacetonitrile (41 mg, 0.31 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the mixture was filtered with ethyl acetate and washed to give compound 3i (66 mg, 83% yield) as a yellow solid.

[0160] 1 H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.62 (s, 1H), 8.73 (d, J =8.2 Hz, 1H), 8.43 (s, 1H), 7.94 (t, J = 8.1 Hz, 2H), 7.72 (d, J= 8.3 Hz, 1H),7.62-7.48 (m, 3H), 7.40 (d, J = 8.2 Hz, 2H), 4.07 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.52, 155.25, 153.64, 152.45, 136.75, 136.34, 130.09, 129.29, 128.89, 127.36, 125.58, 125.44, 124.07, 119.76, 111.14, 22.46. MS (ESI) m / z for C 20 H4ClN7[M + Calculated value: 387.8; Experimental value: 388.4 [M] + + H + ].

[0161] Synthetic example of 2-(4-((4-((4-oxo-4,5-dihydrothiazol-2-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3j) 1) 2-((2-chloroquinazoline-4-yl)amino)thiazol-4(5H)-one (2j) In a dry flask, sodium hydride (NaH) (221 mg, 5.53 mmol) was dissolved in anhydrous DMF (15 mL), and 2-amino-1,3-thiazolin-4-one (641.88 mg, 5.53 mmol) was added dropwise while stirring at 5 °C. After 30 minutes, a solution of 2,4-dichloroquinazoline (1.0 g, 5.02 mmol) dissolved in DMF (2 mL) was added dropwise to the reaction mixture, and the mixture was heated at room temperature for 2.5 hours. The reaction mixture was dissolved in ethyl acetate and washed three times with ammonium chloride. The organic layer was dried with Na₂SO₄, and the solvent was removed under vacuum. The crude mixture was purified by column chromatography (25% EtOAc: hexane) to give compound 2j (555 mg, 40% yield).

[0162] 1 H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.39 (dd, J = 8.3, 1.4 Hz, 1H), 8.01 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.93(m, 1H), 7.73 (ddd, J= 8.2, 6.9,1.2 Hz, 1H), 4.07 (s, 2H). MS (ESI) m / z calcd C 11 H7ClN4OS [M + ], 278.0 ; found,279.2 [M + + H + ].

[0163] 2) 3j Compound 2j (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of 4-aminophenylacetonitrile (50 mg, 0.38 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.012 mL of 37% HCl aqueous solution and stirring. After 16 hours, the solvent was evaporated, and the mixture was then dissolved in EtOAc and washed with water. The organic layer was dried with Na2SO4 and purified by column chromatography (50% Hex / EtOAc) to give compound 3j (76 mg, 84% yield).

[0164] 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.35 (s, 1H), 9.41 (s, 1H), 8.24–8.13 (m, 1H), 8.07–7.95 (m, 2H), 7.82–7.71 (m, 1H), 7.68–7.56 (m, 1H), 7.40–7.24 (m, 3H), 4.05 (s, 2H), 3.98 (s, 2H). MS (ESI) m / z for C 19 H 14 N6OS [M + Calculated value: 374.1; Experimental value: 375.3 [M] + + H + ].

[0165] Synthetic example of 2-(4-((4-((2-fluorophenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3k) 1) 2-Chloro-N-(2-fluorophenyl)quinazoline-4-amine (2k) Sodium tert-butoxide (121 mg, 1.26 mmol) was added to a solution of 2,4-dichloroquinazoline (138 mg, 0.69 mmol) and 2-fluoroaniline (0.061 mL, 0.63 mmol) dissolved in tetrahydrofuran (THF), and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over Na₂SO₄. The residue was filtered and purified to give a white solid compound 2k (78 mg, 45% yield).

[0166] 1 H NMR (400 MHz, DMSO) δ 10.31 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.92(t, J = 7.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.56 (t, J =7.8 Hz, 1H), 7.47-7.34 (m, 2H), 7.34-7.25 (m, 1H).

[0167] 2) 3k A mixture of 2-chloro-N-(2-fluorophenyl)quinazolin-4-amine (50 mg, 0.18 mmol), 2-(4-aminophenyl)acetonitrile (36 mg, 0.27 mmol), and ethanol (2 mL) was stirred for 4 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was filtered and purified, and washed with MeOH to give a beige solid compound 3k (34 mg, 51% yield).

[0168] 1 H NMR (400 MHz, DMSO) δ 12.98 (s, 1H), 11.29 (s, 1H), 10.52 (s, 1H), 8.58 (d, J = 8.2 Hz, 1H), 7.94 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58(t, J = 7.9 Hz, 2H), 7.53-7.41 (m, 2H), 7.41-7.30 (m, 3H), 7.19 (d, J= 8.0 Hz, 2H), 3.98 (s, 2H).

[0169] Synthesis example of 2-(4-((4-((5-cyclopropyl-1,3,4-thiadiazol-2-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3l) 1) N-(2-chloroquinazoline-4-yl)-5-cyclopropyl-1,3,4-thiadiazole-2-amine (2l) Cesium carbonate (327 mg, 1.01 mmol) was added to a mixed solution of 2,4-dichloroquinazoline (100 mg, 0.50 mmol), 5-cyclopropyl-1,3,4-thiadiazol-2-amine (78 mg, 0.55 mmol), and 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted twice with ethyl acetate. The organic layer was dried over Na₂SO₄. The residue was filtered and purified to give 2 μL of a white solid (84 mg, 55% yield).

[0170] 1 H NMR (300 MHz, DMSO) δ 8.58 (s, 1H), 7.93 (ddd, J = 8.3, 6.9, 1.4 Hz,1H), 7.79 (d, J = 8.3 Hz, 1H), 7.66 (td, J = 8.3, 1.3 Hz, 1H), 2.43 (td, J = 8.3,4.2 Hz, 1H), 1.23-1.11 (m, 2H), 1.10-0.99 (m, 2H).

[0171] 2) 3l A mixture of N-(2-chloroquinazoline-4-yl)-5-cyclopropyl-1,3,4-thiadiazol-2-amine (50 mg, 0.17 mmol), 2-(4-aminophenyl)acetonitrile (33 mg, 0.25 mmol), and ethanol (2 mL) was stirred for 2 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was filtered and purified, and washed with methanol to give 3 l (47 mg, 71% yield) of a yellow solid.

[0172] 1 H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.86(t,J = 7.8 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.61-7.39 (m, 5H), 4.15 (s, 2H), 2.29-2.18 (m, 1H), 1.25-1.13 (m, 2H), 0.78 (s, 2H).

[0173] Synthesis example of tert-butyl carbamate (3m) 1) (3-((2-chloroquinazoline-4-yl)amino)phenyl)tert-butyl carbamate (2m) DIPEA (0.126 mL, 0.72 mmol) was added dropwise to a stirred solution of 2,4-dichloroquinazoline (105 mg, 0.53 mmol), tert-butyl (3-aminophenyl)carbamate (100 mg, 0.48 mmol), and MeCN (5 mL) at room temperature. The reaction mixture was heated and stirred at 45 °C. After 2 days, an equal volume of water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na₂SO₄. After filtration, the residue was purified by column chromatography (30% Hex / EA) to give a white solid compound 2m (151 mg, 85% yield).

[0174] 1 H NMR (300 MHz, DMSO) δ 10.22 (s, 1H), 9.49 (s, 1H), 8.60 (d, J = 8.4Hz, 1H), 8.00-7.77 (m, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 1.50 (s, 9H).

[0175] 2) 3m A mixture of tert-butyl (3-((2-chloroquinazoline-4-yl)amino)phenyl)carbamate (100 mg, 0.27 mmol), 2-(4-aminophenyl)acetonitrile (53 mg, 0.40 mmol), and ethanol (3 mL) was stirred for 4 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was filtered and purified, and washed with EtOAc to give compound 3m (131 mg, 104% yield).

[0176] 1 H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 10.57 (s, 1H), 9.58 (s, 1H), 8.62 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.8 Hz, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.54-7.47 (m, 2H), 7.36-7.20 (m, 5H), 4.01(s, 2H), 1.48 (s, 9H).

[0177] Synthesis of 2-(4-((4-((3-aminophenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3n) Compound 3m (80 mg, 0.17 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (TFA) (0.5 mL) was added dropwise, with stirring at room temperature for 12 hours. The solvent was evaporated, and the addition of DCM was repeated twice. The solvent was evaporated, and the addition of diethyl ether was repeated several times. The solvent was evaporated, the residue was dissolved in EtOAc, and washed twice with saturated NaHCO3 solution. The organic layer was dried with Na2SO4. The residue was purified by preparative grade thin-layer chromatography (prep TLC) (DCM 92:MeOH 7:NH4OH 1) to give a bright orange solid compound 3n (30 mg, 48% yield).

[0178] 1 H NMR (300 MHz, DMSO) δ 9.42 (s, 1H), 9.14 (s, 1H), 8.38 (dd, J = 8.3, 1.4 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.74-7.59 (m, 1H), 7.48 (dd,J = 8.4, 1.2Hz, 1H), 7.31-7.17 (m, 3H), 7.13 (s, 1H), 7.09-6.98 (m, 2H), 6.46-6.37 (m,1H), 5.12 (s, 2H), 3.94 (s, 2H).

[0179] Synthesis of 2-(4-((4-((1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3o) At 120°C, 2-chloro-N-(1H-pyrazol-3-yl)quinazolin-4-amine (2-chloro- N -(1 H A mixture of pyrazol-3-yl)quinazolin-4-amine (80 mg, 0.33 mmol) and 2-(4-aminophenyl)acetonitrile (65 mg, 0.49 mmol) was stirred in a sealed test tube for 3 hours. The reaction mixture was cooled and the solvent was evaporated. The crude product was filtered, washed, and purified to give a beige solid compound 3o (53 mg, 48% yield). 1 H NMR (300 MHz, DMSO) δ 13.05 (s, 1H), 11.60 (s, 1H), 10.67 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.51(t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.56 (s, 1H), 4.08 (s, 2H). 13C NMR (101 MHz, DMSO) δ 158.93, 152.12, 145.54, 139.86, 136.23, 136.20, 130.17, 129.35, 128.94, 125.72, 124.72, 124.63, 119.83, 118.10, 110.57, 100.09, 22.41. MS (ESI) m / z for C 19 H 15 N7[M + Calculated value: 341.1; Experimental value: 342.1 [M] + + H + ].

[0180] 2-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile ( ...acetonitrile (2-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)acetonitrile (2-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)acetonitrile (2-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)acetonitrile (2-(4-( H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile) (3p) 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2-chloro- N- (5-methyl-1 H 3-pyrazol-3-yl)quinazolin-4-amine (28 mg, 0.11 mmol) and 2-(4-aminophenyl)acetonitrile (21 mg, 0.16 mmol) were dissolved in tert-butanol (2 mL). Heating was performed at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After 5 hours, the solvent was evaporated, and the product was recovered by washing with EtOAc and filtration, yielding a pale reddish-yellow solid compound 3p (35 mg, 91% yield). 1 H NMR (400MHz, DMSO) δ 11.52 (s, 1H), 10.54 (s, 1H), 8.66 (d, J = 8.3 Hz, 1H), 7.87 (t, J =7.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.50 (t, J= 7.7Hz, 1H), 7.42 (d, J = 8.1 Hz, 2H), 6.30 (s, 1H), 4.09 (s, 2H), 2.23 (s, 3H). 13 CNMR (101 MHz, DMSO) δ 158.62, 152.29, 145.88, 139.63, 136.39, 136.07, 129.84, 129.23, 128.96, 125.46, 125.08, 124.66, 119.73, 118.04, 110.80, 99.42, 22.42, 22.38, 11.17. MS (ESI) m / z for C 20 H 17 N7[M + Calculated value: 355.2; Experimental value: 356.2 [M] + + H + ].

[0181] 2-(4-((4-((5-bromo-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile ( ... H Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile)(3q) N-(5-bromo-1H-pyrazol-3-yl)-2-chloroquinazoline-4-amine dissolved in ethanol (3 mL) N -(5-bromo-1 H A mixture of pyrazol-3-yl)-2-chloroquinazolin-4-amine (32 mg, 0.10 mmol) and 2-(4-aminophenyl)acetonitrile (20 mg, 0.15 mmol) was stirred in a sealed test tube at 120 °C for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The crude product was filtered with methanol, washed, and purified to give an ivory-colored solid compound 3q (34 mg, 81% yield). 1 H NMR (300 MHz, DMSO) δ11.90 (s, 1H), 10.77 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 7.89 (t, J= 7.8 Hz, 1H),7.75 - 7.65 (m, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 6.56 (s, 1H), 4.11 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 158.47, 152.72, 136.29, 136.18, 129.51, 129.15, 125.50, 124.90, 124.62, 119.61, 119.01, 110.77, 22.54. MS (ESI) m / z for C 19 H 14 BrN7[M + Calculated value: 419.1; Experimental value: 420.1 [M] + + H + ].

[0182] 2-(4-((4-((5-methoxy-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile ( ...acetonitrile (2-(4-((4-((5-methoxy-1H-pyrazol-3-yl)amino)acetonitrile (2-(4-((5-methoxy-1H-pyraz H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile) (3r) 2-chloro-N-(5-methoxy-1H-pyrazole-3-yl)quinazolin-4-amine (2-chloro- N -(5-methoxy-1 H A mixture of pyrazol-3-yl)quinazolin-4-amine (36 mg, 0.13 mmol) and 2-(4-aminophenyl)acetonitrile (26 mg, 0.20 mmol) was stirred in a sealed test tube at 120 °C for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by column chromatography (5% DCM / MeOH) to give an ivory-colored solid compound 3r (39 mg, 81% yield). 1 H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 10.60 (s, 1H), 9.85 (s, 1H), 8.30 (dd,J = 8.4, 1.4 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.74 - 7.66 (m, 1H), 7.58 (dd, J = 8.4, 1.2 Hz,1H), 7.38 - 7.23 (m, 3H), 5.55 (d, J = 2.3 Hz, 1H), 3.98 (s, 2H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 162.52, 156.95, 155.92, 151.70, 140.89, 133.88, 128.95, 126.55, 123.76, 123.32, 123.05, 120.05, 118.92, 111.60, 78.00, 55.75, 22.28. MS (ESI) m / z for C 20 H 17 N7O [M + Calculated value: 371.2; Experimental value: 372.1 [M] + + H + ].

[0183] Synthesis of 2-(4-((4-((1H-indazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3S) 2-chloro-N-(1H-indazol-3-yl)quinazolin-4-amine (2-chloro- N -(1 H (-indazol-3-yl)quinazolin-4-amine (50 mg, 0.17 mmol) and 2-(4-aminophenyl)acetonitrile (34 mg, 0.25 mmol) were added to ethanol (3 mL) and stirred in a sealed test tube at 120 °C for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was purified by filtration and washed with ethyl acetate to give a yellow solid of the 3S substance (27 mg, 41% yield). 1 H NMR (300 MHz, DMSO) δ 13.26(s, 1H), 11.75 (s, 1H), 10.58 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 7.96 (d, J= 7.6Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.69 - 7.54 (m, 3H), 7.51 - 7.39 (m, 1H), 7.20 - 7.02 (m, 3H), 6.83 (d, J = 8.2 Hz, 2H), 3.88 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 161.79, 151.61, 141.69, 140.31, 138.81, 136.60, 136.21, 128.42, 127.44, 127.25, 125.76, 125.15, 122.23, 121.16, 120.98, 119.53, 118.28, 118.04, 111.18, 110.63, 22.19. MS (ESI) m / z for C 23 H 17 N7[M + Calculated value: 391.2; Experimental value: 392.2 [M] + + H + ].

[0184] Synthesis example of 2-(4-((4-((2-(benzyloxy)phenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3t) 1) N-(2-(benzyloxy)phenyl)-2-chloroquinazoline-4-amine (2t) At room temperature, 2,4-dichloro-quinazoline (300 mg, 1.51 mmol) and 2-(benzyloxy)aniline (330 mg, 1.66 mmol) were dissolved in MeCN (10 mL), and DIPEA (0.395 mL, 2.26 mmol) was added at room temperature. After overnight incubation, the solvent was evaporated, the residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4. The residue was purified by column chromatography (10% Hex / EA) to give a bright brown solid compound 2t (120 mg, 22% yield).

[0185] 1 H NMR (400 MHz, DMSO) δ 10.04 (s, 1H), 8.46 (dd, J = 8.4, 1.3 Hz, 1H), 7.87 (td, J = 8.3, 1.3 Hz, 1H), 7.71 (dd, J= 8.3, 1.2 Hz, 1H), 7.62 (td, J = 8.3, 1.3 Hz, 1H), 7.47 (dd, J = 7.7, 1.7 Hz, 1H), 7.36-7.21 (m, 6H), 7.18 (dd, J =8.4, 1.3 Hz, 1H), 7.06 (td, J = 7.6, 1.3 Hz, 1H), 5.18 (s, 2H).

[0186] 2) 3t A mixture of N-(2-(benzyloxy)phenyl)-2-chloroquinazoline-4-amine (70 mg, 0.19 mmol), 2-(4-aminophenyl)acetonitrile (38 mg, 0.29 mmol), and ethanol (3 mL) was stirred for 2 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was filtered and purified, and washed with EtOAc to give 3t (82 mg, 98% yield) of an ivory-colored solid compound.

[0187] 1 H NMR (300 MHz, DMSO) δ 11.08 (s, 1H), 10.49 (s, 1H), 8.55 (d, J = 8.2Hz, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 7.7 Hz,1H), 7.53-7.40 (m, 2H), 7.39-7.28 (m, 3H), 7.28-7.22 (m, 2H), 7.22-7.07 (m,6H), 5.13 (s, 2H), 3.98 (s, 2H).

[0188] Synthesis example of 2-(4-((4-((2-hydroxyphenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (3u) 1,2-(4-((4-(((2-(benzyloxy)phenyl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (50 mg, 0.11 mmol) and 10% Pd / C (10 mg) were dissolved in methanol (2 mL) and stirred under hydrogen for 3 hours. The residue was filtered through fluorite and the filtrate was evaporated. The residue was purified by column chromatography (3% DCM / MeOH), filtered with gasoline and washed, to give a light gray solid compound 3u (27 mg, 68% yield).

[0189] 1 H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.22 (s, 1H), 9.15 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.70-7.57 (m, 2H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.30-7.21 (m, 1H), 7.19-7.02 (m, 3H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.90 (td, J = 7.5, 1.5 Hz, 1H), 3.90 (s, 2H).

[0190] The compounds represented by chemical formulas 1-2 according to the present invention can be prepared according to the following reaction formula 2, but are not limited thereto.

[0191] <Reaction 2>

[0192] In the reaction formula 2, Ar 1 This is the same as the definition above. N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -Phenylenol-2,4-diamine (N 4 -(5-cyclopropyl-1 H -pyrazol-3-yl)-N 2 Synthesis of 2,4-phenylquinazoline-2,4-diamine (4a) Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of aniline (34 mg, 0.37 mmol) was added to tert-butanol (0.5 mL). An aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was heated at 110 °C with stirring. After 6 hours, the solvent was evaporated, and the crude product was dissolved in DCM. The reaction mixture was purified by column chromatography (4% DCM / MeOH) to ensure the yield of compound 4a (139 mg, 98% yield). 1 H NMR (300 MHz, DMSO-d6) δ11.51 (s, 1H), 10.56 (s, 1H), 8.68 (d, J = 8.2 Hz, 1H), 7.90-7.85 (m, 1H), 7.63(d, J = 8.2 Hz, 1H), 7.57-7.40 (m, 5H), 7.37-7.24 (m, 2H), 6.17 (s, 1H), 1.89-1.83 (m, 1H), 1.01-0.88 (m, 2H), 0.66-0.53 (m, 2H). MS (ESI) m / z for C 20 H 18 N6[M + Calculated value: 342.2; Experimental value: 343.4 [M] + + H + ].

[0193] N 2 -(4-Bromophenyl)-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -(4-bromophenyl)-N 4 -Synthesis of (5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine) (4b) A mixture of compound 2a (300 mg, 1.05 mmol) in ethanol (5 mL) and 4-bromoaniline (271 mg, 1.58 mmol) was stirred in a sealed test tube for 3 hours at 120 °C. The reaction mixture was cooled and evaporated under vacuum. The residue was washed with MeOH and purified by filtration to give compound 4b as a white solid (423 mg, 98% yield). 1H NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.54 (s, 1H), 8.66 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.71-7.58 (m, 3H), 7.58-7.42 (m, 3H), 6.13 (s,1H), 1.88 (td, J = 8.5, 5.1 Hz, 1H), 1.02-0.91 (m, 2H), 0.66-0.53 (m, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 158.45, 152.30, 146.96, 145.78, 136.50, 136.03, 132.30, 126.28, 125.45, 125.10, 118.37, 118.14, 110.86, 95.68, 8.39, 7.30. MS(ESI) m / z for C 20 H 17 BrN6[M + Calculated value: 421.3; Experimental value: 421.2 [M] + + H + ].

[0194] N 2 -(4-bromo-2-fluorophenyl)-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -(4-bromo-2-fluorophenyl)-N 4 Synthesis of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine)(4c) A mixture of compound 2a (300 mg, 1.05 mmol) in EtOH (5 mL) and 4-bromo-2-fluoroaniline (299 mg, 1.58 mmol) was stirred in a sealed test tube (vial) for 3 hours at 120 °C. The reaction mixture was cooled and evaporated under vacuum. The residue was washed with MeOH and purified by filtration to give compound 4c (359 mg, 78% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 10.29 (s, 1H), 8.69 (d, J = 8.3 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.80 (dd, J = 9.9, 2.1Hz, 1H), 7.75-7.60 (m, 2H), 7.59-7.46 (m, 2H), 5.94 (s, 1H), 1.83 (td, J = 8.5,4.4 Hz, 1H), 1.01-0.92 (m, 2H), 0.63-0.49 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 158.11, 157.94, 155.43, 152.67, 146.74, 145.92, 136.11, 130.11, 128.49, 128.46, 125.70, 125.17, 124.41, 120.16, 119.93, 118.11, 110.82, 95.28, 8.39, 7.30. MS (ESI) m / z for C 20 H 16 BrFN6[M + Calculated value: 439.3; Experimental value: 439.3 [M] + + H + ].

[0195] Synthesis of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzonitrile (4d) Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of 4-aminophenylacetonitrile (43 mg, 0.37 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. The reaction mixture was heated at 110 °C while stirring with the addition of 0.012 mL of 37% HCl aqueous solution. After 6 hours, the mixture was filtered with methanol and washed to give compound 4d (76 mg, 84% yield).

[0196] 1 H NMR (300 MHz, DMSO-d6) δ 11.57 (s, 1H), 11.04 (s, 1H), 8.67 (d, J=8.2 Hz, 1H), 7.94-7.80 (m, 5H), 7.67 (dd, J = 8.4, 1.1 Hz, 1H), 7.56-7.47 (m, 1H), 6.15 (s, 1H), 1.98-1.91 (m, 1H), 1.05-0.92 (m, 2H), 0.73-0.58 (m, 2H). MS (ESI) m / z for C 21 H 17 N7[M + Calculated value: 367.2; Experimental value: 368.3 [M] + + H + ].

[0197] N 2 -(4-((1H-tetrazol-5-yl)methyl)phenyl)-N 4 Synthesis example of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (4e) Compound 2a (1.50 g, 5.25 mmol) was dissolved in 15 mL of tert-butanol, and a solution of 4-aminobenzonitrile (1.04 g, 7.87 mmol) dissolved in 5 mL of tert-butanol was added to the mixture. The reaction mixture was heated at 110 °C while stirring with the addition of 0.100 mL of 37% HCl aqueous solution. After 6 hours, the solvent was evaporated, and the product was filtered and washed with methanol to give a white solid compound. A mixture of the resulting white solid compound (50 mg, 0.131 mmol), NaN3 (59.6 mg, 0.92 mmol), NH4Cl (49.1 mg, 0.92 mmol), and DMF (0.437 mL) was stirred for 2 days at 120 °C. The reaction mixture was extracted with EtOAc and washed with water. The organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was pulverized with 5% DCM / MeOH to give a yellow solid compound 4e (2.7 mg, 4.85% yield).

[0198] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 Synthesis example of -(4-((methylsulfonyl)methyl)phenyl)quinazolin-2,4-diamine (4f) A mixture of compound 2a (71.4 mg, 0.25 mmol), 4-((methanesulfonyl)methyl)aniline (48.6 mg, 0.26 mmol), and isopropanol (IPA) (0.833 mL) containing dioxane (0.188 mL, 0.75 mmol) in 4 M HCl was irradiated for 30 min in a microwave reactor at 150 °C. The reaction mixture was pulverized with IPA. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was pulverized with diethyl ether to give compound 4f (17 mg, 15% yield) as a yellow solid.

[0199] Synthesis example of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzenesulfonamide (4g) A mixture of compound 2a (71.4 mg, 0.25 mmol), 4-aminobenzenesulfonamide (51.7 mg, 0.30 mmol), and 1,4-dioxane (0.188 mL, 0.75 mmol) in 4 M HCl was irradiated for 30 min at 130 °C using a microwave reactor. The reaction mixture was pulverized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was purified by column chromatography (EtOAc:Hex = 1:2 in 10% (7 N ammonia in MeOH) solution) to give 4 g (26 mg, 24% yield) of a yellow solid.

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.39 (s, 1H), 8.42 (s,1H), 8.09 (d, J = 8.6 Hz, 2H), 7.75-7.73 (m, 2H), 7.57 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 1.99-1.88 (m, 1H), 0.98-0.89 (m, 2H), 0.82-0.69 (m, 2H) Synthesis example of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-methylbenzenesulfonamide (4h) A mixture of compound 2a (71.4 mg, 0.25 mmol), 4-amino-N-methylbenzenesulfonamide (69.8 mg, 0.38 mmol), and IPA (0.833 mL) containing dioxane (0.188 mL, 0.75 mmol) in 4 M HCl was irradiated for 1 hour at 150 °C using a microwave reactor. The reaction mixture was pulverized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was purified by column chromatography (EtOAc:Hex = 1:1 containing 2–10% (7 N ammonia in MeOH solution) to give a yellow solid compound 4h (79 mg, 73%).

[0201] Synthetic example of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide (4i) A mixture of compound 2a (71.4 mg, 0.25 mmol), 4-amino-N-(2-hydroxyethyl)benzenesulfonamide (70.3 mg, 0.33 mmol), and IPA (0.833 mL) containing dioxane (0.188 mL, 0.75 mmol) in 4 M HCl was irradiated for 30 min in a microwave reactor at 150 °C. The reaction mixture was pulverized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4 and filtered and concentrated. The residue was purified by column chromatography (EtOAc:Hex = 1:1 containing 5–15% (7 N ammonia in MeOH solution) and pulverized with diethyl ether to give compound 4i (62 mg, 53% yield) as a white solid.

[0202] Synthesis example of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N,N-dimethylbenzenesulfonamide (4j) Compound 2a (90 mg, 0.32 mmol) was dissolved in tert-butanol (4.5 mL), and a solution of N,N-4-aminobenzenesulfonamide (95 mg, 0.47 mmol) dissolved in tert-butanol (0.75 mL) was added to the mixture. The reaction mixture was heated at 110 °C while stirring with the addition of 0.015 mL of 37% HCl aqueous solution. After 6 hours, the solvent was evaporated, and compound 4j (139 mg, 98% yield) was obtained by recrystallization (EtOAc:Hex = 4:1).

[0203] N 2 -(4-chloro-3-(trifluoromethyl)phenyl)-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -(4-chloro-3-(trifluoromethyl)phenyl)-N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine) (4k) A mixture of compound 2a (71.4 mg, 0.25 mmol), 4-chloro-3-(trifluoromethyl)aniline (51.3 mg, 0.26 mmol), and dioxane (0.188 mL, 0.75 mmol) in 4M HCl was added to IPA (0.833 mL), and the mixture was irradiated in a microwave reactor at 150 °C for 0.5 h. The reaction mixture was filtered and washed with IPA. The filter cake was tritized with DCM. The solid was dissolved in methanol and tritized with diethyl ether to prepare the ivory-colored solid compound 4k (69 mg, 62% yield). 1 H NMR (400 MHz, DMSO-d6) δ11.44 (s, 1H), 10.59 (s, 1H), 8.64 (d, J = 7.5 Hz, 1H), 8.10 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H), 7.90 (t, J = 7.4 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.2Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 6.08 (s, 1H), 1.85 (td, J = 8.5, 4.5 Hz, 1H), 0.94-0.93 (m, 2H), 0.57 (s, 2H).

[0204] N 2 -(5-(benzo[d]thiazo-2-yl)-2-methylphenyl)-N 4 Synthesis of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (4l) A mixture of compound 2a (100 mg, 0.35 mmol), 5-(benzo[d]thiazol-2-yl)-2-methylaniline (126 mg, 0.53 mmol), and ethanol (2 mL) was stirred for 2 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was washed with methanol and filtered to give compound 4l (116 mg, 68% yield) as a bright yellow solid.

[0205] 1 H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 12.42 (s, 1H), 11.54 (s,1H), 10.22 (s, 1H), 8.71 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.59-7.41 (m, 3H), 5.85 (s, 1H), 2.37 (s, 3H), 1.46 (s, 1H), 0.63 (s, 2H), 0.25 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 167.03, 157.81, 153.99, 153.17, 146.26, 139.72, 138.52, 135.94, 134.91, 132.25, 132.02, 127.16, 126.40, 126.03, 125.34, 125.19, 123.26, 122.83, 117.78, 110.89, 95.31, 18.46, 7.95, 6.96. MS (ESI) m / z for C 28 H 23 N7S [M + Calculated value: 489.6; Experimental value: 490.3 [M] + + H + ].

[0206] N 2 -(4-(benzo[d]thiazo-2-yl)phenyl)-N 4Synthesis example of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (4m) A mixture of compound 2a (100 mg, 0.35 mmol), 4-(benzo[d]thiazol-2-yl)aniline (119 mg, 0.53 mmol), and ethanol (2 mL) was stirred for 2 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The residue was washed with methanol and filtered to give a yellow solid, compound 4m (158 mg, 95% yield).

[0207] 1 H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.83 (s, 1H), 8.67 (d, J =8.3 Hz, 1H), 8.24-8.11 (m, 3H), 8.07 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.3 Hz, 1H), 7.60-7.38 (m, 3H), 6.24(s, 1H), 1.87 (td, J = 8.5, 4.5 Hz, 1H), 0.96-0.78 (m, 2H), 0.69-0.48 (m, 2H). MS (ESI) m / z for C 27 H 21 N7S [M + Calculated value: 475.6; Experimental value: 476.3 [M] + + H + ].

[0208] N 2 N 4 Synthesis example of bis(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (4n) Compound 2a (100 mg, 0.35 mmol) and 5-cyclopropyl-1H-pyrazole-3-amine (52 mg, 0.42 mmol) were dissolved in tert-butanol (2 mL), and the mixture was heated and stirred at 110 °C after the addition of 0.010 mL of 37% HCl aqueous solution. After overnight incubation, the product was recovered by column chromatography (5% DCM / MeOH), filtered with diethyl ether and washed to give a bright yellow solid compound 4n (49 mg, 37% yield).

[0209] 1 H NMR (300 MHz, DMSO) δ 12.36 (s, 1H), 10.74 (s, 2H), 8.70-8.32 (m,1H), 7.84-7.69 (m, 1H), 7.67-7.25 (m, 2H), 6.97 (s, 1H), 5.98 (s, 1H), 2.06-1.84 (m, 2H), 1.06-0.86 (m, 4H), 0.75 (td, J = 6.3, 2.7 Hz, 4H).

[0210] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)methyl benzoate (Methyl 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)benzoate H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoate) (4o) Compound 2a (200 mg, 0.70 mmol) and methyl 4-aminobenzoate (127 mg, 0.84 mmol) were dissolved in tert-butanol (3 mL). An aqueous solution of 37% HCl (0.050 mL) was added, and the reaction mixture was heated while stirring at 110 °C. After 6 hours, to obtain a white solid compound 4o, the product was recovered by washing with EtOAc and filtering. (296 mg, 106% yield) 1 H NMR (300 MHz, DMSO) δ 11.58 (s, 1H), 10.97 (s, 1H), 8.68 (d, J = 7.3 Hz, 1H), 8.05-7.96 (m, 2H), 7.94-7.85 (m, 1H),7.75 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.15(s, 1H), 3.87 (s, 3H), 1.90 (tt, J = 8.4, 5.1 Hz, 1H), 0.99-0.89 (m, 2H), 0.66-0.53 (m, 2H). MS (ESI) m / z for C 22 H 20N6O2[M + Calculated value: 400.2; Experimental value: 401.4 [M] + + H + ].

[0211] Synthesis of tert-butyl 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoate (4p) Compound 2a (200 mg, 0.70 mmol) and tert-butyl 4-aminobenzoate (162 mg, 0.84 mmol) were dissolved in tert-butanol (3 mL). An aqueous solution of 37% HCl (0.020 mL) was added, and the reaction mixture was heated while stirring at 110 °C. After 5 hours, to obtain a white solid compound 4p, the product was recovered by washing with EtOAc and filtering. (325 mg, 105% yield) 1 H NMR (300 MHz, DMSO) δ 11.62 (s, 1H), 10.95 (s, 1H), 8.69 (d, J = 8.3 Hz, 1H), 8.01 - 7.83 (m, 3H), 7.75 - 7.59 (m, 3H), 7.52 (t, J = 7.7 Hz,1H), 6.14 (s, 1H), 1.89 (t, J = 4.3 Hz, 1H), 1.57 (s, 9H), 1.00 - 0.87 (m, 2H), 0.64 - 0.52 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 164.85, 158.92, 152.02, 147.17,145.54, 141.43, 136.20, 130.43, 127.85, 125.64, 125.21, 122.47, 118.19,110.89, 95.84, 81.00, 28.28, 9.22, 8.46, 7.25.

[0212] MS (ESI) m / z for C 25 H 26 N6O2[M + Calculated value: 442.2; Experimental value: 443.5 [M]+ + H + ].

[0213] Synthesis example of 2-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)tert-butyl acetate (4q) Compound 2a (130 mg, 0.46 mmol) and tert-butyl 2-(4-aminophenyl)acetate (113 mg, 0.55 mmol) were dissolved in tert-butanol (4 mL), and 0.010 mL of 37% HCl aqueous solution was added. The mixture was heated and stirred at 110 °C. After 5 hours, the product was filtered and washed with EtOAc to give a white solid compound 4q (232 mg, 112% yield).

[0214] 1 H NMR (300 MHz, DMSO) δ 12.65 (s, 1H), δ 11.52 (s, 1H), 10.57 (s,1H), 8.68 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.5 Hz, 1H), 7.68-7.56 (m, 1H), 7.54-7.41 (m, 3H), 7.37-7.29 (m, 2H), 6.21 (s, 1H), 3.62 (s, 2H), 1.88 (tt, J = 8.4,5.1 Hz, 1H), 1.42 (s, 9H), 1.00-0.88 (m, 2H), 0.66-0.49 (m, 2H).

[0215] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)benzoic acid (4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)benzoic acid H Synthesis of pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoic acid)(4r) Compound 4p (150 mg, 0.34 mmol) was dissolved in DCM (3 mL). Trifluoroacetic acid (TFA) (1 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the addition of DCM was repeated twice. The solvent was evaporated, and the addition of diethyl ether was repeated several times. The solvent was evaporated, and the solid was filtered through diethyl ether to give a white solid, compound 4r (156 mg, 119% yield). 1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 10.89 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.88 (t, J = 7.9 Hz, 1H), 7.75 (d, J = 8.3Hz, 2H), 7.62 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 6.19 (s, 1H), 1.89(tt, J = 8.5, 5.0 Hz, 1H), 1.01 - 0.85 (m, 2H), 0.67 - 0.54 (m, 2H). 13 C NMR (101MHz, DMSO) δ 166.85, 160.07, 159.73, 159.39, 158.53, 152.01, 146.78, 145.18, 141.57, 135.50, 130.32, 126.47, 124.91, 124.45, 121.63, 117.92, 114.98, 110.54, 95.49, 7.85, 6.90. MS (ESI) m / z for C 21 H 18 N6O2[M + Calculated value: 386.2; Experimental value: 387.4 [M] + + H + ].

[0216] Synthesis of 2-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetic acid (4S) Compound 4q (150 mg, 0.33 mmol) was dissolved in DCM (3 mL). TFA (1 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the addition of DCM was repeated twice. The solvent was evaporated, and the addition of diethyl ether was repeated several times. The solvent was evaporated, and the solid was filtered through diethyl ether to give a white solid, compound 4s. (150 mg, 115% yield) 1 H NMR (300 MHz, DMSO) δ 11.49 (s, 1H), 10.49 (s, 1H), 8.66 (d, J= 8.3 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.35 (d, J = 8.2 Hz, 2H), 6.22 (s, 1H), 3.63 (s, 2H), 1.85 (td, J = 8.5, 4.3 Hz,1H), 1.01 - 0.88 (m, 2H), 0.59 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 173.02, 160.42, 160.09, 158.52, 152.48, 146.90, 145.96, 135.92, 135.70, 132.78, 130.89, 130.44, 125.18, 124.98, 123.85, 118.63, 115.69, 110.78, 95.92, 40.70, 8.33, 7.32. MS (ESI) m / z for C 22 H 20 N6O2[M + Calculated value: 400.2; Experimental value: 401.4 [M] + + H + ].

[0217] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)benzamide (4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)benzamide H Synthesis of pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzamide)(4t) DIPEA (0.136 mL, 0.78 mmol) and HATU (197 mg, 0.52 mmol) were added to a solution of 4r (100 mg, 0.26 mmol) dissolved in 1,4-dioxane (3 mL). The reaction mixture was stirred for 20 minutes at room temperature. Ammonium chloride (138 mg, 2.59 mmol) was added to the mixture and stirred for 2 days at room temperature. EtOAc was added to the mixture and the mixture was washed twice with water. The organic layer was washed several times with brine. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (DCM 92:MeOH 7:NH4OH 1) to give an ivory-colored solid compound 4t (20 mg, 20% yield). 1 H NMR (300 MHz, DMSO) δ 12.53 (d, J = 180.9 Hz, 1H), 10.39(d, J = 138.2 Hz, 1H), 9.72 (d, J = 187.0 Hz, 1H), 8.61 - 8.22 (m, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.93 - 7.75 (m, 3H), 7.75 - 7.45 (m, 2H), 6.68 (s, 1H), 2.08 -1.80 (m, 1H), 0.93 (s, 2H), 0.75 (s, 2H). MS (ESI) m / z for C 21 H 19 N7O [M + Calculated value: 385.4; Experimental value: 386.4 [M] + + H + ].

[0218] Synthesis of 2-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)acetamide (4u) DIPEA (0.092 mL, 0.52 mmol) and HATU (134 mg, 0.35 mmol) were added to a solution of 4s (70 mg, 0.18 mmol) dissolved in 2 mL of 1,4-dioxane, and the mixture was stirred at room temperature for 20 minutes. Ammonium chloride (94 mg, 1.75 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 days. EtOAc was added and the mixture was washed twice with water. The organic layer was washed several times with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (DCM 92:MeOH 7:NH4OH 1) to give an ivory-colored solid compound 4u (9 mg, 12% yield).

[0219] 1 H NMR (300 MHz, DMSO) δ 12.50 (d, J = 190.2 Hz, 1H), 10.30 (d, J = 144.4Hz, 1H), 9.40 (d, J = 201.9 Hz, 1H), 8.51-8.20 (m, 1H), 7.92-7.73 (m, 2H), 7.65(s, 1H), 7.55-7.34 (m, 2H), 6.85 (s, 1H), 6.68 (s, 1H), 3.33 (s, 2H), 2.06-1.80 (m, 1H), 0.93 (s, 2H), 0.75 (s, 2H).

[0220] N 2 -(4-Aminophenyl)-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -(4-aminophenyl)-N 4 -Synthesis of (5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine) (4v) A mixture of compound 2a (100 mg, 0.35 mmol) in ethanol (3 mL) and benzene-1,4-diamine (57 mg, 0.53 mmol) was stirred in a sealed test tube for 2 hours at 120 °C. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by washing with 5% DCM / MeOH and diethyl ether and filtering to produce a dark green solid compound 4v (124 mg, 99% yield). 1H NMR (300 MHz, DMSO) δ 12.54 (s, 1H), 11.29 (s, 1H), 10.07 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.21 (s, 2H), 6.84 - 6.64 (m,2H), 6.25 (s, 1H), 1.97 - 1.78 (m, 1H), 1.06 - 0.88 (m, 2H), 0.79 - 0.50 (m,2H). 13 C NMR (101 MHz, DMSO) δ 157.78, 153.24, 135.55, 126.14, 124.86, 116.00, 110.73, 95.50, 8.39, 8.32, 7.49. MS (ESI) m / z for C 20 H 19 N7[M + Calculated value: 357.2; Experimental value: 358.5 [M] + + H + ].

[0221] Synthesis of (2-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoylamino)ethyl)tert-butyl carbamate (4w) Compound 4r (150 mg, 0.39 mmol) and PyBOP (404 mg, 0.78 mmol) were dissolved in DMF (3 mL). Tert-butyl (2-aminoethyl)carbamate was then added dropwise to the solution. tert-butyl (2-aminoethyl)carbamate (0.123 mL, 0.78 mmol) and TEA (0.108 mL, 0.78 mmol). The reaction mixture was stirred at room temperature for 24 hours. After confirmation by thin-layer chromatography (TLC), the reaction mixture was quenched with water and extracted with EA. The organic layer was washed several times with saturated NaHCO3 and brine. The bound organic layer was dried on Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (5% DCM / MeOH) and filtered with diethyl ether to give the white solid product compound 4w (95 mg, 47% yield). 1 H NMR (300 MHz, DMSO) δ 12.57 (d, J = 150.3 Hz, 1H), 10.59 (s,1H), 9.83 (d, J = 101.7 Hz, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 8.00 (d, J = 8.4 Hz,1H), 7.94 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.78-7.64 (m, 2H), 7.64-7.49 (m,2H), 7.43 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 6.6 Hz, 1H), 6.93 (t, J = 5.4 Hz, 1H), 6.53 (s, 1H), 3.30-3.23 (m, 2H), 3.18-3.05 (m, 2H), 1.91 (tt, J = 8.4, 5.0 Hz, 1H), 1.39 (s, 9H), 0.98-0.86 (m, 2H), 0.77-0.66 (m, 2H). MS (ESI) m / z for C 28 H 32 N8O3[M + Calculated value: 528.3; Experimental value: 529.7 [M] + + H + ].

[0222] Synthesis of (3-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoylamino)propyl)tert-butyl carbamate (4x) Compound 4r (150 mg, 0.39 mmol) and PyBOP (404 mg, 0.78 mmol) were dissolved in DMF (3 mL). Tert-butyl (3-aminopropyl)carbamate was then added dropwise to the solution. tert -butyl (3-aminopropyl)carbamate (0.136 mL, 0.78 mmol) and TEA (0.108 mL, 0.78 mmol). The reaction mixture was stirred for 24 hours at room temperature. After confirmation by TLC, the reaction mixture was quenched with water and extracted with EA. The organic layer was washed several times with saturated NaHCO3 and brine. The bound organic layer was dried on Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (5% DCM / MeOH) and filtered with diethyl ether to give an ivory-colored solid product (96 mg, 46% yield). 1 HNMR (300 MHz, DMSO) δ 12.52 (d, J = 180.8 Hz, 1H), 10.37 (d, J = 154.5 Hz, 1H), 9.38 (d, J = 191.9 Hz, 1H), 8.42 (s, 1H), 8.26 (s, 1H), 8.00 (d, J = 8.4 Hz, 2H),7.93-7.75 (m, 2H), 7.69 (s, 1H), 7.55 (s, 1H), 7.30 (s, 1H), 6.84 (t, J = 5.2Hz, 1H), 6.58 (d, J = 67.6 Hz, 1H), 5.84 (s, 1H), 3.26 (q, J = 6.3 Hz, 2H), 2.99(q, J= 6.5 Hz, 2H), 2.02-1.84 (m, 1H), 1.77-1.56 (m, 2H), 1.39 (s, 9H), 1.09 -0.85 (m, 2H), 0.87-0.56 (m, 2H). MS (ESI) m / z for C 29 H 34 N8O3[M + Calculated value: 542.3; Experimental value: 543.7 [M] + + H + ].

[0223] Synthesis of (4-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoylamino)butyl)carbamate)(4y) Compound 4r (150 mg, 0.39 mmol) and PyBOP (404 mg, 0.78 mmol) were dissolved in DMF (3 mL), and tert-butyl (4-aminobutyl)carbamate was added dropwise to the solution. tert -butyl (4-aminobutyl)carbamate (0.149 mL, 0.78 mmol) and TEA (0.108 mL, 0.78 mmol). The reaction mixture was stirred at room temperature for 24 hours. After confirmation by TLC, the reaction mixture was quenched with water and extracted with EA. The organic layer was washed several times with saturated NaHCO3 and brine. The bound organic layer was dried on Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (5% DCM / MeOH) and filtered with diethyl ether to give a light pink solid product (105 mg, 49% yield). 1 H NMR (300 MHz, DMSO) δ 12.51 (d, J = 180.8 Hz, 1H), 10.36 (d, J = 143.4 Hz, 1H), 9.38 (d, J = 194.3 Hz, 1H), 8.42 (s, 1H), 8.30-8.21 (m, 1H), 8.00 (d, J =8.7 Hz, 2H), 7.82 (d, J= 8.5 Hz, 2H), 7.76-7.62 (m, 1H), 7.55 (s, 1H), 7.30(s, 1H), 6.82 (t, J = 5.6 Hz, 1H), 6.58 (d, J = 68.2 Hz, 1H), 5.85 (s, 1H), 3.24(q, J = 6.3 Hz, 2H), 2.95 (q, J = 6.3 Hz, 2H), 1.93 (tt, J = 8.8, 5.2 Hz, 1H), 1.56-1.32 (m, 13H), 1.03-0.85 (m, 2H), 0.85-0.63 (m, 2H). MS (ESI) m / z for C 30 H 36 N8O3[M + Calculated value: 556.3; Experimental value: 557.8 [M] + + H + ].

[0224] Synthesis of (5-(4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzoylamino)pentyl)carbamate (4z) Compound 4r (150 mg, 0.39 mmol) and PyBOP (404 mg, 0.78 mmol) were dissolved in DMF (3 mL). Tert-butyl (5-aminopentyl)carbamate was then added dropwise to the solution. tert 5-butyl (5-aminopentyl)carbamate (0.162 mL, 0.78 mmol) and TEA (0.108 mL, 0.78 mmol). The reaction mixture was stirred at room temperature for 24 hours. After confirmation by TLC, the reaction mixture was quenched with water and extracted with EA. The organic layer was washed several times with saturated NaHCO3 and brine. The bound organic layer was dried on Na2SO4 and evaporated under vacuum. The crude product was purified by column chromatography (5% DCM / MeOH) and filtered with diethyl ether to give a bright yellow solid product (121 mg, 55% yield). 1HNMR (300 MHz, DMSO) δ 12.52 (d, J = 181.9 Hz, 1H), 10.36 (d, J = 143.0 Hz, 1H), 9.37 (d, J = 190.8 Hz, 1H), 8.42 (s, 1H), 8.29-8.16 (m, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.74-7.62 (m, 1H), 7.55 (s, 1H), 7.29 (s, 1H),6.79 (t, J = 5.7 Hz, 1H), 6.56 (d, J = 75.3 Hz, 1H), 5.84 (s, 1H), 3.25 (q, J = 6.6Hz, 2H), 2.92 (q, J = 6.6 Hz, 2H), 2.01-1.85 (m, 1H), 1.60-1.46 (m, 2H), 1.46-1.33 (m, 11H), 1.33-1.21 (m, 2H), 1.02-0.85 (m, 2H), 0.85-0.63 (m, 2H). MS(ESI) m / z for C 31 H 38 N8O3[M + Calculated value: 570.3; Experimental value: 571.8 [M] + + H + ].

[0225] Synthesis of N-(2-aminoethyl)-4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzamide. trifluoroacetic acid (4aa) Compound 4w (50 mg, 0.10 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and the diethyl ether was added several times. A white solid product was given. (62 mg, quant.) 1 H NMR (400 MHz, DMSO) δ 8.57 (s, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.84 (s, 5H), 7.60 (d, J = 8.3Hz, 1H), 7.50-7.37 (m, 1H), 6.24 (s, 1H), 3.55-3.51 (m, 2H), 3.01 (q, J = 6.1Hz, 2H), 1.89 (tt, J = 9.0, 5.1 Hz, 1H), 0.97-0.88 (m, 2H), 0.72-0.56 (m, 2H). MS (ESI) m / z for C 23 H 24 N8O [M + Calculated value: 428.2; Experimental value: 429.7 [M] + + H + ].

[0226] Synthesis of N-(3-aminopropyl)-4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzamide·trifluoroacetic acid (4ab) Compound 4x (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and the diethyl ether was added several times. A white solid product was given. (63 mg, quantified) 1 H NMR (400 MHz, DMSO) δ8.58 (s, 2H), 7.91 (d, J= 8.3 Hz, 2H), 7.86-7.68 (m, 6H), 7.59 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 6.5 Hz, 1H), 6.21 (s, 1H), 3.36 (q, J = 6.4 Hz, 2H), 2.87 (q, J =6.4 Hz, 2H), 1.93-1.85 (m, 1H), 1.85-1.77 (m, 2H), 0.96-0.87 (m, 2H), 0.67-0.53 (m, 2H). MS (ESI) m / z for C 24 H 26 N8O [M + Calculated value: 442.2; Experimental value: 443.7 [M] + + H + ].

[0227] Synthesis of N-(4-aminobutyl)-4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)benzamide.trifluoroacetic acid)(4ac) Compound 4y (50 mg, 0.09 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and the diethyl ether was added several times. A white solid product was given. (65 mg, quantified) 1 H NMR (400 MHz, DMSO) δ8.59 (d, J = 8.1 Hz, 1H), 8.54-8.41 (m, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.84 (t, J =8.0 Hz, 1H), 7.75 (s, 4H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 6.21 (s, 1H), 3.31 (q,J = 6.3 Hz, 2H), 2.84 (q, J = 6.3 Hz, 2H), 1.88 (tt, J =8.4, 5.1 Hz, 1H), 1.67-1.51 (m, 4H), 0.99-0.85 (m, 2H), 0.69-0.55 (m, 2H). MS(ESI) m / z for C 25 H 28 N8O [M + Calculated value: 456.2; Experimental value: 457.8 [M] + + H + ].

[0228] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 Synthesis of -(4-methoxybenzyl)quinazolin-2,4-diamine (4ad) A mixed solution of compound 2a (71.4 mg, 0.25 mmol) and 4-methoxybenzylamine (0.147 mL, 0.750 mmol) was irradiated for 1 hour at 150 °C using a microwave reactor. The reaction mixture was pulverized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4, filtered, and concentrated. The residue was pulverized with DCM and diethyl ether to give compound 4ad (46 mg, 48% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 12.20 (d, J = 251.2 Hz, 1H), 10.12 (d, J = 189.7 Hz, 1H), 8.26(d, J = 51.1 Hz, 1H), 7.51-7.28 (m, 5H), 7.09 (d, J = 42.3 Hz, 2H), 6.99-6.81 (m,2H), 4.51 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 1.92-1.79 (m, 1H), 0.96-0.83 (m, 2H), 0.80-0.48 (m, 2H).

[0229] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-methylbenzamide (4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-methylbenzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of -methylbenzamide (4ae) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. A methylamine solution (THF 2 M, 0.647 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried with anhydrous Na₂SO₄ and filtered, then washed with diethyl ether to ensure an ivory-colored solid (69 mg, 67%). 1 H NMR (400 MHz, DMSO) δ 12.51 (d, J = 240.1 Hz, 1H), 10.36 (d, J = 207.1 Hz, 1H), 9.36(d, J = 260.1 Hz, 1H), 8.42 (s, 1H), 8.24 (d, J = 5.3 Hz, 1H), 8.00 (d, J = 8.4 Hz,2H), 7.90 - 7.75 (m, 2H), 7.69 (s, 1H), 7.56 (s, 1H), 7.29 (s, 1H), 6.68 (s,1H), 2.79 (d, J = 4.4 Hz, 3H), 2.00 - 1.88 (m, 1H), 1.02 - 0.85 (m, 2H), 0.85 -0.64 (m, 2H). 13C NMR (101 MHz, DMSO) δ 167.92, 152.67, 145.23, 134.64, 134.58, 129.29, 128.03, 127.33, 124.72, 123.97, 119.09, 27.71, 16.68, 9.32. MS (ESI) m / z for C 22 H 21 N7O [M + Calculated value: 399.2; Experimental value: 400.5 [M] + + H + ].

[0230] 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-ethylbenzamide (4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-ethylbenzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of -ethylbenzamide (4af) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Ethylamine (0.085 mL, 1.29 mmol) was added to the mixture, and it was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried with anhydrous Na₂SO₄ and washed, filtered, and purified with diethyl ether to obtain an ivory-colored solid. (56 mg, 53%) 1 H NMR (400MHz, DMSO) δ 12.50 (d, J = 241.7 Hz, 1H), 10.36 (d, J = 194.2 Hz, 1H), 9.37 (d, J =257.6 Hz, 1H), 8.41 (s, 1H), 8.27 (d, J = 5.8 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.82 (d, J= 7.9 Hz, 2H), 7.69 (s, 1H), 7.55 (s, 1H), 7.29 (s, 1H), 6.68 (s,1H), 3.32-3.25 (m, 2H), 1.99-1.87 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.02-0.85(m, 2H), 0.85-0.65 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 166.14, 151.64, 144.16, 133.47, 128.29, 127.13, 126.35, 123.63, 118.11, 112.04, 34.39, 15.64, 15.46, 8.27. MS (ESI) m / z for C 23 H 23 N7O [M + Calculated value: 413.2; Experimental value: 414.5 [M] + + H + ].

[0231] Synthesis of 6-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (4 ag) Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid (73 mg, 0.37 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding and stirring DIPEA (48 mg, 0.37 mmol). After 4 days, the solvent was evaporated, and the mixture was purified by column chromatography (4% DCM / MeOH) to give compound 4ag (20 mg, 18% yield). MS (ESI) m / z against C 24 H 29 N7O2[M + Calculated value: 447.2; Experimental value: 448.6 [M] + + H + ].

[0232] Synthesis of 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-(cyclopropylmethyl)benzamide (4ah) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Cyclopropylmethanamine (0.112 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried over anhydrous Na₂SO₄ and purified by filtration with 3% DCM / MeOH to ensure an ivory-colored solid. (58 mg, 51%) 1 H NMR (400 MHz, DMSO) δ 12.52 (d, J = 242.1 Hz, 1H), 10.37 (d, J = 194.0 Hz, 1H), 9.70 (d, J = 252.9 Hz, 1H), 8.54-8.25 (m, 2H), 8.00 (d, J = 8.5Hz, 2H), 7.89-7.76 (m, 2H), 7.69 (s, 1H), 7.55 (s, 1H), 7.29 (s, 1H), 6.26(d, J = 343.1 Hz, 1H), 3.15 (t, J = 6.2 Hz, 2H), 1.97-1.86 (m, 1H), 1.10-1.00 (m,1H), 1.00-0.86 (m, 2H), 0.76 (s, 2H), 0.49-0.38 (m, 2H), 0.29-0.18 (m, 2H). 13 CNMR (101 MHz, DMSO) δ 166.30, 151.64, 144.20, 133.58, 128.38, 127.09, 126.34, 123.62, 122.98, 117.94, 112.04, 43.86, 11.64, 8.26, 3.77. MS (ESI) m / z for C 25 H 25 N7O [M + Calculated value: 439.2; Experimental value: 440.5 [M] + + H + ].

[0233] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-(2-methylbutyl)benzamide (4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-(2-methylbutyl)benzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of -(2-methylbutyl)benzamide)(4ai) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. 2-Methylbut-1-amine (0.153 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried over anhydrous Na₂SO₄ and filtered, then washed with diethyl ether to ensure an ivory-colored solid. (69 mg, 58%) 1 H NMR (400MHz, DMSO) δ 12.53 (d, J = 238.8 Hz, 1H), 10.38 (d, J = 193.6 Hz, 1H), 9.39 (d, J =249.2 Hz, 1H), 8.42 (s, 1H), 8.25 (t, J = 5.9 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.74-7.63 (m, 1H), 7.61-7.47 (m, 1H), 7.29 (s, 1H), 6.27 (d, J = 334.4 Hz, 1H), 3.20 (dt, J = 12.6, 6.1 Hz, 1H), 3.07 (dt, J = 12.6, 6.1 Hz, 1H), 1.93 (tt, J = 8.6, 5.0 Hz, 1H), 1.65 (ddd, J= 14.1, 9.6, 5.9 Hz,1H), 1.43 (tt, J = 12.5, 7.5 Hz, 1H), 1.17-1.06 (m, 1H), 1.02-0.85 (m, 8H), 0.80-0.64 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 166.49, 151.66, 144.15, 133.58, 128.36, 127.25, 126.30, 123.67, 122.96, 117.93, 112.04, 45.40, 35.05, 27.13, 17.67, 11.70, 8.26. MS (ESI) m / z for C 26 H 29 N7O [M + Calculated value: 455.2; Experimental value: 456.6 [M] + + H + ].

[0234] 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N,N-dimethylbenzamide (4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N,N-dimethylbenzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N , N Synthesis of -dimethylbenzamide)(4aj) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Dimethylamine (0.087 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried over anhydrous Na₂SO₄ and filtered, then washed with diethyl ether to prepare an ivory-colored solid (55 mg, 52%). 1 H NMR (400 MHz, DMSO)δ 12.53 (d, J = 241.7 Hz, 1H), 10.35 (d, J = 192.0 Hz, 1H), 9.66 (d,J = 248.9 Hz,1H), 8.41 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.76-7.61 (m, 1H), 7.54 (s, 1H), 7.47-7.34 (m, 2H), 7.28 (s, 1H), 6.26 (d, J = 332.8 Hz, 1H), 3.00 (s, 6H), 1.93(tt, J = 8.8, 5.1 Hz, 1H), 0.99-0.86 (m, 2H), 0.83-0.65 (m, 2H). 13 C NMR (101MHz, DMSO) δ 170.73, 151.71, 142.81, 133.59, 128.54, 126.26, 123.61, 122.88, 118.00, 111.99, 55.38, 40.60, 40.44, 8.27. MS (ESI) m / z for C 23 H 23 N7O [M + Calculated value: 413.2; Experimental value: 414.5 [M] + + H + ].

[0235] (4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)(morpholino)methyl ketone ((4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)(morpholino)methyl ketone H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)phenyl)(morpholino)methanone) (4ak) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Morpholine (0.112 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried over anhydrous Na₂SO₄ and filtered, then washed with diethyl ether to ensure an ivory-colored solid. (62 mg, 53%) 1H NMR (300 MHz, DMSO) δ12.52 (d, J = 175.8 Hz, 1H), 10.35 (d, J = 142.2 Hz, 1H), 9.38 (d, J = 184.6 Hz,1H), 8.41 (s, 1H), 8.01 (d, J = 8.6 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.62-7.49(m, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.29 (s, 1H), 6.26 (d, J = 240.2 Hz, 1H),3.69-3.46 (m, 8H), 1.92 (dq, J = 8.7, 4.4 Hz, 1H), 1.01-0.84 (m, 2H), 0.84-0.65(m, 2H). 13 C NMR (101 MHz, DMSO) δ 169.82, 151.67, 143.10, 133.59, 128.69, 127.60, 126.27, 123.61, 122.93, 118.11, 111.99, 66.67, 40.63, 40.42, 40.21, 8.29. MS (ESI) m / z for C 25 H 25 N7O2[M + Calculated value: 455.2; Experimental value: 456.5 [M] + + H + ].

[0236] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-phenylbenzamide (4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-phenylbenzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of -phenylbenzamide (4al) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Aniline (0.118 mL, 1.29 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The combined organic layer was dried with anhydrous Na₂SO₄, and washed, filtered, and purified with diethyl ether to obtain an ivory-colored solid. (79 mg, 66%) 1 H NMR (300MHz, DMSO) δ 12.53 (d, J = 177.2 Hz, 1H), 10.55 (d, J = 114.5 Hz, 1H), 10.07 (s,1H), 9.52 (s, 1H), 8.43 (s, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.5 Hz,2H), 7.85-7.76 (m, 2H), 7.71 (t, J = 7.6 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.41-7.25 (m, 3H), 7.14-7.04 (m, 1H), 6.28 (d, J = 248.0 Hz, 1H), 1.94 (ddd, J = 13.4,7.1, 4.4 Hz, 1H), 1.02-0.87 (m, 2H), 0.83-0.65 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 165.61, 151.60, 144.79, 139.98, 133.64, 129.04, 127.04, 126.37, 123.76, 123.10, 120.71, 117.96, 112.10, 15.65, 8.30. MS (ESI) m / z for C 27 H 23 N7O [M + Calculated value: 461.2; Experimental value: 462.5 [M] + + H + ].

[0237] 4-((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)-N-(4-fluorophenyl)benzamide ( ...-N-(4-fluorophenyl)benzamide) H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of 4-(fluorophenyl)benzamide (4am) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. 4-fluoroaniline (0.050 mL, 0.49 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture. The solid was filtered and washed with water and ether to give a white solid (81 mg, 63%). 1 HNMR (400 MHz, DMSO) δ 12.52 (d, J = 242.6 Hz, 1H), 10.40 (d, J = 187.1 Hz, 1H),10.12 (s, 1H), 9.48 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 8.02-7.86(m, 2H), 7.86-7.77 (m, 2H), 7.70 (s, 1H), 7.64-7.49 (m, 1H), 7.30 (s, 1H),7.25-7.15 (m, 2H), 6.28 (d, J = 337.7 Hz, 1H), 1.97-1.87 (m, 1H), 1.02-0.85 (m, 2H), 0.85-0.64 (m, 2H). MS (ESI) m / z for C 27 H 22 FN7O [M + Calculated value: 479.2; Experimental value: 480.5 [M] + + H + ].

[0238] 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-phenylethylbenzamide (4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-phenylethylbenzamide H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of phenethylbenzamide (4an) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Phenylethylamine (0.065 mL, 0.52 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The mixed organic layer was dried over anhydrous Na₂SO₄ and purified by column chromatography (5% DCM / MeOH) to prepare a light pink solid (49 mg, 39%). 1 H NMR (400 MHz, DMSO) δ 12.53 (d, J = 245.5 Hz, 1H), 10.37 (d, J = 202.2 Hz, 1H), 9.70 (d, J = 262.3 Hz, 1H), 8.52-8.30 (m, 2H), 8.00 (d, J = 8.4 Hz, 2H),7.87-7.50 (m, 4H), 7.38-7.18 (m, 6H), 6.27 (d, J = 345.3 Hz, 1H), 3.49 (dd, J =13.9, 6.0 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.01-1.85 (m, 1H), 1.02-0.84 (m, 2H), 0.84-0.64 (m, 2H). MS (ESI) m / z for C 29 H 27 N7O [M + Calculated value: 489.2; Experimental value: 490.5 [M] + + H + ].

[0239] 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-(4-fluorobenzyl)benzamide ( ...-N-(4-fluorobenzyl)benzamide) H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N -(4-fluorobenzyl)benzamide) (4ao) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. (4-fluorophenyl)methylamine (0.059 mL, 0.52 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The mixed organic layer was dried over anhydrous Na₂SO₄ and purified by column chromatography (5% DCM / MeOH) to prepare a light pink solid (75 mg, 59%). 1 H NMR (400 MHz, DMSO) δ 12.52 (d, J = 244.1 Hz, 1H), 10.38 (d, J = 201.6Hz, 1H), 9.72 (d, J = 258.9 Hz, 1H), 8.88 (s, 1H), 8.54-8.28 (m, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.95-7.79 (m, 2H), 7.77-7.48 (m, 2H), 7.42-7.21 (m, 3H), 7.21-7.10 (m, 2H), 6.26 (d, J = 344.8 Hz, 1H), 4.47 (d, J = 5.9 Hz, 2H), 2.00-1.86 (m, 1H), 1.02-0.84 (m, 2H), 0.84-0.64 (m, 2H). MS (ESI) m / z for C 28 H 24 FN7O [M + Calculated value: 493.2; Experimental value: 494.6 [M] + + H+ ].

[0240] 4-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-N-(2,4-difluorobenzyl)benzamide ( ...-N-(2,4-difluorobenzyl)benzamide) H -pyrazol-3-yl)amino)quinazolin-2-yl)amino)- N Synthesis of -(2,4-difluorobenzyl)benzamide)(4ap) DMF (2 mL) was added to a solution of compound 4r (100 mg, 0.26 mmol), followed by DIPEA (0.181 mL, 1.04 mmol), EDC·HCl (99 mg, 0.52 mmol), and HOBt (70 mg, 0.52 mmol). The reaction mixture was stirred for 20 minutes at room temperature. (2,4-Difluorophenyl)methylamine (0.062 mL, 0.52 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. EtOAc was added to the reaction mixture. The organic layer was washed several times with water and brine. The mixed organic layer was dried over anhydrous Na₂SO₄ and filtered, and purified by column chromatography (5% DCM / MeOH) to prepare a light pink solid (75 mg, 56%). 1 H NMR (400 MHz, DMSO) δ 12.52 (d, J = 242.7 Hz, 1H), 10.38 (d, J =196.4 Hz, 1H), 9.73 (d, J = 254.4 Hz, 1H), 8.85 (s, 1H), 8.53-8.28 (m, 1H), 8.02 (d, J = 8.6 Hz, 2H), 7.87 (s, 2H), 7.69 (s, 1H), 7.63-7.48 (m, 1H), 7.43(td, J = 8.6, 6.6 Hz, 1H), 7.36-7.18 (m, 2H), 7.07 (td, J = 8.6, 2.6 Hz, 1H), 6.26 (d, J = 341.9 Hz, 2H), 4.49 (d, J= 5.7 Hz, 2H), 2.00-1.84 (m, 1H), 1.02-0.84 (m, 2H), 0.84-0.62 (m, 2H). MS (ESI) m / z for C 28 H 23 F2N7O [M + Calculated value: 511.2; Experimental value: 512.6 [M] + + H + ].

[0241] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 Synthesis example of -(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-2,4-diamine (4bg) 0–1 μL of concentrated HCl was added to a mixture of compound 2a (100 mg, 0.35 mmol), 1H-pyrrolo[2,3-b]pyridine-5-amine (70 mg, 0.53 mmol), ethanol (2 mL), and amine (1.5 equivalent, 0.53 mmol). The reaction mixture was stirred at 120 °C for 2 to 24 hours. The reaction mixture was cooled, and the solvent was evaporated. The crude product was purified by filtration and washed with MeOH or EA to give 4 bg (125 mg, 94% yield) of a gray solid.

[0242] 1 H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 11.89 (s, 1H), 11.47 (s,1H), 10.32 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.84(t, J = 7.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.61-7.54 (m, 1H), 7.46 (t, J = 7.7Hz, 1H), 6.54 (s, 1H), 5.58 (s, 1H), 1.54 (s, 1H), 0.75 (s, 2H), 0.11 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 157.83, 153.68, 147.44, 146.52, 141.16, 139.80, 135.81, 128.02, 126.00, 125.18, 120.05, 117.85, 110.79, 100.70, 95.17, 95.15, 8.15, 7.05. MS (ESI) m / z for C 21 H 18 N8[M + Calculated value: 382.4; Experimental value: 383.3 [M] + + H + ].

[0243] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 Synthesis example of -(imidazo[1,2-b]pyridazin-3-yl)quinazolin-2,4-diamine (4bh) Compound 2a (100 mg, 0.35 mmol) and imidazo[1,2-b]pyridazine-3-amine (70 mg, 0.53 mmol) were reacted in the same manner as compound 4bg and purified by preparative grade thin-layer chromatography (prep TLC) to give green solid compound 4bh (38 mg, 29% yield).

[0244] 1 H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.92 (s, 1H), 9.95 (d, J =9.5 Hz, 1H), 9.16 (dd, J = 4.6, 1.5 Hz, 1H), 8.72 (d, J = 8.3 Hz, 1H), 8.06-7.86(m, 4H), 7.71-7.61 (m, 1H), 6.67 (s, 2H), 6.23 (s, 1H), 2.04 (td, J = 8.6, 4.4Hz, 1H), 1.09-0.96 (m, 2H), 0.87-0.73 (m, 2H). 13C NMR (101 MHz, DMSO) δ 159.33, 150.78, 149.85, 148.11, 146.80, 146.53, 136.62, 134.85, 132.02, 127.72, 127.13, 125.95, 124.83, 124.40, 114.29, 99.82, 95.56, 8.64, 7.42. MS (ESI) m / z for C 20 H 17 N9[M + Calculated value: 383.4; Experimental value: 384.3 [M] + + H + ].

[0245] Synthetic example of 5-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)indoline-2-one (4bi) Compound 2a (100 mg, 0.35 mmol) and 5-aminoindoline-2-one (78 mg, 0.53 mmol) were reacted in the same manner as compound 4bg to give a dark green solid compound 4bi (66 mg, 48% yield).

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.40 (s, 1H), 10.57 (s,1H), 10.28 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.54-7.16 (m, 3H), 6.91 (d, J = 8.2 Hz, 1H), 6.01 (s, 1H), 3.53(s, 2H), 1.81 (s, 1H), 0.90 (d, J = 8.2 Hz, 2H), 0.51 (s, 2H). 13C NMR (101 MHz, DMSO) δ 176.80, 158.00, 153.14, 146.41, 142.48, 135.76, 130.41, 126.97, 125.01, 122.23, 122.16, 118.09, 110.73, 109.85, 95.66, 36.50, 8.19, 7.23. MS (ESI) m / z for C 22 H 19 N7O [M + Calculated value: 397.4; Experimental value: 398.3 [M] + + H + ].

[0247] N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 4 Synthesis of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine)(4ca) A mixture of compound 2a (200 mg, 0.7 mmol) and 2,4-dimethoxybenzylamine (0.315 mL, 2.10 mmol) was irradiated in a microwave reactor at 150 °C for 1.5 h. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with water, dried with Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography. The residue was pulverized with DCM and diethyl ether, yielding a pale yellow solid (221 mg). At room temperature, N... 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(2,4-dimethoxybenzyl)quinazolin-2,4-diamine N 4 -(5-cyclopropyl-1 H -pyrazol-3-yl)- N 2 A solution of (2,4-dimethoxybenzyl)quinazoline-2,4-diamine (70 mg, 0.168 mmol) was stirred in a DCE of 25% TFA for 4 hours. The reaction mixture was diluted with EtOAc and washed with a saturated NaHCO3 solution. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was pulverized with diethyl ether to give a pale yellow solid compound 4ca (23 mg, 51%). N 4-(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -Methylquinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of 2,4-methylquinazoline-2,4-diamine (4cb) A mixture of compound 2a (71.4 mg, 0.25 mmol) and methylamine hydrochloride (50.6 mg, 0.75 mmol) in IPA (0.3 M) was irradiated for 0.5 h at 150 °C using a microwave reactor. The reaction mixture was tritized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4 and filtered and concentrated. Purification was carried out by column chromatography (5% (7N ammonia in MeOH solution)) with EtOAc:Hex = 2:1, followed by tritization with diethyl ether, to prepare a pale yellow solid compound 4cb. (3 mg, 5% yield) 1 H NMR (400 MHz, DMSO-d6) δ12.39 (d, J = 217.0 Hz, 1H), 10.08 (d, J = 143.9 Hz, 1H), 8.28 (s, 1H), 7.61-7.49(m, 1H), 7.40-7.24 (m, 2H), 7.20-6.98 (m, 1H), 6.70 (s, 1H), 2.86 (d, J = 4.6Hz, 3H), 1.92-1.80 (m, 1H), 0.98-0.85 (m, 2H), 0.79-0.63 (m, 2H) MS (ESI) m / z for C 15 H 16 N6[M + Calculated value: 280.1; Experimental value: 281.1 [M] + + H + ].

[0248] N 2 -Benzyl-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -benzyl-N 4 Synthesis of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine (4cc) A mixture of compound 2a (71.4 mg, 0.25 mmol) and benzylamine (246 μL, 2.25 mmol) was irradiated in a microwave reactor at 150 °C for 1.5 h. The reaction mixture was tritized with diethyl ether. The filtrate was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic residue was dried with Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to prepare the desired product (3% (7N ammonia in MeOH solution) EtOAc:Hex = 1:2-1:1). The product was tritized with DCM and diethyl ether to prepare a pale yellow solid compound 4 cc (54 mg, 61% yield). 1 HNMR (400 MHz, DMSO-d6) δ 12.42 (d, J = 257.5 Hz, 1H), 10.13 (d, J = 193.8 Hz, 1H), 8.27 (d, J = 44.5 Hz, 1H), 7.51-7.04 (m, 10H), 4.59 (d, J = 6.0 Hz, 2H), 1.91-1.76 (m, 1H), 0.96-0.80 (m, 2H), 0.77-0.61 (m, 2H). MS (ESI) m / z for C 21 H 20 N6[M + Calculated value: 356.2; Experimental value: 357.1 [M] + + H + ].

[0249] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(4-Methoxybenzyl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(4-methoxybenzyl)quinazoline-2,4-diamine)(4Cd) A mixture of compound 2a (71.4 mg, 0.25 mmol) and 4-methoxybenzylamine (0.147 mL, 0.750 mmol) was irradiated in a microwave reactor at 150 °C for 1.0 h. The reaction mixture was tritized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried on Na2SO4, filtered, and concentrated. The residue was tritized with DCM and diethyl ether to give compound 4cd as a white solid (46 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (d, J = 251.2 Hz, 1H), 10.12 (d, J = 189.7 Hz, 1H), 8.26 (d, J = 51.1 Hz, 1H), 7.51-7.28 (m, 5H), 7.09 (d, J = 42.3 Hz, 2H),6.99-6.81 (m, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H), 1.92-1.79 (m, 1H), 0.96-0.83 (m, 2H), 0.80-0.48 (m, 2H) MS (ESI) m / z for C 22 H 22 N6O [M + Calculated value: 386.2; Experimental value: 387.1 [M] + + H + ].

[0250] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -Phenethylquinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of phenethylquinazoline-2,4-diamine (4ce) A mixture of compound 2a (71.4 mg, 0.25 mmol) and 2-phenylethyl-1-amine (0.303 mL, 2.40 mmol) in IPA (0.3 M) was irradiated for 1.5 h at 150 °C using a microwave reactor. The reaction mixture was tritized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic layer was dried with Na2SO4, filtered, and concentrated. The residue was tritized with DCM and diethyl ether to give a white solid compound 4ce (41 mg, 44% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (d, J = 238.6 Hz, 1H), 10.10 (d, J =175.1 Hz, 1H), 8.31 (s, 1H), 7.53 (s, 1H), 7.31-7.20 (m, 8H), 7.07 (s, 1H), 6.74 (d, J = 87.9 Hz, 2H), 3.57 (d, J = 4.2 Hz, 2H), 2.90 (s, 2H), 1.93-1.81 (m, 1H), 0.97-0.83 (m, 2H), 0.80-0.52 (m, 2H). MS (ESI) m / z for C 22 H 22 N6[M + Calculated value: 370.2; Experimental value: 371.1 [M] + + H + ].

[0251] 2-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)ethyl-1-ol hydrochloride (2-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)ethyl-1-ol hydrochloride) H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)ethan-1-olhydrochloride) (4cf) A mixture of compound 2a (71.4 mg, 0.25 mmol) and 2-aminoethanol (45.8 mg, 0.75 mmol) in IPA (0.833 mL) was irradiated for 0.5 h at 150 °C using a microwave reactor. The reaction mixture was tritized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic residue was dried with Na2SO4, filtered, and concentrated. The residue was dissolved in MeOH and concentrated, then tritized with diethyl ether. The residue was dissolved in 20% MeOH in DCM and concentrated, then tritized with n-hexane. Half of the resulting solid was added dropwise to dioxane (64.4 μL, 0.26 mmol) in DCM and 4M HCl at 0 °C and dissolved. The mixture was heated to room temperature and stirred for 0.5 h. The reaction mixture was concentrated and tritized with diethyl ether to prepare a white solid compound 4cf. (16 mg, 19% yield) MS (ESI) m / z against C 16 H 18 N6O [M + Calculated value: 310.2; Experimental value: 311.1 [M] + + H + ].

[0252] Synthesis of 6-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (4cg) Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was added to tert-butanol (0.5 mL). tert -butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate (73 mg, 0.37 mmol). DIPEA (48 mg, 0.37 mmol) was added, and the reaction mixture was heated with stirring at 110 °C. After 4 days, the solvent was evaporated, and the mixture was purified by column chromatography (4% DCM / MeOH) to ensure a yield of 4 cg of the compound. (20 mg, 18% yield) MS (ESI) m / z against C 24 H 29N7O2[M + Calculated value: 447.2; Experimental value: 448.6 [M] + + H + ].

[0253] 4-(((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)methyl)benzonitrile (4-(((4-((5-cyclopropyl-1H-pyrazole-3-yl)amino)quinazolin-2-yl)amino)methyl)benzonitrile H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)methyl)benzonitrile) (4ch) Compound 2a (150 mg, 0.53 mmol) and 4-(aminomethyl)benzonitrile (83 mg, 0.63 mmol) were dissolved in tert-butanol (2 mL). 0.010 mL of 37% HCl aqueous solution was added, and the reaction mixture was heated at 110 °C with stirring. After 2 days, the white solid was recovered by column chromatography (3% DCM / MeOH), thus ensuring the yield of compound 4ch. (20 mg, 10% yield) 1 H NMR (300 MHz, DMSO) δ 12.44 (d, J = 181.1 Hz, 1H), 10.20 (d, J = 136.1 Hz,1H), 8.46-8.17 (m, 1H), 7.79 (d, J = 7.8 Hz, 2H), 7.71-7.40 (m, 3H), 7.40-7.21 (m, 1H), 7.21-6.99 (m, 1H), 6.73 (s, 1H), 4.68 (s, 2H), 1.86 (s, 1H), 1.04-0.27 (m, 4H). MS (ESI) m / z for C 22 H 19 N7[M + Calculated value: 381.2; Experimental value: 382.4 [M] + + H + ].

[0254] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-indol-4-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2Synthesis of -(1H-indol-4-yl)quinazoline-2,4-diamine (4da) The solid charcoal compound 4da was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 1H-indole-4-amine (69 mg, 0.53 mmol). (55 mg, 42% yield) 1 H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H),11.44 (d, J = 7.7 Hz, 2H), 10.56 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 7.85 (t, J =7.8 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.52-7.37 (m, 3H), 7.37-7.27 (m, 1H),7.17 (t, J = 7.8 Hz, 1H), 6.59 (s, 1H), 6.10 (s, 1H), 1.82 (s, 1H), 0.98-0.84(m, 2H), 0.56 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 158.25, 152.62, 146.50, 139.67, 137.47, 135.92, 126.07, 125.22, 125.14, 123.24, 121.60, 117.71, 110.74, 110.44, 99.45, 95.74, 8.39, 7.28. MS (ESI) m / z for C 22 H 19 N7[M + Calculated value: 381.4; Experimental value: 382.3 [M] + + H + ].

[0255] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-indol-5-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(1H-indol-5-yl)quinazoline-2,4-diamine (4dB) The white solid compound 4db was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 1H-indole-5-amine (69 mg, 0.53 mmol). (109 mg, 82% yield) 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (s,1H), 11.40 (d, J = 16.1 Hz, 2H), 10.30 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H), 7.89-7.75 (m, 1H), 7.71-7.57 (m, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.48-7.38 (m, 2H), 7.16 (dd, J = 8.6, 2.1 Hz, 1H), 6.50 (s, 1H), 5.78 (s, 1H), 1.57 (s, 1H), 0.76 (s, 2H), 0.14 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.81, 153.25, 146.45, 139.72, 135.80, 128.35, 127.10, 125.02, 119.66, 117.50, 112.38, 110.67, 101.91, 95.55, 8.13, 7.07. MS (ESI) m / z for C 22 H 19 N7[M + Calculated value: 381.4; Experimental value: 382.3 [M] + + H + ].

[0256] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-indol-6-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(1H-indol-6-yl)quinazoline-2,4-diamine)(4dc) The dark brown solid compound 4dc was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 1H-indole-6-amine (69 mg, 0.53 mmol). (90 mg, 68% yield) 1 H NMR (300 MHz, DMSO-d6) δ 12.49 (s,1H), 11.34 (d, J = 28.9 Hz, 2H), 10.43 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.82(t, J = 7.8 Hz, 1H), 7.73-7.51 (m, 3H), 7.51-7.34 (m, 2H), 7.12 (dd, J = 8.4, 1.9Hz, 1H), 6.50 (s, 1H), 6.11 (s, 1H), 1.69 (s, 1H), 0.79 (s, 2H), 0.38 (s, 2H). 13 C10 NMR (101 MHz, DMSO-d6) δ 157.70, 153.26, 147.03, 136.34, 135.60, 126.70, 124.97, 120.86, 117.14, 110.85, 108.49, 101.68, 95.24, 8.16, 7.31. MS(ESI) m / z for C10 NMR 22 H 19 N7[M + Calculated value: 381.4; Experimental value: 382.3 [M] + + H + ].

[0257] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-indazol-5-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(1H-indazol-5-yl)quinazoline-2,4-diamine)(4dd) The green solid compound 4dd was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 1H-indazole-5-amine (70 mg, 0.53 mmol). (104 mg, 78% yield) 1H NMR (300 MHz, DMSO-d6) δ 13.31 (s,1H), 12.55 (s, 1H), 11.47 (s, 1H), 10.50 (s, 1H), 8.67 (d, J = 8.3 Hz, 1H),8.14 (s, 1H), 7.91 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.64 (t, J = 8.7 Hz, 2H),7.52-7.37 (m, 2H), 5.83 (s, 1H), 1.63 (s, 1H), 0.76 (s, 2H), 0.20 (s, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 158.03, 153.21, 146.35, 139.74, 138.86, 135.84, 134.13, 125.12, 123.44, 111.28, 110.72, 95.56, 8.08, 7.03. MS (ESI) m / z for C 21 H 18 N8[M + Calculated value: 382.4; Experimental value: 383.3 [M] + + H + ].

[0258] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-indazol-6-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(1H-indazol-6-yl)quinazoline-2,4-diamine)(4de) The ivory solid compound 4de was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 1H-indazole-6-amine (70 mg, 0.53 mmol). (133 mg, 99% yield) 1 H NMR (300 MHz, DMSO-d6) δ 13.20 (s,1H), 12.58 (s, 1H), 11.51 (s, 1H), 10.70 (s, 1H), 8.69 (d, J= 8.3 Hz, 1H),8.13 (s, 1H), 7.93-7.80 (m, 2H), 7.76 (s, 1H), 7.65 (dd, J = 8.4, 1.1 Hz, 1H),7.48 (s, 1H), 7.24 (dd, J = 8.6, 1.7 Hz, 1H), 6.15 (s, 1H), 1.69 (s, 1H), 0.93-0.57 (m, 2H), 0.34 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 158.00, 152.80, 140.57, 135.85, 133.94, 125.23, 125.09, 121.51, 118.50, 110.85, 95.42, 8.06, 7.10. MS (ESI) m / z for C 21 H 18 N8[M + Calculated value: 382.4; Experimental value: 383.3 [M] + + H + ].

[0259] N 2 -(1H-benzo[d]imidazol-5-yl)-N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine (N 2 -(1H-benzo[d]imidazol-5-yl)-N 4 Synthesis of -(5-cyclopropyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine)(4df) By reacting compound 2a (100 mg, 0.35 mmol) with 1H-benzo[d]imidazole-5-amine (1 H -benzo[ d The reaction of imidazol-5-amine (70 mg, 0.53 mmol) with 4df (66 mg, 49% yield) yielded a white solid compound. 1 H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 11.08 (s, 1H), 10.25 (s, 1H), 8.75 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.09 (s, 1H), 7.79 (t,J = 7.7 Hz, 1H), 7.73(d, J = 8.7 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.40 (t, J =7.7 Hz, 1H), 6.18 (s, 1H), 1.77 (s, 1H), 0.97 - 0.68 (m, 2H), 0.48 (s, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 157.65, 154.35, 142.06, 134.99, 124.58, 124.32, 120.10, 115.70, 111.30, 8.13. MS (ESI) m / z for C 21 H 18 N8[M + Calculated value: 382.4; Experimental value: 383.3 [M] + + H + ].

[0260] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline-2,4-diamine)(4dg) By reacting compound 2a (100 mg, 0.35 mmol) with 1H-pyrrolo[2,3-b]pyridine-5-amine (1 H -pyrrolo[2,3- b The reaction of pyridin-5-amine (70 mg, 0.53 mmol) with pyridin-5-amine (125 mg, 94% yield) yielded a gray solid compound, 4 dg. 1 H NMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 11.89 (s, 1H), 11.47 (s, 1H), 10.32 (s, 1H), 8.68 (d, J= 8.3 Hz, 1H), 8.30 (s, 1H), 8.08 (s, 1H), 7.84 (t, J =7.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.61-7.54 (m, 1H), 7.46 (t, J = 7.7 Hz,1H), 6.54 (s, 1H), 5.58 (s, 1H), 1.54 (s, 1H), 0.75 (s, 2H), 0.11 (s, 2H). 13 CNMR (101 MHz, DMSO-d6) δ 157.83, 153.68, 147.44, 146.52, 141.16, 139.80, 135.81, 128.02, 126.00, 125.18, 120.05, 117.85, 110.79, 100.70, 95.17, 95.15, 8.15, 7.05. MS (ESI) m / z for C 21 H 18 N8[M + Calculated value: 382.4; Experimental value: 383.3 [M] + + H + ].

[0261] N 4 -(5-Cyclopropyl-1H-pyrazole-3-yl)-N 2 -(imidazo[1,2-b]pyridazin-3-yl)quinazolin-2,4-diamine (N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 Synthesis of -(imidazo[1,2-b]pyridazin-3-yl)quinazoline-2,4-diamine)(4dh) By reacting compound 2a (100 mg, 0.35 mmol) with imidazo[1,2-b]pyridazine-3-amine (imidazo[1,2-b]pyridazine-3-amine) b The reaction of pyridazin-3-amine (70 mg, 0.53 mmol) with purification yielded a green solid compound, 4dh (38 mg, 29% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.92 (s, 1H), 9.95 (d, J= 9.5Hz, 1H), 9.16 (dd, J = 4.6, 1.5 Hz, 1H), 8.72 (d, J = 8.3 Hz, 1H), 8.06-7.86 (m,4H), 7.71-7.61 (m, 1H), 6.67 (s, 2H), 6.23 (s, 1H), 2.04 (td, J = 8.6, 4.4 Hz,1H), 1.09-0.96 (m, 2H), 0.87-0.73 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 159.33, 150.78, 149.85, 148.11, 146.80, 146.53, 136.62, 134.85, 132.02, 127.72, 127.13, 125.95, 124.83, 124.40, 114.29, 99.82, 95.56, 8.64, 7.42. MS (ESI) m / z for C 20 H 17 N9[M + Calculated value: 383.4; Experimental value: 384.3 [M] + + H + ].

[0262] 5-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)indoline-2-one (5-((4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)indoline-2-one H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)amino)indolin-2-one) (4di) The dark green solid compound 4di was prepared by reacting compound 2a (100 mg, 0.35 mmol) with 5-aminoindolin-2-one (78 mg, 0.53 mmol). (66 mg, 48% yield) 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s,1H), 11.40 (s, 1H), 10.57 (s, 1H), 10.28 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.61 (d, J= 8.3 Hz, 1H), 7.54-7.16 (m, 3H), 6.91 (d, J =8.2 Hz, 1H), 6.01 (s, 1H), 3.53 (s, 2H), 1.81 (s, 1H), 0.90 (d, J = 8.2 Hz, 2H), 0.51 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 176.80, 158.00, 153.14, 146.41, 142.48, 135.76, 130.41, 126.97, 125.01, 122.23, 122.16, 118.09, 110.73, 109.85, 95.66, 36.50, 8.19, 7.23. MS (ESI) m / z for C 22 H 19 N7O [M + Calculated value: 397.4; Experimental value: 398.3 [M] + + H + ].

[0263] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)quinazolin-4-amine (6a) Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL), and a solution of amine (1.5 equivalent, 0.37 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. DIPEA (1.5 equivalent, 0.37 mmol) and 1,4-dioxa-8-azaspiro[4,5]decane (53 mg, 0.37 mmol) were added, and the reaction mixture was heated at 110 °C while stirring for 30 hours to 4 days. The solvent was evaporated, and the mixture was purified by column chromatography (DCM / MeOH) to give compound 6a (77 mg, 80% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.00 (s, 1H), 8.34(d, J = 8.1 Hz, 1H), 7.61-7.48 (m, 1H), 7.32 (d, J= 8.3 Hz, 1H), 7.15-7.03 (m, 1H), 6.33 (s, 1H), 3.94 (s, 5H), 3.94-3.84 (m, 7H), 2.00-1.84 (m, 1H), 1.73-1.58 (m, 4H), 1.03-0.90 (m, 2H), 0.73-0.62 (m, 2H). MS (ESI) m / z for C 21 H 24 N6O2[M + Calculated value: 392.2; Experimental value: 393.4 [M] + + H + ].

[0264] Example of synthesis of 9-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (6b) Compound 2a (70 mg, 0.25 mmol) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylic acid (93 mg, 0.37 mmol) were reacted in the same manner as compound 6a to give compound 6b (33 mg, 27% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 9.95 (s, 1H), 8.32 (d, J = 8.2Hz, 1H), 7.59-7.48 (m, 1H), 7.36-7.26 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.35 (s, 1H), 3.87-3.73 (m, 4H), 1.98-1.86 (m, 1H), 1.56-1.33 (m, 17H), 1.02-0.91 (m, 2H), 0.73-0.63 (m, 2H). MS (ESI) m / z for C 28 H 37 N7O2[M + Calculated value: 503.3; Experimental value: 504.6 [M] + + H + ].

[0265] Example of synthesis of 7-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (6c) Compound 2a (70 mg, 0.25 mmol) and tert-butyl 2,7-diazaspiro[3,5]nonane-2-carboxylic acid (83 mg, 0.37 mmol) were reacted in the same manner as compound 6a to give compound 6c (75 mg, 64% yield).

[0266] 1 H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 9.97 (s, 1H), 8.32 (d, J =8.2 Hz, 1H), 7.60-7.48 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14-7.02 (m, 1H), 6.33 (s, 1H), 3.76 (s, 4H), 3.62 (s, 4H), 2.00-1.85 (m, 1H), 1.70 (t, J = 5.4Hz, 4H), 1.40 (s, 9H), 1.04-0.91 (m, 2H), 0.75-0.63 (m, 2H). MS (ESI) m / z for C 26 H 33 N7O2[M + Calculated value: 475.3; Experimental value: 476.6 [M] + + H + ].

[0267] Synthesis example of 2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (6d) Compound 2a (70 mg, 0.25 mmol) and tert-butyl 2,7-diazaspiro[3,5]nonane-7-carboxylic acid (83 mg, 0.37 mmol) were reacted in the same manner as compound 6a to give compound 6d (92 mg, 79% yield). 1 HNMR (300 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.08 (s, 1H), 8.37 (d, J = 7.6 Hz,1H), 7.61-7.48 (m, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.10 (t, J= 7.5 Hz, 1H), 6.58(s, 1H), 3.82 (s, 4H), 2.01-1.85 (m, 1H), 1.71 (t, J = 5.5 Hz, 4H), 1.41 (s, 9H), 1.01-0.88 (m, 2H), 0.78-0.66 (m, 2H). MS (ESI) m / z for C 26 H 33 N7O2[M + Calculated value: 475.3; Experimental value: 476.5 [M] + + H + ].

[0268] The compounds represented by chemical formulas 3-5 according to the present invention can be prepared according to the following reaction formula 3, but are not limited thereto.

[0269] <Reaction Formula 3>

[0270] In the aforementioned reaction formula 3, Ar 1 This is the same as the definition above. Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-yl)quinazolin-4-amine (5) A mixture of compound 2a (1.0 g, 3.50 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2,3,6-tetrahydropyridine (1.70 g, 5.25 mmol), and ethanol (10 mL) was stirred for 4 hours at 120 °C. The reaction mixture was cooled and evaporated under vacuum. The solid was filtered through 3% DCM / MeOH to give compound 5 (1.25 g, 78%) as a white solid.

[0271] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-phenyl-3,6-dihydropyridin-1(2H)-yl)quinazolin-4-amine (6e) Compound 5 (100 mg, 0.22 mmol) and bromobenzene (51 mg, 0.33 mmol) were dissolved in a 1,4-dioxane:H₂O = 5:1 solution, and K₂CO₃ (2.5 equivalents) and Pd(PPh₃)₄ (10 mol%) were added. The mixture was stirred at 110 °C for 1 h in a microwave reactor. The reaction mixture was filtered through fluorite, extracted with EtOAc and washed with water. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (DCM / MeOH) to give an orange solid, compound 6e (35 mg, 40% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.02(s, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.56 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.53-7.46 (m, 2H), 7.36 (ddd, J = 7.8, 4.2, 2.6 Hz, 3H), 7.30-7.22 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 4.44 (d, J = 3.2 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 2.59 (s, 2H), 2.05-1.87 (m, 1H), 1.04-0.88 (m, 2H), 0.78-0.65(m, 2H).

[0272] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-yl)quinazolin-4-amine (6f) Compound 5 (100 mg, 0.22 mmol) and 4-bromobenzotrifluoride (74 mg, 0.33 mmol) were reacted in the same manner as compound 6e to give compound 6f (55 mg, 53% yield), an orange-red solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.04 (s, 1H), 8.37 (d, J=8.2 Hz, 1H), 7.71 (s, 4H), 7.57 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 6.46 (s, 1H), 4.47 (d, J = 3.2 Hz, 2H), 4.08 (t, J = 5.6 Hz, 2H), 2.63 (s, 2H), 1.96 (tt, J = 8.6, 5.0 Hz, 1H), 1.05-0.90 (m, 2H), 0.80-0.67 (m, 2H).

[0273] Synthesis example of N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-(4-(3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-yl)quinazolin-4-amine (6g) Compound 5 (200 mg, 0.44 mmol) and 3-bromotrifluorotoluene (147 mg, 0.65 mmol) were reacted in the same manner as compound 6e to give 6 g of orange solid (106 mg, 51% yield). 1 H NMR (500 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.04 (s, 1H), 8.38 (d, J =8.2 Hz, 1H), 7.84-7.78 (m, 2H), 7.66-7.59 (m, 2H), 7.59-7.54 (m, 1H), 7.37(d, J = 8.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.52-6.45 (m, 2H), 4.50-4.42 (m,2H), 4.08 (t, J = 5.6 Hz, 2H), 2.69-2.59 (m, 2H), 2.01-1.92 (m, 1H), 1.03-0.95 (m, 2H), 0.79-0.70 (m, 2H).

[0274] Synthesis example of 2-(4-benzyl-3,6-dihydropyridine-1(2H)-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (6h) Compound 5 (100 mg, 0.22 mmol) and benzylbromide (56 mg, 0.33 mmol) were reacted in the same manner as compound 6e to give the orange solid compound 6h (30 mg, 32% yield). 1 H NMR(300 MHz, DMSO-d6) δ 12.18 (s, 1H), 9.99 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H),7.60-7.47 (m, 1H), 7.38-7.25 (m, 3H), 7.25-7.14 (m, 3H), 7.08 (t, J = 7.3 Hz,1H), 6.38 (s, 1H), 5.59 (s, 1H), 4.24 (s, 2H), 3.88 (t, J = 5.7 Hz, 2H), 3.34(s, 2H), 2.03 (s, 2H), 1.92 (tt, J = 8.8, 5.0 Hz, 1H), 1.30-1.19 (m, 1H), 1.02-0.90 (m, 2H), 0.76-0.62 (m, 2H).

[0275] Synthetic example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(naphth-1-yl)-3,6-dihydropyridin-1(2H)-yl)quinazolin-4-amine (6i) Compound 5 (150 mg, 0.33 mmol) and 1-bromonaphthalene (102 mg, 0.49 mmol) were reacted in the same manner as compound 6e and purified by preparative grade thin-layer chromatography (prep TLC) (3% DCM / MeOH) to give compound 6i (19 mg, 12% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.19(s, 1H), 10.05 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.05-7.91 (m, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.58 (t, J= 7.8 Hz, 1H), 7.55-7.45 (m, 3H), 7.37 (t, J = 8.7 Hz, 2H), 7.13 (t, J = 7.6 Hz, 1H), 6.45 (s, 1H), 5.91 (s, 1H), 4.51 (d, J = 3.7 Hz, 2H), 4.19 (t, J = 5.4 Hz, 2H), 2.57 (s, 2H), 1.97-1.85 (m, 1H), 0.96-0.87 (m, 2H), 0.75-0.63 (m, 2H).

[0276] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(2,4-dimethylphenyl)-3,6-dihydropyridin-1(2H)-yl)quinazolin-4-amine (6j) Compound 5 (150 mg, 0.33 mmol) and 1-bromo-2,4-dimethylbenzene (91 mg, 0.49 mmol) were reacted in the same manner as compound 6e, and purified by preparative grade thin-layer chromatography (prep TLC) (3% DCM / MeOH) to give compound 6j (25 mg, 18% yield). 1 H NMR (500 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.07 (s,1H), 8.37 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 7.04-6.98 (m, 2H), 6.96 (d, J = 7.8 Hz, 1H), 6.43 (s,1H), 5.68 (s, 1H), 4.39 (s, 2H), 4.06 (t, J = 5.6 Hz, 2H), 2.38 (s, 2H), 2.25(d, J = 11.8 Hz, 6H), 1.93 (tt, J = 8.4, 5.0 Hz, 1H), 1.01-0.89 (m, 2H), 0.73-0.66 (m, 2H).

[0277] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)quinazolin-4-amine (6k) Compound 5 (150 mg, 0.33 mmol) and 1-bromo-2-fluorobenzene (86 mg, 0.49 mmol) were reacted in the same manner as compound 6e to give compound 6k (66 mg, 47% yield), a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.03 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 7.57 (t, J =7.6 Hz, 1H), 7.46-7.27 (m, 3H), 7.26-7.15 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.46 (s, 1H), 6.14 (t, J = 3.3 Hz, 1H), 4.50-4.38 (m, 2H), 4.05 (t, J = 5.5 Hz,2H), 2.56 (s, 2H), 1.95 (tt, J = 8.5, 5.0 Hz, 1H), 1.03-0.91 (m, 2H), 0.76-0.65 (m, 2H).

[0278] Synthetic example of 2-(4-(4-chloro-2-methylphenyl)-3,6-dihydropyridin-1(2H)-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (6l) Compound 5 (150 mg, 0.33 mmol) and 2-bromo-5-chlorotoluene (101 mg, 0.49 mmol) were reacted in the same manner as compound 6e to give a pink solid compound 6l (79 mg, 53% yield). 1 H NMR (300MHz, DMSO-d6) δ 12.20 (s, 1H), 10.02 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.56(t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 2.2 Hz, 1H), 7.21 (dd,J = 8.2, 2.2 Hz, 1H), 7.17-7.05 (m, 2H), 6.44 (s, 1H), 5.74 (t, J = 1.6 Hz, 1H), 4.39 (d, J = 3.1 Hz, 2H), 4.06 (t, J = 5.4 Hz, 2H), 2.39 (s, 2H), 2.27 (s, 3H), 1.93 (tt, J = 8.5, 5.0 Hz, 1H), 1.03-0.89 (m, 2H), 0.75-0.64 (m, 2H).

[0279] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(2-ethylphenyl)-3,6-dihydropyridine-1(2H)-yl)quinazolin-4-amine (6m) Compound 5 (150 mg, 0.33 mmol) and 1-bromo-2-ethylbenzene (91 mg, 0.49 mmol) were reacted in the same manner as compound 6e to give a bright orange solid compound 6m (41 mg, 28% yield). 1 H NMR (500MHz, DMSO-d6) δ 12.21 (s, 1H), 10.05 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.57(t, J = 7.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.27-7.19 (m, 2H), 7.19-7.07 (m,3H), 6.43 (s, 1H), 5.70 (s, 1H), 4.39 (d, J = 3.2 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 2.61 (q, J = 7.5 Hz, 2H), 2.40 (s, 2H), 1.93 (tt, J = 8.9, 5.2 Hz, 1H), 1.14(t, J = 7.5 Hz, 3H), 0.98-0.90 (m, 2H), 0.73-0.65 (m, 2H).

[0280] Synthesis example of 2-(4-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorophenyl)acetonitrile (6n) Compound 5 (150 mg, 0.33 mmol) and 4-bromo-2-fluorobenzyl cyanide (105 mg, 0.49 mmol) were reacted in the same manner as compound 6e to give a bright pink solid compound 6n (74 mg, 49% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.03 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.48-7.43 (m, 1H), 7.42-7.32(m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 6.52-6.40 (m, 2H), 4.45 (d, J = 3.3 Hz, 2H),4.12-3.98 (m, 4H), 2.58 (s, 2H), 1.96 (tt, J = 8.6, 5.1 Hz, 1H), 1.05-0.92 (m, 2H), 0.80-0.70 (m, 2H).

[0281] Synthesis example of 5-chloro-2-(1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (6o) Compound 5 (150 mg, 0.33 mmol) and 2-bromo-5-chlorobenzonitrile (106 mg, 0.49 mmol) were reacted in the same manner as compound 6e to give ivory-colored solid compound 6o (86 mg, 56% yield).

[0282] 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.05 (s, 1H), 8.38 (d, J =8.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.77 (dd, J= 8.5, 2.3 Hz, 1H), 7.63-7.52(m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.44 (d, J = 2.2 Hz,1H), 6.24-6.17 (m, 1H), 4.46 (d, J = 3.5 Hz, 2H), 4.07 (t, J = 5.5 Hz, 2H), 2.59(s, 2H), 1.94 (tt, J = 8.6, 5.1 Hz, 1H), 1.02-0.91 (m, 2H), 0.75-0.66 (m, 2H).

[0283] The compounds represented by chemical formulas 3-6 according to the present invention can be prepared according to the following reaction formula 4, but are not limited thereto.

[0284] <Reaction Formula 4>

[0285] In the aforementioned reaction formula 4, Ar 1 This is the same as the definition above. Synthesis example of 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (7) Under nitrogen atmosphere, 1,4-dioxane (7.5 mL) and water (1.5 mL) were added to a mixture of compound 2a (500 mg, 1.75 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxabortane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (812 mg, 2.63 mmol), potassium carbonate (484 mg, 3.50 mmol), and PdCl2(dppf)-CH2Cl2 adduct (286 mg, 0.35 mmol), and then heated overnight at 100 °C. The residue was filtered through fluorite, extracted with EtOAc, and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give compound 7 (382 mg, 51% yield) as a bright yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ12.21 (s, 1H), 10.25 (s, 1H), 8.59 (d, J= 8.3 Hz, 1H), 7.85-7.64 (m, 2H), 7.49(t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 4.13 (s, 2H), 3.56 (t, J = 5.4Hz, 2H), 2.69 (s, 2H), 2.03-1.92 (m, 1H), 1.45 (s, 9H), 1.04-0.92 (m, 2H), 0.78-0.69 (m, 2H).

[0286] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)quinazolin-4-amine·trifluoroacetic acid (8) Compound 7 (380 mg, 0.88 mmol) was dissolved in DCM (6 mL), and a DCM solution containing 50% TFA (4 mL) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and diethyl ether was added several times. The solvent was evaporated, and the solid was filtered and washed with diethyl ether to give a yellow solid, compound 8 (489 mg, 125% yield). 1 H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 9.01 (s, 2H), 8.67(d, J = 8.3 Hz, 1H), 7.95-7.78 (m, 2H), 7.67-7.56 (m, 1H), 7.14 (s, 1H), 6.51(s, 1H), 3.95 (s, 2H), 3.38 (d, J = 5.8 Hz, 2H), 2.88 (s, 2H), 1.98 (tt, J =8.4, 5.1 Hz, 1H), 1.05-0.94 (m, 2H), 0.80-0.71 (m, 2H).

[0287] Synthesis example of (4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-3,6-dihydropyridine-1(2H)-yl)(phenyl)methyl ketone (9a) Compound 8 (50 mg, 0.11 mmol) was dissolved in DCM (1 mL), and TEA (0.031 mL, 0.22 mmol) and DMAP (1 mg, 0.008 mmol) were added at 0 °C under a nitrogen atmosphere. Benzoyl chloride (0.014 mL, 0.12 mmol) was added to the mixture over 5 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% NaOH aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4 to remove the solvent, and then purified by column chromatography (5% DCM / MeOH) to give ivory-colored solid compound 9a (23 mg, 46% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 10.28 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 7.85-7.64 (m, 2H), 7.49 (d, J = 4.4 Hz, 6H), 7.14 (d, J = 55.9 Hz, 1H), 6.56(s, 1H), 4.30 (d, J = 58.5 Hz, 2H), 3.98-3.46 (m, 2H), 2.79 (s, 2H), 1.96 (s,1H), 0.97 (s, 2H), 0.73 (s, 2H).

[0288] Synthetic example of 1-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylpropane-1-one (9b) Compound 8 (70 mg, 0.16 mmol) was dissolved in DCM (2 mL), and TEA (0.043 mL, 0.31 mmol) and DMAP (1 mg, 0.011 mmol) were added under a nitrogen atmosphere at 0 °C. Isobutyryl chloride (0.018 mL, 0.17 mmol) was added to the mixture over a period of 5 minutes. The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 10% NaOH aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4 to remove the solvent, and then purified by column chromatography (3% DCM / MeOH) to give compound 9b (11 mg, 17% yield) as a bright yellow solid. 1H NMR(400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.31 (d, J = 32.9 Hz, 1H), 8.58 (d, J =8.3 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.50 (t, J =7.6 Hz, 1H), 7.17 (s, 1H), 6.56 (s, 1H), 4.30 (d, J = 54.4 Hz, 2H), 3.78 -3.61 (m, 2H), 3.10 - 2.85 (m, 1H), 2.78 (s, 1H), 2.67 (s, 1H), 2.03 - 1.91 (m, 1H), 1.10 - 1.01 (m, 6H), 1.01 - 0.92 (m, 2H), 0.72 (d, J = 25.5 Hz, 2H).

[0289] (4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)benzyl)(methyl)tert-butyl carbamate H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)benzyl)(methyl)carbamate) (9c) Add compound 2a (100 mg, 0.35 mmol), (4-(((tert-butyloxycarbonyl)(methyl)amino)methyl)phenyl)boronic acid ((4-((( tert A mixture of 111 mg (0.42 mmol) of methylaminophenylboronic acid (PPH3)4 (40 mg, 0.035 mmol) and 97 mg (0.700 mmol) of K2CO3 was stirred overnight at 100 °C. The resulting mixture was diluted with EtOAc and washed twice with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative-grade TLC (DCM 92:MeOH 7:NH4OH 1) to give a pale yellow solid compound 9c (46 mg, 28%). 1H NMR (300 MHz, DMSO) δ 12.28 (s, 1H), 10.41 (s, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.44 (d, J = 8.0Hz, 2H), 7.83 (d, J = 4.0 Hz, 2H), 7.54 (dt, J = 8.3, 4.1 Hz, 1H), 7.38 (d, J = 8.0Hz, 2H), 6.67 (s, 1H), 4.47 (s, 2H), 2.82 (s, 3H), 2.00 (dq, J = 8.7, 4.4 Hz, 1H), 1.43 (s, 9H), 1.05-0.97 (m, 2H), 0.81-0.75 (m, 2H).

[0290] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-((methylamino)methyl)phenyl)quinazolin-4-amine hydrogen chloride (9d) At 0 °C, 0.159 mL (0.64 mmol) of dioxane in 4 M HCl (10 equivalents) was added to a solution of compound 9c (30 mg, 0.064 mmol) in DCM (1 mL), and the mixture was stirred for 4 hours. The resulting mixture was filtered and washed with DCM. The filter cake was dissolved in MeOH (0.5 mL) and tritized with diethyl ether to give a bright yellow solid. (16 mg, 63% yield) 1 H NMR (300 MHz, DMSO) δ 12.00 (s, 1H), 9.52 (s, 2H), 8.86 (d, J = 8.4Hz, 1H), 8.51 (d, J = 8.4 Hz, 2H), 8.40 (d, J = 8.4 Hz, 1H), 8.08 (t, J = 7.8 Hz, 1H), 7.85 (d, J= 8.2 Hz, 2H), 7.83 - 7.76 (m, 1H), 6.61 (s, 1H), 4.27 (t, J =5.9 Hz, 2H), 2.59 (t, J = 5.3 Hz, 3H), 2.04 (tt, J = 8.4, 5.1 Hz, 1H), 1.09 -1.00 (m, 2H), 0.84 - 0.74 (m, 2H). MS (ESI) m / z for C 22 H 22 N6[M + Calculated value: 370.2; Experimental value: 371.5 [M] + + H + ].

[0291] Synthesis example of 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (10) Compound 2a (500 mg, 1.75 mmol) was dissolved in tert-butanol (21 mL), and a solution of piperazine-1-carboxylic acid tert-butyl ester (489 mg, 2.63 mmol) dissolved in tert-butanol (3.5 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding DIPEA (339 mg, 2.63 mmol) and stirring. After 4 days, the solvent was evaporated, the residue was dissolved in DCM, and the reaction mixture was purified by column chromatography (4% DCM / MeOH) to give compound 10 (420 mg, 55% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.03 (s, 1H), 8.35 (d, J = 8.2Hz, 1H), 7.59-7.54 (m, 1H), 7.36-7.33 (m, 1H), 7.15-7.09 (m, 1H), 6.34 (s, 1H), 3.79-3.76 (m, 4H), 3.49-3.36 (m, 4H), 2.02-1.88 (m, 1H), 1.44 (s, 9H), 1.02-0.92 (m, 2H), 0.76-0.65 (m, 2H). MS (ESI) m / z for C 23 H 29 N7O2[M + Calculated value: 435.2; Experimental value: 436.5 [M] + + H+ ].

[0292] The compounds represented by chemical formulas 3-7 according to the present invention can be prepared according to the following reaction formula 5-1, but are not limited thereto.

[0293] <Reaction Formula 5-1>

[0294] {In reaction formula 5-1, Ar' is the same as defined above.} N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine N -(5-cyclopropyl-1 H -Synthesis of -pyrazol-3-yl)-2-(4-methylpiperazin-1-yl)quinazolin-4-amine) (12a) A mixture of compound 2a (71 mg, 0.25 mmol) and 1-methylpiperazine (0.083 mL, 0.75 mmol) in IPA (0.833 mL) was irradiated for 30 min at 150 °C using a microwave reactor. The reaction mixture was tritized with diethyl ether. The filter cake was neutralized with saturated NaHCO3 solution and extracted with EtOAc and water. The organic residue was dried with Na2SO4, filtered, and concentrated. The residue was tritized with diethyl ether in 10% DCM and dried. The product was dissolved in 10% MeOH in DCM and concentrated, and then tritized with n-hexane to prepare compound 12a as a white solid. (18 mg, 21% yield) MS (ESI) m / z against C 19 H 23 N7[M + Calculated value: 349.2; Experimental value: 350.1 [M] + + H + ].

[0295] Synthetic example of 2-(4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)piperazin-1-yl)ethane-1-ol (12b) A mixture of compound 2a (71 mg, 0.25 mmol), 2-(piperazin-1-yl)ethane-1-ol (0.046 mL, 0.38 mmol), and IPA (0.833 mL) was irradiated for 30 min at 150 °C using a microwave reactor. The reaction mixture was concentrated, neutralized with saturated NaHCO3 solution, and extracted with EtOAc and water. The residue was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (in a 1:1 solution of EtOAc:Hex containing 3% (7 N ammonia in MeOH)) to give compound 12b (23 mg, 24% yield) as a white solid.

[0296] The compounds represented by chemical formulas 3-7 according to the present invention can be prepared according to the following reaction formulas 5-2, but are not limited thereto.

[0297] <Reaction 5-2>

[0298] {In reaction formula 5-2, Ar' is the same as defined above.} N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-(piperazin-1-yl)quinazolin-4-amine N -(5-cyclopropyl-1 H Synthesis of -pyrazol-3-yl)-2-(piperazin-1-yl)quinazolin-4-amine) (11) A mixture of compound 2a (200 mg, 0.7 mmol) and piperazine (181 mg, 2.10 mmol) contained in IPA (2.33 mL) was irradiated for 30 min at 150 °C using a microwave reactor. The resulting mixture was concentrated under reduced pressure, diluted with EtOAc, and neutralized with a saturated NaHCO3 solution. The organic residue was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give ivory-colored solid compound 11. (8.9 mg, 3% yield) MS (ESI) m / z against C 18 H 21 N7[M + Calculated value: 335.2; Experimental value: 336.1 [M] + + H + ].

[0299] Synthetic example of 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-ethylpiperazine-1-carboxamide (12c) Ethyl isocyanate (3.54 μL, 0.045 mmol) was added to a mixed solution of compound 11 (20 mg, 0.06 mmol), TEA (8.31 μL, 0.06 mmol), and THF (0.2 mL) at 0 °C, and the mixture was heated to room temperature and stirred for 1 hour. Ethyl isocyanate (1.65 μL, 0.015 mmol) was added at 0 °C and stirred for 15 minutes. The mixture was diluted with EtOAc and washed with water. The residue was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography to give a grayish-white solid, compound 12c (8 mg, 33% yield).

[0300] Synthetic example of 4-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-(4-fluorophenyl)piperazine-1-carboxamide (12d) 4-Fluorophenyl isocyanate (6.70 μL, 0.06 mmol) was added to a mixed solution of compound 11 (20 mg, 0.06 mmol), TEA (8.31 μL, 0.06 mmol), and THF (0.2 mL), and the mixture was stirred at 0 °C for 15 min. The mixture was diluted with EtOAc and washed with water. The residue was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography to give compound 12d (11 mg, 39% yield) as a grayish-white solid.

[0301] Example of synthesis of 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (13) Compound 2a (200 mg, 0.70 mmol) was dissolved in tert-butanol (9 mL), and a solution of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (208 mg, 1.05 mmol) dissolved in tert-butanol (2 mL) was added to the mixture. The reaction mixture was heated at 110 °C while stirring with the addition of DIPEA (136 mg, 1.05 mmol). After 30 hours, the solvent was evaporated, the residue was dissolved in DCM, and then purified by column chromatography (4% DCM / MeOH) to give compound 13 (230 mg, 73% yield).

[0302] 1 H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H), 10.56 (s, 1H), 8.72-8.63(m, 1H), 7.87 (ddd, J= 8.4, 7.1, 1.2 Hz, 1H), 7.63 (dd, J = 8.4, 1.1 Hz, 1H),7.57-7.40 (m, 5H), 7.37-7.24 (m, 2H), 6.17 (s, 1H), 1.86 (ddd, J = 8.5, 5.1, 3.4 Hz, 1H), 1.01-0.88 (m, 2H), 0.66-0.53 (m, 2H). MS (ESI) m / z for C 24 H 29 N7O2[M + Calculated value: 447.2; Experimental value: 448.6 [M] + + H + ].

[0303] Synthetic example of 2-(2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine·trifluoroacetic acid (14) Compound 13 (138 mg, 0.31 mmol) was dissolved in DCM (3 mL), and a DCM solution containing 50% TFA (2 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and diethyl ether was added several times. The solvent was evaporated, the solid was filtered, and then washed with diethyl ether to give a white solid compound 14 (230 mg, quantified).

[0304] 1 H NMR (300 MHz, DMSO-d6) δ 11.54 (s, 1H), 9.53 (s, 1H), 8.92 (s, 1H), 8.66 (d, J = 8.3 Hz, 1H), 7.97-7.84 (m, 1H), 7.71 (s, 1H), 7.50 (t, J = 7.7 Hz,1H), 6.42 (s, 1H), 5.17 (d, J = 45.8 Hz, 1H), 4.66 (s, 1H), 3.88 (s, 2H), 3.47(d, J = 38.9 Hz, 2H), 2.26 (d, J= 11.2 Hz, 1H), 2.14–1.92 (m, 2H), 1.07–0.94 (m, 2H), 0.83–0.69 (m, 2H). MS (ESI) m / z for C 19 H 21 N7[M + Calculated value: 347.2; Experimental value: 348.5 [M] + + H + ].

[0305] The compounds represented by chemical formulas 3-8 according to the present invention can be prepared according to the following reaction formula 6-1, but are not limited thereto.

[0306] <Reaction Formula 6-1>

[0307] In the reaction formula 6-1, Ar 1 This is the same as the definition above. Synthesis example of 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-ethyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (15a) Compound 14 (170 mg, 0.44 mmol) was dissolved in DCM (6 mL), and DIPEA (0.116 mL, 0.66 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. Ethyl isocyanate (39 μL, 0.49 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The residue was diluted with DCM, washed with a saturated ammonium chloride solution, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative-grade TLC (8% DCM / MeOH) to give compound 15a (27 mg, 15% yield).

[0308] The compounds represented by chemical formulas 3-8 according to the present invention can be prepared according to the following reaction formulas 6-2, but are not limited thereto.

[0309] <Reaction 6-2>

[0310] In the reaction formula 6-2, Ar 1 This is the same as the definition above. Synthesis example of 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (15b) 1) 5-(isopropylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17a) Compound 16 (300 mg, 1.51 mmol) was dissolved in DCM (15 mL) and TEA (0.63 mL, 4.54 mmol) was added. The mixture was then stirred at 0 °C for 10 min. Isopropyl isocyanate (0.16 mL, 1.67 mmol) was added to the stirred solution, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water. The organic layer was washed with 10% NH4Cl solution and water. The organic layer was dried with Na2SO4 and evaporated under vacuum. The residue was filtered and purified, and washed with hexane to give compound 17a (343 mg, 80% yield) as a white solid.

[0311] 1 H NMR (300 MHz, Chloroform- d ) δ 4.67-4.37 (m, 2H), 3.97 (p, J = 6.5Hz, 1H), 3.42 (d, J = 9.9 Hz, 1H), 3.37-3.18 (m, 3H), 1.80 (s, 2H), 1.45 (s,9H), 1.15 (dd, J = 6.5, 2.9 Hz, 6H).

[0312] 2) N-Isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (18a) Compound 17a (417 mg, 1.47 mmol) was dissolved in DCM (4 mL), and a DCM solution containing 33% TFA (6 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to obtain compound 18a (168 mg, 62%).

[0313] 3) 15b Compound 2a (70 mg, 0.25 mmol) and compound 18a (54 mg, 0.29 mmol) were dissolved in ethanol (3 mL) and heated at 110 °C for 2 days. The solvent was evaporated and purified by column chromatography (6% DCM / MeOH) to give a white solid compound 15b (38 mg, 36% yield).

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.07 (s, 1H), 8.36 (d, J =8.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.5Hz, 1H), 6.60-6.31 (m, 1H), 5.94 (d, J = 7.8 Hz, 1H), 5.02-4.73 (m, 1H), 4.59(s, 1H), 3.81-3.36 (m, 4H), 2.01-1.78 (m, 3H), 1.10-0.89 (m, 8H), 0.76-0.64(m, 2H). 13 C NMR (101 MHz, DMSO) δ 157.66, 156.39, 152.48, 133.20, 125.27, 123.77, 121.25, 110.97, 94.44, 57.59, 56.45, 56.29, 55.23, 53.93, 53.61, 41.90, 37.12, 23.56, 23.45, 23.37, 8.43, 7.98, 7.56. MS (ESI) m / z for C 23 H 28 N8O[M + Calculated value: 432.5; Experimental value: 433.5 [M] + + H + ].

[0315] Synthetic example of 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (15c) 1) 5-(phenylcarbamoyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17b) Compound 16 (300 mg, 1.51 mmol) was dissolved in DCM (15 mL), and TEA (0.63 mL, 4.54 mmol) was added at 0 °C, followed by stirring for 10 min. Phenyl isocyanate (0.18 mL, 1.67 mmol) was then added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction mixture was quenched with water. The organic layer was washed with 10% NH4Cl solution and water. The bound organic layer was dried over Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography (66% Hex / EA) to give compound 17b (455 mg, 95% yield) as a white solid.

[0316] 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.23(t, J = 7.9 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 4.64 (s, 1H), 4.40 (d, J = 12.0 Hz,1H), 3.53-3.38 (m, 2H), 3.32-3.19 (m, 2H), 1.92-1.76 (m, 2H), 1.41 (d, J = 8.5Hz, 9H).

[0317] 2) N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (18b) Compound 17b (509 mg, 1.60 mmol) was dissolved in DCM (4 mL), and a 33% TFA solution in DCM (6 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM addition was repeated twice. The solvent was evaporated, and diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 18b (132 mg, 38% yield).

[0318] 3) 15c Compound 2a (70 mg, 0.25 mmol) and compound 18b (64 mg, 0.29 mmol) were dissolved in ethanol (3 mL) and heated at 110 °C for 2 days. The solvent was evaporated and purified by column chromatography (3% DCM / MeOH) to give compound 15c (27 mg, 24% yield) as a white solid.

[0319] 1 H NMR (300 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.08 (s, 1H), 8.48-8.14(m, 2H), 7.65-7.40 (m, 3H), 7.33 (s, 1H), 7.26-6.99 (m, 3H), 6.90 (t, J = 7.3Hz, 1H), 6.49 (s, 1H), 4.87 (d, J = 51.7 Hz, 2H), 3.86-3.42 (m, 4H), 2.12-1.76(m, 3H), 1.08-0.84 (m, 2H), 0.84-0.57 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 157.77, 154.37, 152.51, 140.74, 133.19, 128.73, 125.36, 123.80, 122.14, 121.29, 119.87, 111.03, 94.53, 57.63, 56.87, 55.43, 54.03, 53.75, 37.08, 8.45, 7.97, 7.58. MS (ESI) m / z for C 26 H 26 N8O [M + Calculated value: 466.6; Experimental value: 467.6 [M] + + H + ].

[0320] Synthesis example of 1-(5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-methylpropane-1-one (15d) 1) 5-Isobutyryl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17c) Compound 16 (300 mg, 1.51 mmol) was dissolved in DCM (15 mL), and TEA (0.32 mL, 2.27 mmol) was added at 0 °C. Isobutyryl chloride (0.17 mL, 1.66 mmol) was added dropwise, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM. The organic layer was washed with saturated NH4Cl solution and brine. The organic layer was dried with Na2SO4 and evaporated under vacuum to give a pink solid, compound 17c (426 mg, 105% yield).

[0321] 1 H NMR (300 MHz, DMSO-d6) δ 4.64 (d, J = 8.6 Hz, 1H), 4.44-4.30 (m, 1H), 3.64-3.39 (m, 1H), 3.30-3.02 (m, 3H), 2.75 (p, J = 6.7 Hz, 1H), 1.94-1.70 (m,2H), 1.40 (d, J = 6.2 Hz, 9H), 0.98 (ddd, J = 15.3, 7.7, 5.7 Hz, 6H).

[0322] 2) 1-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpropane-1-one (18c) Compound 17c (419 mg, 1.56 mmol) was dissolved in DCM (4 mL), and a 33% TFA solution in DCM (6 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM addition was repeated twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 18c (168 mg, 64% yield).

[0323] 3) 15d Compound 2a (80 mg, 0.28 mmol) and compound 18c (57 mg, 0.34 mmol) were dissolved in ethanol (3 mL) and heated at 110 °C for 2 days. The solvent was evaporated and purified by column chromatography (DCM:MeOH:H2O=79:9:1) to give a yellow solid compound 15d (90 mg, 77% yield).

[0324] 1 H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.10 (s, 1H), 8.37 (d, J =8.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5Hz, 1H), 6.44 (s, 1H), 5.10-4.73 (m, 2H), 3.76-3.38 (m, 4H), 2.91-2.74 (m,1H), 2.07-1.84 (m, 3H), 1.09-0.92 (m, 6H), 0.85 (d, J = 6.6 Hz, 2H), 0.76-0.63(m, 2H). 13 C NMR (101 MHz, DMSO) δ 174.54, 174.43, 157.85, 157.65, 152.62, 133.14, 129.37, 128.67, 125.43, 123.78, 121.25, 97.45, 57.91, 56.37, 55.63, 36.26, 31.59, 31.20, 20.14, 19.57, 19.39, 19.19, 11.50. MS (ESI) m / z for C 23 H 27 N7O [M + Calculated value: 417.5; Experimental value: 418.5 [M] + + H + ].

[0325] Synthesis example of (5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone (15e) 1) 5-benzoyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17d) Compound 16 (300 mg, 1.51 mmol) was dissolved in DCM (15 mL), and TEA (0.42 mL, 3.03 mmol) and DMAP (13 mg, 0.11 mmol) were added at 0 °C under a nitrogen atmosphere. Benzoyl chloride (0.19 mL, 1.66 mmol) was added dropwise, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with 10% NaOH aqueous solution and extracted with DCM. The organic layer was dried with Na2SO4 and evaporated under vacuum. The residue was purified by column chromatography (3% DCM / MeOH) to give a yellow oily compound 17d (483 mg, 106% yield).

[0326] 1 H NMR (300 MHz, Chloroform- d ) δ 7.55-7.33 (m, 5H), 4.84 (d, J = 97.4Hz, 1H), 4.45 (d, J = 41.2 Hz, 1H), 3.72-3.30 (m, 4H), 1.96-1.76 (m, 2H), 1.46(d, J = 16.8 Hz, 9H).

[0327] 2) (2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone (18d) Compound 17d (478 mg, 1.58 mmol) was dissolved in DCM (4 mL), and a 33% TFA solution in DCM (6 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM addition was repeated twice. The solvent was evaporated, and diethyl ether was added several times. The solvent was evaporated under vacuum, and the TFA salt was dissolved in MeOH with the addition of saturated NaHCO3. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 18d (232 mg, 73% yield).

[0328] 3) 15e Compound 2a (40 mg, 0.14 mmol) and compound 18d (34 mg, 0.17 mmol) were dissolved in ethanol (3 mL) and stirred overnight at 110 °C. The solvent was evaporated and purified by column chromatography (5% DCM / MeOH) and preparative TLC (5% DCM / MeOH) to give compound 15e (45 mg, 71% yield) as a bright yellow solid.

[0329] 1 H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.14 (s, 1H), 8.37 (t, J =10.0 Hz, 1H), 7.67-7.43 (m, 5H), 7.44-7.27 (m, 2H), 7.11 (q, J = 9.6, 8.6 Hz, 1H), 6.39 (d, J = 51.5 Hz, 1H), 5.14-4.35 (m, 2H), 3.88-3.55 (m, 3H), 3.48 (d, J = 11.2 Hz, 1H), 2.19-1.84 (m, 3H), 1.35-1.11 (m, 1H), 0.98 (d, J = 8.5 Hz, 2H), 0.72 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 169.25, 168.57, 136.27, 133.26, 130.73, 130.43, 128.95, 128.73, 127.74, 125.27, 123.82, 121.43, 110.96, 94.36, 60.39, 57.08, 55.90, 55.38, 54.65, 53.50, 37.93, 36.26, 8.51, 8.46, 7.56. MS (ESI) m / z for C 26 H 25 N7O [M + Calculated value: 451.5; Experimental value: 452.5 [M] + + H + ].

[0330] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15f) 1) 5-Isobutyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17e) Compound 16 (300 mg, 1.51 mmol) was dissolved in DMF (10 mL), and potassium carbonate (627 mg, 4.54 mmol) was added. 2-Methylbromopropyl (0.181 mL, 1.66 mmol) dissolved in DMF (2 mL) was added dropwise, and the mixture was stirred for 2 days at room temperature to 80 °C under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried with Na₂SO₄ and evaporated under vacuum. The residue was purified by column chromatography to give compound 17e (136 mg, 35% yield).

[0331] 1 H NMR (300 MHz, DMSO-d6) δ 4.12 (d, J = 7.5 Hz, 1H), 3.34-3.23 (m, 2H), 3.11-2.97 (m, 1H), 2.79 (d, J = 9.4 Hz, 1H), 2.44-2.33 (m, 1H), 2.24 (qd, J =11.7, 7.1 Hz, 2H), 1.70 (d, J = 9.4 Hz, 1H), 1.64-1.49 (m, 2H), 1.39 (s, 9H), 0.85 (d, J = 6.7 Hz, 6H).

[0332] 2) 2-Isobutyl-2,5-diazabicyclo[2.2.1]heptane (18e) Compound 17e (460 mg, 1.81 mmol) was dissolved in DCM (4 mL), and a DCM solution containing 33% TFA (6 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give a brown oily compound 18e (216 mg, 77% yield).

[0333] 3) 15f Compound 2a (80 mg, 0.28 mmol) and compound 18e (52 mg, 0.34 mmol) were dissolved in ethanol (3 mL) and heated at 110 °C for 2 days. The solvent was evaporated and purified by column chromatography (DCM:MeOH:H2O = 79:9:1) to give a brown solid compound 15f (48 mg, 42% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s,1H), 10.08 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.47 (d, J = 61.4 Hz, 1H), 4.76 (s, 1H), 3.92-3.38 (m, 3H), 2.99 (s, 2H), 2.42-2.10 (m, 2H), 2.03-1.68 (m, 3H), 1.71-1.44 (m, 1H), 1.03-0.63 (m, 10H). 13 C NMR (101 MHz, DMSO) δ 157.56, 157.37, 152.42, 133.18, 125.20, 123.78, 121.21, 110.95, 94.32, 62.46, 60.48, 50.80, 31.43, 29.48, 22.54, 21.05, 20.98, 14.44, 8.45, 7.56. MS (ESI) m / z for C 23 H 29 N7[M + Calculated value: 403.5; Experimental value: 404.5 [M] + + H + ].

[0334] Example of synthesis of 2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (15 g) 1) 5-Benzyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17f) Compound 16 (300 mg, 1.51 mmol) was dissolved in DMF (10 mL), and potassium iodide (251 mg, 1.51 mmol) and potassium carbonate (627 mg, 4.54 mmol) were added. Benzyl chloride (0.19 mL, 1.66 mmol) dissolved in DMF (2 mL) was added dropwise, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 3.5 h. The reaction mixture was quenched with water and extracted with acetate. The organic layer was washed with brine. The organic layer was dried with Na₂SO₄, evaporated under vacuum, and the residue was purified by column chromatography to give compound 17f (408 mg, 94% yield).

[0335] 1 H NMR (400 MHz, DMSO-d6) δ 7.40-7.27 (m, 4H), 7.27-7.17 (m, 1H), 4.16(d, J = 14.1 Hz, 1H), 3.67 (s, 2H), 3.44-3.35 (m, 2H), 3.16-3.02 (m, 1H), 2.76(t, J = 8.8 Hz, 1H), 2.48-2.39 (m, 1H), 1.79 (d, J = 9.7 Hz, 1H), 1.68-1.56 (m,1H), 1.40 (d, J = 4.9 Hz, 9H).

[0336] 2) 2-Benzyl-2,5-diazabicyclo[2.2.1]heptane (18f) Compound 17f (770 mg, 2.67 mmol) was dissolved in DCM (4 mL), and a DCM solution containing 33% TFA (6 mL) was added at 0 °C, followed by stirring at room temperature for 1 hour. The solvent was evaporated, and the DCM addition was repeated twice. The solvent was also evaporated, and diethyl ether was added multiple times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 18f (382 mg, 76% yield).

[0337] 3) 15g Compound 2a (100 mg, 0.35 mmol) and compound 18f (79 mg, 0.42 mmol) were dissolved in ethanol (3 mL) and heated at 110 °C for 4 days. The solvent was evaporated and purified by column chromatography (DCM:MeOH:H2O=79:9:1) to give 15 g (52 mg, 34%) of white solid compound. 1 H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 10.03 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.38 - 7.12(m, 6H), 7.07 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 68.4 Hz, 1H), 4.76 (s, 1H), 3.85- 3.62 (m, 3H), 3.57 (s, 1H), 3.43 (s, 1H), 2.91 (d, J = 9.2 Hz, 1H), 2.63 -2.54 (m, 1H), 2.03 - 1.86 (m, 2H), 1.86 - 1.76 (m, 1H), 0.95 (d, J = 8.4 Hz, 2H), 0.68 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 157.67, 152.82, 140.20, 137.82, 133.07, 129.37, 128.67, 128.65, 128.63, 127.16, 125.78, 125.34, 123.73, 120.93, 61.37, 59.69, 58.20, 51.56, 21.51, 8.42, 8.40. MS (ESI) m / z for C 26 H 27 N7[M + Calculated value: 437.6; Experimental value: 438.5 [M] + + H + ].

[0338] Synthetic examples of 18g to 18aa Compound 16 (1 equivalent) was dissolved in DCM, DIPEA (3 equivalents) was added and stirred, and then a DCM solution containing sulfonyl chloride (1.5 equivalents) was added dropwise at 0°C, and stirred overnight at room temperature under a nitrogen atmosphere for 1 hour. After removing the solvent, the solution was purified by column chromatography to obtain compound 17 g to compound 17aa. Compound 17 g to compound 17aa was dissolved in DCM and TFA (TFA / DCM 20% v / v) was added. After confirmation by TLC, the solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and diethyl ether was added several times. The solvent was concentrated by dissolving the TFA salt in MeOH and adding a saturated NaHCO3 solution. All solvent was evaporated, and the residue was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with anhydrous Na2SO4 and evaporated under vacuum to obtain compound 18 g to 18aa.

[0339] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15h) 1) 5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17g) Compound 16 (100 mg, 0.50 mmol) was reacted with isopropylsulfonyl chloride (0.085 mL, 0.76 mmol) to give compound 17 g (111 mg, 73% yield).

[0340] 1 H NMR (300 MHz, Chloroform- d ) δ 4.57 (s, 1H), 4.45 (s, 1H), 3.62-3.25 (m, 4H), 3.17 (p, J = 6.8 Hz, 1H), 1.94-1.81 (m, 2H), 1.65 (s, 1H), 1.49(s, 9H), 1.43 (d, J = 6.9 Hz, 3H), 1.38 (dd, J = 6.8, 2.8 Hz, 6H).

[0341] 2) 2-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18g) Compound 18g (TFA salt, 111mg, 108% yield) was obtained by reacting 17g (103mg, 0.34mmol) of compound.

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 78.0 Hz, 2H), 4.44 (s, 2H), 3.56-3.41 (m, 2H), 3.37 (p, J = 6.8 Hz, 1H), 3.33-3.18 (m, 2H), 2.01-1.81 (m,2H), 1.24 (d, J = 6.7 Hz, 6H).

[0343] 3) 15h Compound 2a (69 mg, 0.24 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18 g (115 mg, 0.36 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of DIPEA (0.063 mL, 0.36 mmol). After 18 hours, the solvent was evaporated, the reaction mixture was dissolved in ethyl acetate, and washed with water. The organic layer was dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by column chromatography (4% DCM / MeOH) to give a yellow solid, compound 15 h (58 mg, 53% yield). 1 H NMR (300MHz, DMSO-d6) δ 12.19 (s, 1H), 10.12 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.56(t, J = 7.4 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.44 (s,1H), 4.97 (s, 1H), 4.48 (s, 1H), 3.86-3.44 (m, 3H), 3.38 (s, 1H), 3.34-3.25(m, 2H), 3.01 (s, 1H), 2.12-1.99 (m, 1H), 2.01-1.83 (m, 2H), 1.57 (s, 1H),1.32 (q, J = 7.3 Hz, 1H), 1.22 (dd, J = 6.8, 2.3 Hz, 7H), 1.02-0.89 (m, 4H), 0.81-0.60 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 157.71, 133.25, 125.32, 123.81, 121.42, 111.02, 60.56, 56.07, 53.41, 52.27, 37.93, 19.90, 16.77, 16.64, 14.01, 8.44. MS (ESI) m / z for C 22 H 27 N7O2S [M + Calculated value: 453.6; Experimental value: 454.5 [M] + + H + ].

[0344] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15i) 1) 5-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17h) Compound 17h (91 mg, 85% yield) was obtained by reacting compound 16 (70 mg, 0.35 mmol) with cyclopropanesulfonyl chloride (0.054 mL, 0.53 mmol).

[0345] 1 H NMR (300 MHz, Chloroform- d ) δ 4.67-4.39 (m, 2H), 3.66-3.26 (m,4H), 2.34 (tt, J = 7.9, 4.9 Hz, 1H), 1.89 (s, 2H), 1.46 (s, 9H), 1.30-1.14(m, 2H), 1.06-0.93 (m, 2H).

[0346] 2) 2-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18h) Compound 18h ​​(23 mg, 38% yield) was obtained by reacting the compound for 17 h (90 mg, 0.30 mmol).

[0347] 1 H NMR (300 MHz, Chloroform- d ) δ 4.44 (d, J = 23.3 Hz, 2H), 3.69-3.39(m, 3H), 2.40 (ddd,J = 8.0, 5.0, 3.0 Hz, 1H), 2.05 (s, 2H), 1.19-1.06 (m, 2H), 1.10-0.93 (m, 2H).

[0348] 3) 15i Compound 2a (45 mg, 0.16 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18h ​​(48 mg, 0.24 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered and washed with ethyl acetate to give compound 15i (50 mg, 70%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 2H), 11.45 (s,1H), 8.64 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 14.2 Hz, 1H), 7.86 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 6.43 (d, J = 30.3 Hz, 1H), 5.57 (s, 1H), 5.10 (s, 1H), 4.63 (d, J = 16.7 Hz, 1H), 3.80 (s, 2H), 3.73-3.48 (m, 3H), 2.87 (t, J = 6.3 Hz,1H), 2.13 (s, 2H), 2.05-1.87 (m, 1H), 1.08-0.90 (m, 6H), 0.74 (d, J = 5.4 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.32, 140.32, 135.63, 124.86, 117.84, 95.64, 59.27, 58.89, 57.26, 54.89, 31.75, 27.53, 27.39, 8.59, 7.39, 5.05, 4.97. MS (ESI) m / z for C 22 H 25 N7O2S [M +Calculated value: 451.6; Experimental value: 452.4 [M] + + H + ].

[0349] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(propylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15j) 1) 5-(propylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17i) Compound 17i (149 mg, 97% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 1-propanesulfonyl chloride (0.085 mL, 0.76 mmol).

[0350] 1 H NMR (300 MHz, chloroform-) d ) δ 4.69-4.50 (m, 1H), 4.47 (s, 1H), 3.58-3.27(m, 4H), 3.03-2.88 (m, 2H), 1.95-1.79 (m, 4H), 1.48 (s, 9H), 1.08 (t, J = 7.5Hz, 3H).

[0351] 2) 2-(propylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18i) Compound 18 (TFA salt, 167 mg, 110% yield) was obtained by reacting compound 17i (145 mg, 0.48 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J = 106.1 Hz, 2H), 4.46 (s,2H), 3.56-3.34 (m, 2H), 3.32-3.09 (m, 4H), 1.90 (dd, J = 34.5, 11.7 Hz, 2H), 1.69 (h, J = 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H).

[0352] 3) 15j Compound 2a (89 mg, 0.31 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18i (149 mg, 0.47 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of DIPEA (0.082 mL, 0.47 mmol). After 18 hours, the solvent was evaporated, and the reaction mixture was dissolved in ethyl acetate and washed with water. The organic layer was dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by column chromatography (5% DCM / MeOH) to give compound 15j (61 mg, 43% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 12.17 (s, 1H), 10.10 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 7.56(t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.46 (s,1H), 4.96 (s, 1H), 4.49 (s, 1H), 3.78-3.41 (m, 4H), 3.31 (s, 2H), 3.17-3.00(m, 2H), 2.06-1.85 (m, 3H), 1.67 (h, J = 7.4 Hz, 2H), 1.05-0.88 (m, 5H), 0.77-0.65 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.72, 133.21, 125.39, 123.80, 121.39, 111.05, 59.92, 55.94, 52.33, 37.49, 17.20, 13.17, 8.44. MS (ESI) m / z for C 22 H 27 N7O2S [M + Calculated value: 453.6; Experimental value: 454.5 [M] + + H + ].

[0353] Synthetic example of 2-(5-(cyclohexylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (15k) 1) 5-(cyclohexylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17j) Compound 17j (101 mg, 58% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with cyclohexanesulfonyl chloride (0.11 mL, 0.76 mmol).

[0354] 1 H NMR (400 MHz, chloroform-) d ) δ 4.69-4.37 (m, 2H), 3.71-3.20 (m, 4H), 2.94-2.76 (m, 1H), 2.25-2.09 (m, 2H), 1.97-1.83 (m, 3H), 1.74 (d, J = 11.3Hz, 1H), 1.60 (s, 2H), 1.49 (s, 9H), 1.27 (q, J = 11.1, 9.6 Hz, 3H).

[0355] 2) 2-(cyclopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18j) Compound 18j (63 mg, 90% yield) was obtained by reacting compound 17i (98 mg, 0.29 mmol).

[0356] 3) 15k Compound 2a (50 mg, 0.18 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18j (64 mg, 0.26 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15k (75 mg, 87% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.99-12.29 (m, 2H), 11.44(s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.04-7.74 (m, 2H), 7.46 (t, J = 7.7 Hz, 1H), 6.41 (d, J = 32.8 Hz, 1H), 5.32 (d, J = 172.8 Hz, 1H), 4.61 (d, J= 19.5 Hz, 1H),3.89-3.68 (m, 2H), 3.68-3.46 (m, 2H), 3.23-3.03 (m, 1H), 2.18-1.93 (m, 4H),1.78 (d, J = 12.2 Hz, 2H), 1.62 (d, J = 12.7 Hz, 1H), 1.47-1.20 (m, 4H), 1.19-1.06 (m, 1H), 1.00 (d, J = 8.4 Hz, 2H), 0.82-0.60 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.34, 135.57, 125.08, 124.87, 117.89, 110.18, 95.51, 61.01, 59.44, 59.17, 57.68, 57.36, 55.11, 26.50, 26.34, 25.24, 24.94, 24.92, 8.61, 7.40. MS (ESI) m / z for C 25 H 31 Calculated value of N7O2S [M+]: 494.6; Experimental value: 502.6 [M+ + H+].

[0357] Synthetic example of 2-(5-(benzylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (15l) 1) 5-(benzylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17k) Compound 17k (138 mg, 78% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with phenylmethanesulfonyl chloride (144 mg, 0.76 mmol).

[0358] 1H NMR (300 MHz, Chloroform-d) δ 7.41 (s, 5H), 4.46 (d, J = 40.4 Hz,1H), 4.26 (s, 2H), 4.17 (s, 1H), 3.39-3.26 (m, 2H), 3.26-3.03 (m, 2H), 1.80-1.66 (m, 2H), 1.48 (s, 9H).

[0359] 2) 2-(benzylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18k) Compound 18k (TFA salt, 128 mg, 85% yield) was obtained by reacting compound 17k (134 mg, 0.41 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.61-7.30 (m, 5H), 4.60-4.44 (m, 2H), 4.43 (s, 1H), 4.34 (s, 1H), 3.41 (d, J = 2.4 Hz, 2H), 3.20 (s,2H), 1.92 (d, 1H), 1.83 (d, 1H).

[0360] 3) 15l Compound 2a (65 mg, 0.23 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18k (125 mg, 0.34 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15l (31 mg, 27% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.10 (s,1H), 8.39 (d, J = 7.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.43-7.26 (m, 6H), 7.12 (t, J =7.5 Hz, 2H), 5.77 (s, 1H), 4.48 (d, J= 2.5 Hz, 1H), 4.36 (s, 1H), 2.46-2.25(m, 15H), 2.03-1.82 (m, 3H), 1.45-1.10 (m, 36H), 1.03-0.92 (m, 2H), 0.88 (t, J = 7.1 Hz, 27H), 0.75-0.57 (m, 4H).

[0361] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15m) 1) 5-(phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17l) Compound 17l (332 mg, 97% yield) was obtained by reacting compound 16 (200 mg, 1.00 mmol) with benzenesulfonyl chloride (0.19 mL, 1.51 mmol).

[0362] 1 H NMR (300 MHz, Chloroform- d ) δ 7.91-7.79 (m, 2H), 7.68-7.47 (m,3H), 4.39 (d, J = 36.1 Hz, 2H), 3.43-3.34 (m, 2H), 3.33-3.13 (m, 2H), 1.68(t, J = 10.5 Hz, 1H), 1.41 (d, J = 8.8 Hz, 9H), 1.32-1.20 (m, 1H).

[0363] 2) 2-(phenylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18l) Compound 18 (TFA salt, 350 mg, 103% yield) was obtained by reacting compound 17 (326 mg, 0.96 mmol). 1 H NMR (300 MHz, chloroform-) d) δ 10.14 (s, 1H), 9.83 (s, 1H), 7.85 (d, J= 7.4 Hz, 2H), 7.70-7.62 (m, 1H), 7.61-7.51 (m, 2H), 4.55 (s, 1H), 4.28 (s,1H), 3.68 (d, J = 11.3 Hz, 1H), 3.37 (dd, J = 8.9, 3.2 Hz, 2H), 3.25 (d, J =11.1 Hz, 1H), 1.93 (d, J = 11.4 Hz, 1H), 1.53 (d, J = 11.5 Hz, 1H).

[0364] 3) 15m Compound 2a (103 mg, 0.36 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18l (190 mg, 0.54 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15m (65 mg, 37% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.06 (s,1H), 8.36 (d, J = 8.3 Hz, 1H), 7.92-7.75 (m, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.55(t, J = 7.5 Hz, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.39 (s,1H), 4.84 (s, 1H), 4.59 (s, 1H), 3.55 (s, 2H), 3.38 (d, J = 9.2 Hz, 1H), 2.00-1.90 (m, 1H), 1.81 (d, J = 9.8 Hz, 1H), 1.24 (s, 1H), 1.22-1.11 (s, 2H), 1.03-0.90 (m, 2H), 0.75-0.65 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 157.63, 138.26, 133.54, 133.31, 129.92, 127.54, 123.83, 110.98, 94.70, 60.54, 55.27, 54.93, 52.13, 36.35, 14.00, 8.42, 7.58. MS (ESI) m / z for C 25 H 25 N7O2S [M + Calculated value: 487.6; Experimental value: 488.4 [M] + + H + ].

[0365] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((4-fluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15n) 1) 5-((4-fluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17m) Compound 17m (254 mg, 94% yield) was obtained by reacting compound 16 (150 mg, 0.76 mmol) with 4-fluorobenzenesulfonyl chloride (0.15 mL, 1.14 mmol). 1 H NMR (400 MHz, DMSO-d6) δ 8.01-7.88 (m,2H), 7.48 (q, J = 8.1 Hz, 2H), 4.46 (s, 1H), 4.27 (d, J = 20.2 Hz, 1H), 3.27-3.06 (m, 4H), 1.70 (d, J = 10.2 Hz, 1H), 1.34 (d, J = 23.7 Hz, 9H), 1.25-1.05(m, 1H).

[0366] 2) 2-((4-fluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18m) Compound 18m (TFA salt, 298 mg, 117% yield) was obtained by reacting compound 17m (246 mg, 0.69 mmol). 1H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J = 64.8 Hz, 2H), 8.01-7.90 (m,2H), 7.58-7.45 (m, 2H), 4.59 (s, 1H), 4.34 (s, 1H), 3.48 (d, J = 11.0 Hz,1H), 3.31-3.12 (m, 3H), 1.66 (d, J = 11.4 Hz, 1H), 1.13 (d, J = 11.3 Hz, 1H).

[0367] 3) 15n Compound 2a (103 mg, 0.36 mmol) was dissolved in tert-butanol (1 mL), and a solution of compound 18m (200 mg, 0.54 mmol) dissolved in tert-butanol (1 mL) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15n (33 mg, 18% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.09 (s,1H), 8.37 (d, J = 8.3 Hz, 1H), 8.01-7.83 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.34(q, J = 8.7 Hz, 3H), 7.12 (t, J = 7.6 Hz, 1H), 6.39 (s, 1H), 4.84 (s, 1H), 4.60(s, 1H), 3.61-3.47 (m, 2H), 3.40 (s, 1H), 2.02-1.89 (m, 1H), 1.85 (d, J = 9.8Hz, 1H), 1.24 (s, 3H), 1.01-0.90 (m, 2H), 0.74-0.65 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 166.23, 163.72, 157.65, 134.79, 133.18, 130.69, 130.60, 125.41, 123.77, 121.47, 117.18, 116.95, 70.26, 60.56, 55.02, 8.40, 7.57. MS (ESI) m / z for C 25 H 24 FN7O2S [M + Calculated value: 505.3; Experimental value: 506.5 [M] + + H + ].

[0368] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15o) 1) 5-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17n) Compound 17n (178 mg, 94% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 2,4-difluorobenzenesulfonyl chloride (0.10 mL, 0.78 mmol).

[0369] 1 H NMR (300 MHz, Chloroform- d ) δ 8.01-7.86 (m, 1H), 7.09-6.88 (m,2H), 4.65-4.38 (m, 2H), 3.62-3.42 (m, 2H), 3.41-3.20 (m, 2H), 1.85 (t, J =11.8 Hz, 1H), 1.67 (s, 1H), 1.47 (d, J = 3.8 Hz, 9H).

[0370] 2) 2-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18n) Compound 18n (TFA salt, 181 mg, 101% yield) was obtained by reacting compound 17n (246 mg, 0.69 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 2H), 7.92 (dd, J = 8.5, 6.2 Hz, 1H), 7.72-7.58 (m, 1H), 7.35 (td, J = 8.5, 2.5 Hz, 1H), 7.29-7.09 (m, 2H), 4.60 (s, 1H), 4.39 (s, 1H), 3.53 (d, J = 10.7 Hz, 1H), 3.24 (s, 2H), 2.30 (s,1H), 1.79 (d, J = 11.4 Hz, 1H), 1.58 (d, J = 11.4 Hz, 1H).

[0371] 3) 15o Compound 2a (100 mg, 0.35 mmol) was dissolved in DMF (5 mL), and TEA (1.05 mL, 0.15 mmol) was added over several minutes. Compound 18n (149 mg, 0.39 mmol) was added, and the mixture was heated from 50°C to 80°C. After 24 hours, the solvent was evaporated to dissolve the compound in ethyl acetate, and the mixture was washed with water and brine. The aqueous layer was extracted multiple times with ethyl acetate. The organic layer was dried with Na₂SO₄ and evaporated under vacuum. The residue was purified by preparative-grade TLC (5% DCM / MeOH) to give compound 15o (80 mg, 44% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.17 (s,1H), 10.09 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 7.90 (td, J = 8.6, 6.3 Hz, 1H),7.61-7.51 (m, 1H), 7.44-7.18 (m, 3H), 7.12 (t, J = 7.4 Hz, 1H), 6.39 (s, 1H), 4.90 (s, 1H), 4.61 (s, 1H), 3.63-3.37 (m, 4H), 3.17 (d, J = 5.2 Hz, 1H), 2.05-1.86 (m, 3H), 1.67 (s, 1H), 0.96 (d, J = 7.9 Hz, 2H), 0.73-0.64 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 157.67, 152.47, 133.16, 133.04, 125.51, 123.80, 121.47, 113.10, 112.88, 111.04, 106.69, 60.71, 55.05, 54.70, 54.68, 49.07, 8.39, 7.39. MS (ESI) m / z for C 25 H 23 F2N7O2S [M + Calculated value: 523.6; Experimental value: 524.5 [M] + + H + ].

[0372] N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((2,6-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15p) 1) 5-((2,6-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17o) Compound 17o (143 mg, 76% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 2,6-difluorobenzenesulfonyl chloride (0.10 mL, 0.76 mmol).

[0373] 1 H NMR (300 MHz, Chloroform- d ) δ 7.52 (tt, J = 8.5, 5.9 Hz, 1H), 7.03(t, J = 9.0 Hz, 2H), 4.66 (s, 1H), 4.50 (d, J = 38.2 Hz, 1H), 3.68-3.35 (m,3H), 3.34-3.27 (m, 1H), 1.91-1.76 (m, 1H), 1.69-1.60 (m, 1H), 1.43 (s, 9H), 1.25 (s, 1H).

[0374] 2) 2-((2,6-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18o) Compound 18 (81 mg, 82%) was obtained by reacting compound 17 (136 mg, 0.36 mmol). 1 HNMR (300 MHz, chloroform- d) δ 7.51 (tt, J = 8.4, 5.9 Hz, 1H), 7.02 (t, J = 8.8 Hz, 2H), 4.60 (s, 1H), 3.93 (s, 1H), 3.52-3.33 (m, 2H), 3.29-3.00 (m, 2H), 2.38 (s, 5H), 1.82 (d, J = 10.4 Hz, 1H), 1.59 (d, J = 10.6 Hz, 1H), 1.22 (s, 1H).

[0375] 3) 15p Compound 2a (60 mg, 0.21 mmol) was dissolved in tert-butanol (1 mL), and tert-butanol containing compound 18o (86 mg, 0.32 mmol) (1 mL) was added. The reaction mixture was heated at 110 °C while adding 0.010 mL of 37% HCl aqueous solution and stirring. After overnight reaction, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15p (84 mg, 76% yield). 1 H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.63 (d, J = 8.3 Hz,1H), 8.11-7.65 (m, 3H), 7.54-7.21 (m, 3H), 6.37 (d, J = 11.8 Hz, 1H), 4.83 (d, J = 11.6 Hz, 1H), 3.92-3.75 (m, 2H), 3.75-3.60 (m, 2H), 3.56-3.46 (m, 2H), 3.25(s, 1H), 2.13-2.04 (m, 1H), 1.99 (tt, J = 8.4, 5.0 Hz, 1H), 1.87-1.63 (m, 1H), 1.07-0.92 (m, 2H), 0.80-0.66 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.59, 158.02, 136.62, 135.62, 125.17, 124.87, 117.88, 114.43, 114.20, 95.65, 58.94, 57.88, 57.04, 52.26, 50.55, 35.52, 8.60, 7.38. MS (ESI) m / z for C 25 H23 F2N7O2S[M + Calculated value: 523.6; Experimental value: 524.5 [M] + + H + ].

[0376] Synthetic example of 2-(5-((3-chlorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (15q) 1) 5-((3-chlorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17p) Compound 17p (263 mg, 93% yield) was obtained by reacting compound 16 (150 mg, 0.76 mmol) with 3-chlorobenzenesulfonyl chloride (0.16 mL, 1.14 mmol).

[0377] 1 H NMR (300 MHz, DMSO-d6) δ 7.93-7.86 (m, 1H), 7.88-7.77 (m, 2H), 7.74-7.60 (m, 1H), 4.52 (d, J = 2.3 Hz, 1H), 4.29 (d, J = 14.3 Hz, 1H), 3.30-3.06 (m, 4H), 1.72 (d, J = 9.6 Hz, 1H), 1.35 (d, J = 18.4 Hz, 9H), 1.18 (dd,J = 31.0, 10.3 Hz, 1H).

[0378] 2) 2-((3-chlorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18p) Compound 18p (205 mg, 75% yield) was obtained by reacting compound 17p (262 mg, 0.70 mmol). 1 H NMR (300 MHz, DMSO-d6) δ 8.92 (s, 2H), 8.01-7.79 (m, 3H), 7.78-7.61 (m,1H), 4.65 (s, 1H), 4.32 (s, 1H), 3.48 (d, J = 11.0 Hz, 1H), 3.31-3.13 (m,3H), 1.67 (d, J = 11.5 Hz, 1H), 1.18 (d, J = 11.3 Hz, 1H).

[0379] 3) 15q Compound 2a (103 mg, 0.36 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18p (200 mg, 0.54 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15q (42 mg, 22% yield).

[0380] 1 H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.07 (s, 1H), 8.37 (d, J =8.2 Hz, 1H), 7.88-7.72 (m, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.60-7.49 (m, 2H),7.31 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.38 (s, 1H), 4.84 (s, 1H), 4.65 (s, 1H), 3.62-3.45 (m, 2H), 3.41-3.36 (m, 1H), 2.01-1.91 (m, 1H), 1.87(s, 1H), 1.33-1.11 (m, 2H), 1.02-0.89 (m, 2H), 0.77-0.65 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 157.69, 152.45, 140.34, 134.65, 133.48, 133.11, 131.87, 127.02, 126.21, 125.53, 123.77, 121.43, 111.05, 60.67, 55.00, 8.41. MS (ESI) m / z for C 25 H 24 ClN7O2S [M + Calculated value: 522.0; Experimental value: 524.4 [M] + + H + ].

[0381] Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((3-methoxyphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15r) 1) 5-((3-methoxyphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17q) Compound 17q (164 mg, 89% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 3-methoxybenzenesulfonyl chloride (0.11 mL, 0.76 mmol).

[0382] 1 H NMR (300 MHz, Chloroform- d ) δ 7.51-7.40 (m, 2H), 7.38-7.33 (m,1H), 7.19-7.09 (m, 1H), 4.41 (d, J = 33.7 Hz, 2H), 3.88 (s, 3H), 3.55-3.35(m, 2H), 3.35-3.17 (m, 2H), 1.77-1.64 (m, 1H), 1.44 (d, J = 8.8 Hz, 9H), 1.35-1.24 (m, 1H).

[0383] 2) 2-((3-methoxyphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18q) Compound 18q (98 mg, 86% yield) was obtained by reacting compound 17q (158 mg, 0.43 mmol).

[0384] 1 H NMR (400 MHz, Chloroform- d ) δ 7.54-7.40 (m, 2H), 7.36 (s, 1H),7.20-7.07 (m, 1H), 4.43 (s, 1H), 3.89 (s, 3H), 3.84 (s, 1H), 3.43-3.25 (m,2H), 3.25-2.96 (m, 2H), 2.69 (s, 3H), 1.67 (d, J = 10.3 Hz, 1H), 1.29 (d, J =10.2 Hz, 1H).

[0385] 3) 15r Compound 2a (70 mg, 0.25 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18q (99 mg, 0.37 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.010 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15r (126 mg, 99% yield). 1 H NMR (300 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.06 (dd, J = 35.5, 8.4 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.55-7.38 (m,3H), 7.38-7.29 (m, 1H), 7.20 (d, J = 7.8 Hz, 1H), 6.35 (d, J = 4.9 Hz, 1H), 4.76 (d, J = 11.7 Hz, 1H), 3.84-3.67 (m, 5H), 3.67-3.53 (m, 2H), 3.29-3.14 (m, 1H), 2.07-1.86 (m, 2H), 1.31 (d, J = 10.1 Hz, 1H), 1.07-0.90 (m, 2H), 0.80-0.68 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 160.15, 139.21, 135.51, 131.32, 124.83, 117.94, 112.57, 112.38, 110.12, 95.68, 59.57, 57.61, 56.66, 56.22, 56.10, 55.29, 36.65, 8.60, 7.41. MS (ESI) m / z for C 26 H 27 N7O3S [M + Calculated value: 517.6; Experimental value: 519.5 [M] + + H + ].

[0386] Synthetic example of 1-(4-((5-(4-(((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)phenyl)ethane-1-one (15s) 1) 5-((4-acetylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17r) Compound 17r (167 mg, 87% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 4-acetylbenzenesulfonyl chloride (165 mg, 0.76 mmol).

[0387] 1 H NMR (400 MHz, Chloroform- d ) δ 8.09 (d, J = 8.1 Hz, 2H), 7.93 (d, J= 8.1 Hz, 2H), 4.53-4.29 (m, 2H), 3.45 (dd, J = 35.5, 9.8 Hz, 2H), 3.33-3.13(m, 2H), 2.65 (s, 3H), 1.78-1.66 (m, 1H), 1.40 (d, J = 15.3 Hz, 9H), 1.34-1.24 (m, 1H).

[0388] 2) 1-(4-((2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)phenyl)ethane-1-one (18r) Compound 18r (102 mg, 85% yield) was obtained by reacting compound 17r (162 mg, 0.43 mmol).

[0389] 3) 15s Compound 2a (65 mg, 0.23 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18r (96 mg, 0.34 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was washed with ethyl acetate and filtered to recover the white solid. The solid was dissolved in DCM and washed with water. The organic layer was dried with Na₂SO₄ and evaporated under vacuum to give the white solid compound 15s (102 mg, 85%).

[0390] 1H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.08 (s, 1H), 8.37 (d, J =8.2 Hz, 1H), 8.06-7.89 (m, 4H), 7.55 (t, J = 7.6 Hz, 1H), 7.32 (s, 1H), 7.12(t, J = 7.6 Hz, 1H), 6.35 (s, 1H), 4.83 (s, 1H), 4.63 (s, 1H), 3.58-3.36 (m,4H), 2.52 (s, 3H), 2.02-1.84 (m, 2H), 1.49-1.31 (m, 1H), 0.97 (d, J = 8.2 Hz, 2H), 0.71 (dd, J = 5.1, 2.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.36, 157.55, 142.19, 140.09, 133.23, 129.51, 127.86, 123.79, 121.55, 110.95, 60.62, 54.96, 54.75, 27.27, 8.40, 7.56. MS (ESI) m / z for C 27 H 27 N7O3S [M + Calculated value: 529.6; Experimental value: 530.6 [M] + + H + ].

[0391] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(m-tolylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15t) 1) 5-(m-Toluenesulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17s) Compound 17s (188 mg, 106% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 3-methylbenzenesulfonyl chloride (0.11 mL, 0.76 mmol).

[0392] 1 H NMR (400 MHz, chloroform-) d) δ 7.71-7.58 (m, 2H), 7.49-7.35 (m, 2H), 4.39(d, J = 45.2 Hz, 2H), 3.54-3.33 (m, 2H), 3.33-3.13 (m, 2H), 2.43 (s, 3H),1.67 (d, J = 12.5 Hz, 1H), 1.41 (d, J = 13.0 Hz, 9H), 1.27 (d, J = 12.5 Hz, 2H).

[0393] 2) 2-(m-Toluylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18s) Compound 18s (114 mg, 86% yield) was obtained by reacting compound 17s (185 mg, 0.53 mmol).

[0394] 3) 15t Compound 2a (85 mg, 0.30 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18s (13 mg, 0.45 mmol) was added. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the mixture was filtered with ethyl acetate and washed to give a white solid, compound 15t (140 mg, 94% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.59 (s, 1H), 11.44 (s,1H), 8.63 (d, J = 8.3 Hz, 1H), 8.01-7.75 (m, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.59-7.35 (m, 3H), 6.36 (s, 1H), 4.72 (d, J = 13.7 Hz, 1H), 3.86-3.45 (m, 4H), 2.32(s, 3H), 2.05-1.82 (m, 2H), 1.36 (d, J = 10.3 Hz, 1H), 1.08-0.91 (m, 2H), 0.81-0.64 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 139.95, 137.98, 135.57, 134.38, 129.88, 127.75, 124.83, 124.75, 117.92, 110.14, 95.71, 67.40, 59.40, 56.55, 31.78, 21.16, 8.59, 7.39. MS (ESI) m / z for C 26 H 27 N7O2S [M + Calculated value: 501.6; Experimental value: 502.6 [M] + + H + ].

[0395] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((3-(trifluoromethyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15u) 1) 5-((3-(trifluoromethyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17t) Compound 17t (154 mg, 75% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with 3-(trifluoromethyl)benzenesulfonyl chloride (0.121 mL, 0.76 mmol).

[0396] 1 H NMR (400 MHz, Chloroform- d ) δ 8.11 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 4.44 (d, J = 46.4Hz, 2H), 3.52-3.33 (m, 2H), 3.33-3.16 (m, 2H), 1.83-1.67 (m, 1H), 1.41 (d, J= 14.6 Hz, 9H), 1.32-1.16 (m, 1H).

[0397] 2) 2-((3-(trifluoromethyl)phenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18t) Compound 18t (111 mg, 98% yield) was obtained by reacting compound 17t (152 mg, 0.37 mmol).

[0398] 3) 15u Compound 2a (85 mg, 0.30 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18t (109 mg, 0.36 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was washed with ethyl acetate, filtered, and the white solid was washed away to give compound 15u (164 mg, 99% yield).

[0399] 1 H NMR (300 MHz, DMSO-d6) δ 12.59 (s, 1H), 11.44 (s, 1H), 8.63 (d, J =8.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H),7.96-7.75 (m, 3H), 7.52-7.39 (m, 1H), 6.36 (s, 1H), 5.11-4.75 (m, 2H), 3.81-3.41 (m, 4H), 2.05-1.90 (m, 2H), 1.49-1.31 (m, 1H), 1.00 (s, 2H), 0.78-0.67(m, 2H). 13 C NMR (101 MHz, DMSO) δ 157.41, 157.23, 139.67, 135.53, 131.72, 130.84, 130.47, 125.10, 124.83, 124.07, 122.39, 117.93, 110.14, 95.67, 67.40, 60.26, 59.60, 59.41, 58.86, 56.77, 55.37, 36.85, 36.20, 31.77, 8.57, 7.39. MS(ESI) m / z for C 26 H 23 F3N7O2S [M + Calculated value: 555.6; Experimental value: 556.6 [M] + + H + ].

[0400] Synthesis example of 2-((5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)benzonitrile (15v) 1) 5-((2-cyanophenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17u) By reacting compound 16 (200 mg, 1.01 mmol) with 2-cyanobenzenesulfonyl chloride (305 mg, 1.51 mmol), a white solid compound 17u (348 mg, 95% yield) was obtained.

[0401] 1 H NMR (300 MHz, Chloroform- d ) δ 8.10 (dd, J = 7.5, 1.6 Hz, 1H), 7.88(dd, J = 7.2, 1.6 Hz, 1H), 7.81-7.63 (m, 2H), 4.71 (d, J = 31.7 Hz, 1H), 4.51(d, J = 31.7 Hz, 1H), 3.65-3.22 (m, 4H), 1.95-1.84 (m, 1H), 1.75 (d, J = 10.3Hz, 1H), 1.44 (s, 9H).

[0402] 2) 2-((2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)benzonitrile (18u) Compound 18 (94 mg, 38% yield) was obtained by reacting compound 17 (343 mg, 0.94 mmol).

[0403] 3) 15V Compound 2a (53 mg, 0.19 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18u (109 mg, 0.36 mmol) was added. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15v (81 mg, 85% yield).

[0404] 1 H NMR (300 MHz, DMSO-d6) δ 12.60 (s, 1H), 11.45 (s, 1H), 8.64 (d, J=8.3 Hz, 1H), 8.27-8.05 (m, 2H), 8.01-7.75 (m, 4H), 7.56-7.39 (m, 1H), 6.46-6.27 (m, 1H), 4.83 (s, 1H), 3.91-3.60 (m, 3H), 3.60-3.31 (m, 2H), 2.12 (d, J =10.3 Hz, 1H), 1.98 (tt, J = 8.4, 5.1 Hz, 1H), 1.82 (d, J = 10.3 Hz, 1H), 1.07-0.89 (m, 2H), 0.84-0.62 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.32, 141.12, 136.77, 135.59, 134.62, 134.23, 130.33, 124.87, 116.84, 110.18, 109.61, 95.62, 60.00, 58.97, 56.79, 55.20, 8.62, 7.39. MS (ESI) m / z for C 26 H 24 N8O2S [M + Calculated value: 512.6; Experimental value: 513.5 [M] + + H + ].

[0405] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((3-fluoro-4-methylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15w) 1) 5-((3-fluoro-4-methylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17v) By reacting compound 16 (200 mg, 1.01 mmol) with 3-fluoro-4-methylbenzenesulfonyl chloride (316 mg, 1.51 mmol), a bright yellow solid compound 17v (344 mg, 92% yield) was obtained.

[0406] 1 H NMR (300 MHz, Chloroform- d) δ 7.56-7.42 (m, 2H), 7.35 (t, J = 7.5Hz, 1H), 4.52-4.27 (m, 2H), 3.56-3.32 (m, 2H), 3.32-3.12 (m, 2H), 2.36 (d, J= 2.1 Hz, 3H), 1.79-1.65 (m, 1H), 1.41 (d, J = 9.2 Hz, 9H), 1.32 (d, J = 10.2Hz, 1H).

[0407] 2) 2-((3-fluoro-4-methylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18v) Compound 18 (60 mg, 24% yield) was obtained by reacting compound 17 (342 mg, 0.93 mmol).

[0408] 3) 15w Compound 2a (52 mg, 0.18 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18v (59 mg, 0.22 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15w (96 mg, 101% yield).

[0409] 1 H NMR (300 MHz, DMSO-d6) δ 12.58 (s, 1H), 11.45 (s, 1H), 8.64 (d, J =8.3 Hz, 1H), 7.86 (s, 2H), 7.72-7.58 (m, 3H), 7.56-7.38 (m, 2H), 6.35 (s,1H), 4.76 (d, J = 15.3 Hz, 1H), 3.79-3.41 (m, 5H), 3.30-3.14 (m, 1H), 2.24 (s,3H), 2.06-1.90 (m, 2H), 1.52-1.34 (m, 1H), 1.07-0.94 (m, 2H), 0.79-0.67 (m,2H). 13C NMR (101 MHz, DMSO) δ 162.04, 159.57, 157.04, 150.38, 140.40, 135.49,133.32, 131.45, 131.29, 131.12, 125.11, 124.81, 123.86, 123.63, 117.92,114.71, 114.45, 114.14, 110.29, 110.08, 95.82, 95.52, 67.40, 60.07, 59.46,58.76, 58.51, 57.62, 56.78, 56.45, 55.34, 54.55, 51.93, 50.87, 36.81, 36.16, 34.84, 31.77, 14.83, 14.80, 14.71, 8.57, 7.42. MS (ESI) m / z for C 26 H 26 N7O2S [M + Calculated value: 519.6; Experimental value: 520.5 [M] + + H + ].

[0410] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((4-propylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15x) 1) 5-((4-propylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17w) By reacting compound 16 (200 mg, 1.01 mmol) with 4-propylbenzenesulfonyl chloride (0.27 mL, 1.51 mmol), a bright yellow solid compound 17w (363 mg, 95% yield) was obtained.

[0411] 1 H NMR (300 MHz, Chloroform- d) δ 7.76 (d, J = 8.1 Hz, 2H), 7.35 (d, J= 8.1 Hz, 2H), 4.40 (d, J = 33.4 Hz, 2H), 3.56-3.34 (m, 2H), 3.34-3.14 (m,2H), 2.68 (t, J = 7.5 Hz, 2H), 1.77-1.62 (m, 3H), 1.43 (d, J = 5.8 Hz, 9H), 1.31-1.19 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H).

[0412] 2) 2-((4-propylphenyl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18w) Compound 18w (128 mg, 48% yield) was obtained by reacting compound 17w (361 mg, 0.95 mmol).

[0413] 3) 15x Compound 2a (105 mg, 0.37 mmol) was dissolved in tert-butanol (2 mL), and a solution of tert-butanol (1 mL) containing compound 18w (124 mg, 0.44 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.015 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was filtered with ethyl acetate and the white solid was washed to give compound 15x (180 mg, 92% yield).

[0414] 1 H NMR (300 MHz, DMSO-d6) δ 12.53 (d, J = 39.5 Hz, 1H), 11.49-11.34 (m,1H), 8.63 (d, J = 8.3 Hz, 1H), 8.07-7.73 (m, 4H), 7.53-7.32 (m, 3H), 6.36 (s,1H), 4.71 (d, J = 13.5 Hz, 1H), 3.79-3.42 (m, 4H), 3.34-3.16 (m, 1H), 2.58 (t, J = 7.5 Hz, 2H), 2.01 (tt, J = 8.5, 5.1 Hz, 1H), 1.93 (d, J = 10.2 Hz, 1H), 1.55(h, J= 7.7 Hz, 2H), 1.33 (d, J = 10.2 Hz, 1H), 1.09-0.93 (m, 2H), 0.85 (t, J = 7.3Hz, 3H), 0.79-0.68 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.08, 148.65, 135.52, 135.36, 129.90, 127.70, 124.83, 117.91, 110.10, 95.67, 60.05, 59.50, 58.77, 56.43, 55.14, 37.28, 36.67, 36.08, 23.97, 13.95, 8.59, 7.42. MS (ESI) m / z for C 28 H 31 N7O2S [M + Calculated value: 529.6; Experimental value: 530.6 [M] + + H + ].

[0415] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(naphthyl-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15y) 1) 5-(naphthalene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17x) Compound 16 (100 mg, 0.50 mmol) was reacted with naphthalene-2-sulfonyl chloride (171 mg, 0.76 mmol) to give a white solid compound 17x (169 mg, 87% yield).

[0416] 1 H NMR (400 MHz, Chloroform- d) δ 8.47-8.32 (m, 1H), 7.95 (dd, J =23.9, 8.3 Hz, 3H), 7.83 (d, J = 8.5 Hz, 1H), 7.72-7.54 (m, 2H), 4.53 (s, 1H), 4.37 (d, J = 44.7 Hz, 1H), 3.55-3.35 (m, 2H), 3.35-3.12 (m, 2H), 1.71-1.61 (m, 1H), 1.46-1.18 (m, 10H).

[0417] 2) 2-(naphthalene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18x) Compound 18x (119 mg, 97% yield) was obtained by reacting compound 17x (150 mg, 0.44 mmol).

[0418] 3) 15y Compound 2a (75 mg, 0.26 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18x (114 mg, 0.39 mmol) was added. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight reaction, the mixture was filtered with ethyl acetate and washed to give a white solid, compound 15y (68 mg, 48% yield).

[0419] 1 H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 10.02 (s, 1H), 8.51 (s,1H), 8.33 (d, J = 8.2 Hz, 1H), 8.19-8.03 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.87(dd, J = 8.7, 1.9 Hz, 1H), 7.75-7.58 (m, 2H), 7.53 (d, J = 7.6 Hz, 1H), 7.27 (s,1H), 7.10 (t, J = 7.6 Hz, 1H), 6.37 (s, 1H), 4.81 (s, 1H), 4.68 (s, 1H), 3.67-3.36 (m, 4H), 1.92 (td, J= 8.7, 4.4 Hz, 1H), 1.81 (d, J = 9.9 Hz, 1H), 1.19 (s,1H), 1.03-0.88 (m, 2H), 0.74-0.63 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 157.54, 135.34, 134.81, 132.23, 130.06, 129.69, 129.40, 128.84, 128.27, 128.07, 123.90, 122.93, 110.88, 60.55, 55.51, 54.97, 36.53, 8.44, 8.41, 7.55. MS(ESI) m / z for C 29 H 27 N7O2S [M + Calculated value: 537.6; Experimental value: 538.6 [M] + + H + ].

[0420] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(quinolin-8-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15z) 1) 5-(quinoline-8-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17y) Compound 16 (100 mg, 0.50 mmol) was reacted with quinoline-8-sulfonyl chloride (172 mg, 0.76 mmol) to give a white solid compound 17y (107 mg, 55% yield).

[0421] 1 H NMR (300 MHz, chloroform-) d) δ 9.07 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.58-7.47 (m, 1H), 5.04 (d, J = 20.1 Hz, 1H), 4.42 (d, J = 30.1 Hz, 1H), 3.79(t, J = 9.4 Hz, 1H), 3.69-3.16 (m, 3H), 1.81-1.67 (m, 1H), 1.41 (d, J = 10.3Hz, 9H), 1.27-1.22 (m, 1H).

[0422] 2) 8-((2,5-diazabicyclo[2.2.1]heptane-2-yl)sulfonyl)quinoline (18y) Compound 18y (92 mg, 145% yield) was obtained by reacting compound 17y (85 mg, 0.22 mmol).

[0423] 3) 15z Compound 2a (75 mg, 0.26 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18y (91 mg, 0.32 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight reaction, the mixture was washed with ethyl acetate and filtered to recover the white solid. The solid was dissolved in DCM and washed with water. The organic layer was dried with Na₂SO₄ and evaporated under vacuum. The residue was purified by preparative-grade TLC (5% DCM / MeOH) to give compound 15z (82 mg, 58% yield).

[0424] 0-7.93 (m, 1H), 7.82-7.63 (m, 1H), 7.63-7.45 (m, 1H), 7.45-7.31 (m,1H), 7.21-6.99 (m, 2H), 6.41 (s, 1H), 4.78 (d, J = 21.1 Hz, 2H), 4.58-4.20 (m,1H), 3.62 (d, J= 8.7 Hz, 1H), 3.30-3.00 (m, 2H), 2.03-1.77 (m, 2H), 1.77-1.63(m, 1H), 1.03-0.87 (m, 2H), 0.64 (d, J = 38.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 152.50, 150.79, 143.43, 136.95, 134.32, 133.07, 133.01, 132.71, 129.19, 125.44, 123.67, 122.27, 121.23, 111.02, 60.11, 56.97, 55.12, 37.92, 8.34, 7.51. MS (ESI) m / z for C 28 H 26 N8O2S [M + Calculated value: 538.6; Experimental value: 539.5 [M] + + H + ].

[0425] Synthetic example of 2-(5-([1,1'-biphenyl]-4-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (15aa) 1) 5-([1,1'-biphenyl]-4-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17z) Compound 17z (155 mg, 74% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with [1,1'-biphenyl]-4-sulfonyl chloride (191 mg, 0.76 mmol).

[0426] 1 H NMR (300 MHz, Chloroform- d ) δ 8.00-7.86 (m, 2H), 7.77 (d, J = 8.1Hz, 2H), 7.71-7.56 (m, 2H), 7.57-7.38 (m, 3H), 4.45 (d, J = 40.8 Hz, 2H), 3.66-3.37 (m, 2H), 3.38-3.19 (m, 2H), 1.78-1.66 (m, 1H), 1.43 (d, J = 14.3Hz, 8H), 1.40-1.24 (m, 2H).

[0427] 2) 2-([1,1'-biphenyl]-4-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18z) Compound 18z (101 mg, 89% yield) was obtained by reacting compound 17z (150 mg, 0.36 mmol).

[0428] 3) 15aa Compound 2a (60 mg, 0.21 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18z (64 mg, 0.26 mmol) was added. The reaction mixture was heated at 110 °C while stirring with the addition of 0.005 mL of 37% HCl aqueous solution. After overnight incubation, the reaction mixture was quenched with water and extracted with acetate. The organic layer was dried with Na₂SO₄ and evaporated under vacuum to give a yellow solid, compound 15aa (119 mg, 101% yield).

[0429] 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.21 (s, 1H), 8.38 (d, J =8.3 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 2H), 7.71-7.63 (m,2H), 7.63-7.27 (m, 5H), 7.21-7.06 (m, 1H), 6.40 (s, 1H), 4.78 (d, J = 71.8 Hz, 2H), 3.68-3.53 (m, 2H), 3.50-3.36 (m, 2H), 1.98-1.82 (m, 2H), 1.24 (s, 1H), 1.03-0.90 (m, 2H), 0.76-0.66 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 157.60, 144.98, 138.73, 137.11, 133.48, 129.55, 129.04, 128.28, 128.05, 127.54, 123.92, 110.89, 94.75, 70.26, 60.51, 60.23, 55.38, 54.96, 21.53, 21.23, 14.56, 8.43, 7.59. MS (ESI) m / z for C 31 H 29 N7O2S [M + Calculated value: 563.68; Experimental value: 564.6 [M] + + H + ].

[0430] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(thiophen-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)quinazolin-4-amine (15ab) 1) 5-(thiophene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17aa) Compound 17aa (165 mg, 95% yield) was obtained by reacting compound 16 (100 mg, 0.50 mmol) with thiophene-2-sulfonyl chloride (138 mg, 0.76 mmol).

[0431] 1 H NMR (300 MHz, chloroform-) d ) δ 7.72-7.53 (m, 2H), 7.16 (dd, J = 5.0, 3.8Hz, 1H), 4.57-4.29 (m, 2H), 3.51 (dd, J = 26.5, 10.0 Hz, 2H), 3.38-3.16 (m,2H), 1.80-1.65 (m, 1H), 1.45 (d, J = 6.2 Hz, 9H), 1.36-1.18 (m, 2H).

[0432] 2) 2-(thiophene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (18aa) Compound 18aa (107 mg, 101% yield) was obtained by reacting compound 17aa (150 mg, 0.44 mmol).

[0433] 3) 15ab Compound 2a (60 mg, 0.21 mmol) was dissolved in tert-butanol (1 mL), and a solution of tert-butanol (1 mL) containing compound 18aa (64 mg, 0.26 mmol) was added. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight reaction, the mixture was filtered with ethyl acetate and washed to give a white solid, compound 15ab (84 mg, 61% yield).

[0434] 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 10.09 (s, 1H), 8.37 (d, J =8.3 Hz, 1H), 8.01-7.85 (m, 1H), 7.77-7.67 (m, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.23-7.06 (m, 2H), 6.40 (s, 1H), 4.88 (s, 1H), 4.56(s, 1H), 3.63-3.48 (m, 2H), 3.47-3.35 (m, 2H), 1.98-1.89 (m, 1H), 1.84 (d, J =10.0 Hz, 1H), 1.28-1.21 (m, 1H), 1.04-0.91 (m, 2H), 0.75-0.62 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 170.82, 157.69, 138.03, 134.01, 133.25, 133.08, 128.75, 123.80, 121.55, 111.02, 94.66, 60.85, 60.23, 55.22, 54.85, 36.14, 21.23, 14.56, 8.43, 8.40, 7.57. MS (ESI) m / z for C 23 H 23 N7O2S2[M + Calculated value: 493.6; Experimental value: 494.5 [M] + + H + ].

[0435] Example of synthesis of 5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (19) Compound 2a (200 mg, 0.70 mmol) was dissolved in 4 mL of tert-butanol, and a solution of compound 21 (178 mg, 0.84 mmol) dissolved in tert-butanol (2 mL) was added to the mixture. The reaction mixture was heated at 110 °C while stirring with 0.020 mL of 37% HCl aqueous solution. After overnight incubation, the product was washed with EA, filtered, and then recovered. The solid was dissolved in MeOH / DCM and purified by column chromatography to give compound 19 (195 mg, 60% yield).

[0436] 1 H NMR (300 MHz, DMSO) δ 12.66 (s, 2H), 11.33 (s, 1H), 8.61 (d, J = 8.2Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 6.39 (d, J = 78.5 Hz, 1H), 5.32-4.80 (m, 1H), 4.43-4.21 (m, 1H), 3.97-3.76(m, 2H), 3.71-3.44 (m, 2H), 2.11-1.82 (m, 5H), 1.43 (d, J = 5.4 Hz, 9H), 1.07-0.91 (m, 2H), 0.80-0.64 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 157.40, 154.05,151.87, 140.78, 135.45, 125.08, 124.77, 118.29, 110.32, 95.15, 79.50, 52.96,52.77, 49.43, 48.90, 46.98, 46.39, 45.20, 44.07, 43.58, 28.57, 24.92, 24.08,8.72, 7.30.

[0437] Synthesis example of 2-(2,5-diazabicyclo[2.2.2]octane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine·trifluoroacetic acid (20) Compound 19 (192 mg, 0.42 mmol) was dissolved in DCM (4 mL), and a DCM solution containing 33% TFA (6 mL) was added at 0 °C. The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum and filtered to give compound 20 (265 mg, quantified) as a light gray solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 11.50 (d, J =26.1 Hz, 1H), 9.46 (d, J = 59.9 Hz, 2H), 8.64 (d, J = 8.6 Hz, 1H), 7.95-7.69 (m,2H), 7.50 (s, 1H), 6.37 (d, J = 78.5 Hz, 1H), 4.85 (s, 1H), 4.18-3.97 (m, 2H), 3.88 (d, J = 12.3 Hz, 1H), 3.67-3.43 (m, 2H), 2.13 (s, 2H), 2.05-1.85 (m, 3H), 1.05-0.91 (m, 2H), 0.74 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 157.49, 151.79,151.26, 147.04, 140.23, 135.91, 125.51, 124.93, 121.11, 118.19, 117.97,115.26, 112.34, 110.41, 95.32, 47.55, 45.31, 43.47, 42.48, 20.55, 19.78,8.64, 7.33.

[0438] 3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ( tert -butyl 3-(4-((5-cyclopropyl-1 H-Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate) (19') At 120 °C, compound 2a (100 mg, 0.35 mmol) dissolved in ethanol (3 mL) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid were mixed. tert A mixture of butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (111 mg, 0.53 mmol) was stirred in a sealed test tube (vial) for 2 hours. The reaction mixture was cooled and the solvent was evaporated. The crude product was washed with EtOAc and filtered for purification to prepare a white solid compound 19' (101 mg, 63%). 1 H NMR (300 MHz, DMSO) δ 12.60 (s, 2H), 11.40 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.47 (t, J =7.7 Hz, 1H), 6.34 (s, 1H), 4.39 (d, J = 12.7 Hz, 2H), 4.30 (s, 2H), 3.30 (s,2H), 2.05-1.97 (m, 1H), 1.91 (s, 2H), 1.73 (s, 2H), 1.46 (s, 9H), 1.07-0.94(m, 2H), 0.76-0.66 (m, 2H). 13 C NMR (101 MHz, DMSO) δ 157.41, 154.02, 153.29, 135.53, 125.31, 124.72, 118.50, 110.34, 95.70, 79.93, 60.23, 55.41, 28.53, 28.43, 21.24, 14.56, 8.65, 7.35. MS (ESI) m / z for C 25 H 31 N7O2[M + Calculated value: 461.3; Experimental value: 462.6 [M] + + H+ ].

[0439] 2-(3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine·trifluoroacetic acid (2-(3,8-diazabicyclo[3.2.1]octan-3-yl)- N -(5-cyclopropyl-1 H Synthesis of pyrazol-3-yl)quinazolin-4-amine trifluoroacetic acid (20') Compound 19' (70 mg, 0.15 mmol) was dissolved in DCM (2 mL), and TFA (0.5 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the addition of DCM was repeated twice. The solvent was evaporated, and the addition of diethyl ether was repeated several times. The solvent was evaporated under vacuum and filtered to give compound 20' (94 mg, quant.). 1 H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 9.47 (d, J = 19.3 Hz, 2H), 8.62 (d, J = 8.3 Hz, 1H), 7.88 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 6.32 (s, 1H), 4.44 (d, J = 13.8 Hz, 2H), 4.29 (s, 2H), 3.60 (d, J = 13.8 Hz, 2H), 2.06-1.81 (m, 5H), 1.05-0.94 (m, 2H), 0.80-0.65 (m, 2H). 13C NMR (101 MHz, DMSO) δ 159.48, 159.14, 158.80, 158.46, 157.74, 153.90, 147.04, 145.89, 140.62, 135.88, 125.65, 124.79, 121.10, 118.51, 118.18, 115.25, 112.33, 110.53, 95.75, 53.60, 48.45, 25.12, 8.67, 7.37. MS (ESI) m / z for C 20 H 23 N7[M + Calculated value: 361.2; Experimental value: 362.5 [M] + + H + ].

[0440] Compounds represented by chemical formulas 3-9 according to the present invention can be prepared according to reaction formula 1 below, but are not limited thereto.

[0441] <Reaction Formula 7>

[0442] In the aforementioned reaction formula 7, Ar 1 This is the same as the definition above. Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-yl)quinazolin-4-amine (24a) 1) 5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (22a) Compound 21 (200 mg, 0.94 mmol) was dissolved in DCM (8 mL), and DIPEA (0.49 mL, 2.83 mmol) was added. Then, a solution of isopropyl sulfonyl chloride (0.16 mL, 1.41 mmol) dissolved in DCM was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then evaporated, and the residue was purified by column chromatography (40% Hex / EA) to give compound 22a (164 mg, 55% yield) as a white solid.

[0443] 1 H NMR (400 MHz, Chloroform- d ) δ 4.39-4.14 (m, 1H), 3.96 (d, J= 14.8Hz, 1H), 3.75-3.68 (m, 1H), 3.66-3.57 (m, 1H), 3.56-3.47 (m, 1H), 3.47-3.37(m, 1H), 3.15 (p, J = 6.7 Hz, 1H), 2.25-2.09 (m, 1H), 2.10-1.89 (m, 1H), 1.89-1.71 (m, 2H), 1.47 (s, 9H), 1.35 (d, J = 6.9, 3.1 Hz, 6H).

[0444] 2) 2-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.2]octane (23a) Compound 22a (160 mg, 0.50 mmol) was dissolved in DCM (1 mL), and a DCM solution containing 33% TFA (2 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 23a (95 mg, 86% yield).

[0445] 3) 24a Compound 2a (100 mg, 0.35 mmol) was dissolved in tert-butanol (2 mL), and a solution of 23a (92 mg, 0.42 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while stirring with 0.005 mL of 37% HCl aqueous solution. After overnight incubation, the mixture was washed with EA and filtered for recovery. The crude solid was dissolved in DCM / MeOH and purified by preparative-grade TLC (3% DCM / MeOH) to give ivory-colored solid compound 24a (26 mg, 16% yield). 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.07 (d, J = 17.7 Hz, 1H), 8.36 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 8.3 Hz, 1H), 7.42-7.23 (m, 1H), 7.09(t, J= 7.5 Hz, 1H), 6.60-6.18 (m, 1H), 5.01 (d, J = 37.2 Hz, 1H), 4.03 (s, 1H), 3.96-3.81 (m, 1H), 3.73 (s, 1H), 3.67-3.51 (m, 2H), 3.44-3.36 (m, 1H), 2.14-1.78 (m, 5H), 1.24 (dd, J = 6.7, 3.0 Hz, 6H), 1.02-0.91 (m, 2H), 0.76-0.61 (m, 2H). MS (ESI) m / z for C 23 H 29 N7O2S [M + Calculated value: 467.6; Experimental value: 468.5 [M] + + H + ].

[0446] Synthetic example of 2-(5-(cyclohexylsulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-yl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)quinazolin-4-amine (24b) 1) 5-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (22b) Compound 21 (200 mg, 0.94 mmol) was dissolved in DCM (8 mL), and DIPEA (0.49 mL, 2.83 mmol) was added, followed by the dropwise addition of a DCM solution containing cyclohexanesulfonyl chloride (0.21 mL, 1.41 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was washed with water and dried over anhydrous Na₂SO₄. The solvent was evaporated, and the crude product was purified by column chromatography (60% Hex / EA) to give compound 22b (186 mg, 55% yield) as a white solid.

[0447] 1 H NMR (400 MHz, Chloroform- d ) δ 4.28 (d, J = 64.7 Hz, 1H), 3.96 (d, J =14.4 Hz, 1H), 3.80-3.57 (m, 2H), 3.55-3.34 (m, 2H), 2.87 (t, J = 12.3 Hz, 1H), 2.15 (d, J= 12.8 Hz, 3H), 2.03 (q, J = 13.5 Hz, 1H), 1.96-1.86 (m, 2H), 1.86-1.76 (m, 2H), 1.76-1.68 (m, 1H), 1.59-1.41 (m, 10H), 1.26 (h, J = 12.5, 11.8Hz, 3H).

[0448] 2) 2-(cyclohexylsulfonyl)-2,5-diazabicyclo[2.2.2]octane (23b) Compound 22b (182 mg, 0.51 mmol) was dissolved in DCM (1 mL). At 0 °C, a DCM solution containing 33% TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the DCM addition was repeated twice. The solvent was evaporated, and diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 23b (43 mg, 33% yield).

[0449] 3) 24b Compound 2a (40 mg, 0.14 mmol) was dissolved in tert-butanol (1 mL), and a solution of 23b (43 mg, 0.17 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.002 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the product was filtered and recovered, and purified with EA to give compound 24b (64 mg, 90% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 12.32 (s, 1H), 11.40 (s, 1H), 8.62 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.85(t, J = 7.9 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 6.37 (d, J = 65.5 Hz, 1H), 5.08 (d, J= 77.2 Hz, 1H), 4.20-3.67 (m, 4H), 3.59 (t, J = 10.7 Hz, 1H), 3.21-3.07 (m,1H), 2.21-1.85 (m, 7H), 1.79 (d, J = 10.7 Hz, 2H), 1.63 (d, J = 12.3 Hz, 1H), 1.48-1.05 (m, 5H), 1.05-0.92 (m, 2H), 0.80-0.62 (m, 2H). MS (ESI) m / z for C 26 H 33 N7O2S [M + Calculated value: 507.7; Experimental value: 508.5 [M] + + H + ].

[0450] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-yl)quinazolin-4-amine (24c) 1) 5-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (22c) Compound 21 (200 mg, 0.94 mmol) was dissolved in DCM (8 mL), and DIPEA (0.49 mL, 2.83 mmol) was added. Then, a DCM solution containing 2,4-difluorobenzenesulfonyl chloride (0.19 mL, 1.41 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, and the solvent was evaporated with anhydrous Na2SO4. The residue was then purified by column chromatography (30% Hex / EA) to give compound 22c (337 mg, 92% yield) as a white solid.

[0451] 1 H NMR (300 MHz, Chloroform- d ) δ 8.00-7.86 (m, 1H), 7.09-6.91 (m,2H), 4.41-4.09 (m, 2H), 3.73-3.43 (m, 3H), 3.43-3.31 (m, 1H), 2.15-1.90 (m,2H), 1.90-1.66 (m, 2H), 1.45 (s, 9H).

[0452] 2) 2-((2,4-difluorophenyl)sulfonyl)-2,5-diazabicyclo[2.2.2]octane (23c) Compound 22c (332 mg, 0.86 mmol) was dissolved in DCM (1 mL), and a DCM solution containing 33% TFA (2 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in a small amount of MeOH, and saturated NaHCO3 was added. The crude product was extracted twice with EtOAc, the organic layer was dried with Na2SO4, and evaporated under vacuum to obtain compound 23c (312 mg, quantified).

[0453] 3) 24c Compound 2a (100 mg, 0.35 mmol) was dissolved in tert-butanol (1 mL), and a solution of 23c (151 mg, 0.53 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the product was filtered and recovered, and purified with EA to give compound 24c (174 mg, 92% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 12.31 (s, 1H), 11.40 (s, 1H), 8.62 (d, J = 8.1 Hz, 1H), 8.12-7.89 (m, 2H), 7.84(t, J = 7.8 Hz, 1H), 7.67-7.38 (m, 2H), 7.39-7.22 (m, 1H), 6.29 (d, J = 25.2 Hz, 1H), 5.10 (d, J = 92.0 Hz, 1H), 4.31 (d, J = 14.5 Hz, 1H), 3.94-3.53 (m, 4H), 2.19-1.73 (m, 5H), 1.12-0.90 (m, 2H), 0.71 (s, 2H). MS (ESI) m / z for C 26 H 25 F2N7O2S [M + Calculated value: 537.6; Experimental value: 538.3 [M] + + H + ].

[0454] Synthesis example of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(5-(thiophen-2-ylsulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-yl)quinazolin-4-amine (24d) 1) 5-(thiophene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (22d) Compound 21 (200 mg, 0.94 mmol) was dissolved in DCM (8 mL), and DIPEA (0.49 mL, 2.83 mmol) was added. Then, a DCM solution of thiophene-2-sulfonyl chloride (258 mg, 1.41 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, dried over anhydrous Na2SO4, and the solvent was evaporated. The residue was purified by column chromatography (30% Hex / EA) to give a white solid compound 22d (338 mg, 100% yield).

[0455] 1 H NMR (300 MHz, chloroform-) d ) δ 7.66-7.55 (m, 2H), 7.17-7.09 (m, 1H), 4.38-4.05 (m, 2H), 3.72-3.34 (m, 3H), 3.34-3.21 (m, 1H), 2.05-1.87 (m, 2H),1.79-1.64 (m, 2H), 1.44 (d, J = 6.7 Hz, 9H).

[0456] 2) 2-(thiophene-2-ylsulfonyl)-2,5-diazabicyclo[2.2.2]octane (23d) Compound 22d (332 mg, 0.93 mmol) was dissolved in DCM (1 mL), and a DCM solution containing 33% TFA (2 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in a small amount of methanol, and saturated NaHCO3 was added. The crude product was extracted twice with EtOAc, the organic layer was dried with Na2SO4, and then evaporated under vacuum to obtain compound 23d (192 mg, 80% yield).

[0457] 3) 24d Compound 2a (100 mg, 0.35 mmol) was dissolved in tert-butanol (1 mL), and a solution of 23d (136 mg, 0.53 mmol) dissolved in tert-butanol (1 mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the product was filtered and recovered, and washed with EtOAc. The crude solid was dissolved in DCM and purified by column chromatography (3% DCM / MeOH) to give compound 24d (39 mg, 22% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.05 (s, 1H), 8.36(d, J = 8.2 Hz, 1H), 7.95 (d, J = 5.0 Hz, 1H), 7.79-7.67 (m, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.19 (s, 1H), 7.09 (t, J = 6.9 Hz, 1H), 6.31(d, J = 19.4 Hz, 1H), 4.96 (d, J = 34.8 Hz, 1H), 4.15 (s, 1H), 3.72-3.47 (m, 3H), 3.47-3.35 (m, 1H), 2.00-1.65 (m, 5H), 1.00 (s, 2H), 0.70 (s, 2H). MS (ESI) m / z for C 24 H 25 N7O2S2[M + Calculated value: 507.6; Experimental value: 508.4 [M] + + H + ].

[0458] Synthesis example of 2-((5-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-yl)sulfonyl)benzonitrile (24e) 1) 5-((2-cyanophenyl)sulfonyl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (22e) Compound 21 (200 mg, 0.94 mmol) was dissolved in DCM (8 mL), and DIPEA (0.49 mL, 2.83 mmol) was added. Then, a DCM solution containing 2-cyanobenzenesulfonyl chloride (285 mg, 1.41 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over anhydrous Na2SO4, and the solvent was evaporated. The residue was purified by column chromatography (60% Hex / EA) to give a white solid, compound 22e (149 mg, 42% yield).

[0459] 1 H NMR (400 MHz, Chloroform- d ) δ 8.10 (t, J = 7.1 Hz, 1H), 7.89 (d, J =7.4 Hz, 1H), 7.79-7.64 (m, 2H), 4.39-4.16 (m, 2H), 3.76-3.58 (m, 2H), 3.58-3.44 (m, 1H), 3.40 (d, J = 11.8 Hz, 1H), 2.19-1.93 (m, 3H), 1.85-1.70 (m, 2H), 1.43 (s, 9H).

[0460] 2) 2-((2,5-diazabicyclo[2.2.2]octane-2-yl)sulfonyl)benzonitrile (23e) Compound 22e (145 mg, 0.38 mmol) was dissolved in DCM (1 mL), and a DCM solution containing 33% TFA (2 mL) was added at 0 °C, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the DCM was added twice more. The solvent was evaporated, and the diethyl ether was added several times. The solvent was evaporated under vacuum. The TFA salt was dissolved in MeOH, and saturated NaHCO3 was added. All solvent was evaporated, and the salt was extracted with 2% DCM / MeOH. After filtration, the organic layer was dried with Na2SO4 and evaporated under vacuum to give compound 23e (84 mg, 79% yield).

[0461] 3) 24e Compound 2a (60 mg, 0.21 mmol) was dissolved in tert-butanol (1 mL), and a solution of 23e (82 mg, 0.29 mmol) dissolved in tert-butanol (mL) was added to the mixture. The reaction mixture was heated at 110 °C while adding 0.005 mL of 37% HCl aqueous solution and stirring. After overnight incubation, the product was filtered and recovered, and purified with EA to give compound 24e (103 mg, 93% yield) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.64 (s, 1H), 11.41 (s, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.24-8.06 (m, 2H), 8.05-7.73 (m, 4H), 7.54-7.37 (m, 1H), 6.31 (d, J = 34.3 Hz, 1H), 5.10 (d, J = 76.0 Hz, 1H), 4.36 (s,1H), 3.93-3.56 (m, 4H), 2.22-1.80 (m, 5H), 1.07-0.90 (m, 2H), 0.81-0.60 (m,2H). 13 C NMR (101 MHz, DMSO) δ 157.41, 141.42, 140.39, 136.77, 135.62, 134.62, 134.20, 130.44, 125.30, 124.82, 118.14, 116.79, 110.35, 109.43, 95.53, 95.27, 52.27, 51.82, 49.70, 48.22, 47.70, 46.52, 25.26, 24.24, 23.62, 8.70, 7.39. MS(ESI) m / z for C 27 H 26 N8O2S [M + Calculated value: 526.6; Experimental value: 527.4 [M] + + H + ].

[0462] 4-((2-((4-(cyanomethyl)phenyl)amino)quinazolin-4-yl)amino)-N,N-dimethylbenzenesulfonamide (4-((2-((4-(cyanomethyl)phenyl)amino)quinazolin-4-yl)amino)- N , NSynthesis example of dimethylbenzenesulfonamide (25a) Compound 2h (88 mg, 0.24 mmol) was dissolved in tert-butanol (3 mL). A solution of 2-(4-aminophenyl)acetonitrile (48.1 mg, 0.36 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. Then, 0.015 mL of 37% HCl aqueous solution was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (2% MeOH / DCM) to prepare compound 25a (52 mg, 47%). 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s,1H), 9.39 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 8.8 Hz, 2H), 7.95 (d, J =8.4 Hz, 2H), 7.82(m, 3H), 7.62-7.52 (m, 1H), 7.41-7.29 (m, 1H), 7.27 (d, J =8.5 Hz, 2H), 3.97 (s, 2H), 2.65 (s, 6H). MS (ESI) m / z for C 24 H 22 N6O2S [M + Calculated value: 458.2; Experimental value: 459.4 [M] + + H + ].

[0463] 4-((2-((4-cyanophenyl)amino)quinazolin-4-yl)amino)-N,N-dimethylbenzenesulfonamide (4-((2-((4-cyanophenyl)amino)quinazolin-4-yl)amino)- N , N Synthesis example of dimethylbenzenesulfonamide (25b) Compound 2h (70 mg, 0.19 mmol) was dissolved in tert-butanol (3 mL). A solution of 4-aminobenzonitrile (34 mg, 0.29 mmol) in tert-butanol (0.5 mL) was added to the mixture. Then, an aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (20–33% EA / Hex) to ensure the purity of compound 25b (21 mg, 25%). 1 H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.85 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.7 Hz, 2H), 8.16 (d, J = 8.8 Hz,2H), 7.85(m, 5H), 7.64 (d, J = 8.2 Hz, 1H), 7.49 (m, 1H), 2.65 (s, 6H). MS (ESI) m / z for C 23 H 20 N6O2S [M + Calculated value: 444.1; Experimental value: 445.4 [M] + + H + ].

[0464] N,N-Dimethyl-4-((2-((4-(trifluoromethyl)phenyl)amino)quinazolin-4-yl)amino)benzenesulfonamide N , N Synthesis of -dimethyl-4-((2-((4-(trifluoromethyl)phenyl)amino)quinazolin-4-yl)amino)benzenesulfonamide) (25c) The compound 2h (70 mg, 0.19 mmol) was dissolved in tert-butanol (3 mL). A solution of 4-(trifluoromethyl)aniline (47 mg, 0.29 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. Then, an aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (20-33% EA / Hex) at 25 °C to ensure the compound was purified. (66 mg, 70% yield) 1 H NMR (300 MHz, DMSO-d6) δ 10.02(s, 1H), 9.74 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.37(m, 2H), 8.15 (d, J = 8.5Hz, 2H), 7.83(m, 3H), 7.68-7.57 (m, 3H), 7.47-7.35 (m, 1H), 2.65 (s, 6H). MS(ESI) m / z for C 23 H 20 F3N5O2S [M + Calculated value: 487.1; Experimental value: 488.4 [M] + + H + ].

[0465] N,N-Dimethyl-4-((2-(phenylamino)quinazolin-4-yl)amino)benzenesulfonamide N , N Synthesis of -dimethyl-4-((2-(phenylamino)quinazolin-4-yl)amino)benzenesulfonamide) (25d) Compound 2h (70 mg, 0.19 mmol) was dissolved in tert-butanol (3 mL). A solution of aniline (27 mg, 0.29 mmol) (0.5 mL) was added to the mixture. Then, an aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (20–33% EA / Hex) to ensure the purity of compound 25d (12 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.32 (s, 1H), 8.44(d, J = 8.3 Hz, 1H), 8.35 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 7.80(m,3H), 7.56 (d, J = 8.2 Hz, 1H), 7.40 (m, 3H), 7.02-6.90 (m, 1H), 2.64 (s, 6H). MS(ESI) m / z for C 22 H 21 N5O2S [M + Calculated value: 419.1; Experimental value: 420.4 [M] + + H + ].

[0466] Synthesis of 2-(4-((4-((4-oxo-4,5-dihydrothiazol-2-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile (2-(4-((4-((4-oxo-4,5-dihydrothiazol-2-yl)amino)quinazolin-2-yl)amino)phenyl)acetonitrile)(26a) Compound 2j (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL). A solution of 2-(4-aminophenyl)acetonitrile (50 mg, 0.38 mmol) dissolved in tert-butanol (0.5 mL) was added to the mixture. Then, an aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (50% EA / Hex) to prepare compound 26a (76 mg, 84%). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 12.35 (s, 1H), 9.41 (s, 1H), 8.24 (m, 1H), 8.07–7.95 (m, 2H), 7.82–7.71 (m, 1H), 7.68 (m, 1H), 7.40–7.24 (m, 3H), 4.05 (s, 2H), 3.98 (s, 2H). MS (ESI) m / z for C 19 H 14N6OS [M + Calculated value: 374.1; Experimental value: 375.3 [M] + + H + ].

[0467] 2-((2-(phenylamino)quinazolin-4-yl)amino)thiazol-4(5H)-one (2-((2-(phenylamino)quinazolin-4-yl)amino)thiazol-4(5H)-one)(26b) Compound 2j (70 mg, 0.25 mmol) was dissolved in tert-butanol (3 mL). A solution of aniline (35 mg, 0.38 mmol) (0.5 mL) was added to the mixture. Then, an aqueous solution of 37% HCl (0.012 mL) was added, and the reaction mixture was stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure. Water was added to the mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ and then purified by column chromatography (33% EA / Hex) to ensure the purity of compound 26b (8 mg, 10%). 1 H NMR (300 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.32 (s, 1H), 8.24(m,1H), 8.05-7.93 (m, 2H), 7.76 (ddd, J = 8.4, 6.9, 1.6 Hz, 1H), 7.60 (d, J = 8.3Hz, 1H), 7.40(m, 3H), 7.05-6.92 (m, 1H), 4.04 (s, 2H). MS (ESI) m / z for C 17 H 13 N5OS [M + Calculated value: 335.1; Experimental value: 336.3 [M] + + H + ].

[0468] N-Isopropyl-5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide ( N -isopropyl-5-(4-((5-methyl-1 H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide) (27a) Compound 2p (70 mg, 0.27 mmol) and compound 18a (59 mg, 0.32 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 110 °C overnight. The solvent was evaporated, and the mixture was purified by column chromatography (6% DCM / MeOH) to give compound 27a as a white solid (70 mg, 63%). 1 H NMR (300 MHz, DMSO-d6) δ 12.19 (s,1H), 10.24 (s, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.25-7.03 (m, 1H), 6.57 (d, J = 18.9 Hz, 1H), 5.95 (t, J = 8.5 Hz,1H), 4.94 (s, 1H), 4.60 (s, 1H), 3.84-3.66 (m, 1H), 3.66-3.45 (m, 2H), 3.24-3.03 (m, 1H), 2.28 (s, 3H), 2.02-1.78 (m, 2H), 1.03 (q, J = 6.3, 5.6 Hz, 6H). 13 CNMR (101 MHz, DMSO) δ 158.87, 158.56, 158.25, 157.48, 156.41, 133.55, 123.98,119.23, 116.25, 110.83, 57.94, 56.98, 56.34, 56.29, 55.57, 55.38, 53.93,53.57, 53.37, 42.20, 41.91, 37.14, 36.92, 23.55, 23.52, 23.44, 23.35, 18.47,17.16, 12.82, 11.48. MS (ESI) m / z for C 21 H 26 N8O [M + Calculated value: 406.5; Experimental value: 407.5 [M] + + H + ].

[0469] 5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide H -pyrazol-3-yl)amino)quinazolin-2-yl)- N Synthesis of 2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (27b) Compound 2p (60 mg, 0.23 mmol) and compound 18b (55 mg, 0.25 mmol) were dissolved in ethanol (2 mL). The reaction mixture was heated at 110 °C for 2 days. The solvent was evaporated, and the mixture was purified by column chromatography (2% DCM / MeOH) to give compound 27b (26 mg, 26%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s,1H), 10.05 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.34 (s, 1H), 7.27-7.14 (m, 2H), 7.09 (t, J = 7.2Hz, 1H), 6.90 (t, J = 7.3 Hz, 1H), 6.58 (s, 1H), 4.98 (s, 1H), 4.78 (s, 1H), 3.78-3.39 (m, 4H), 2.27 (s, 3H), 2.00 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 157.87, 154.36, 152.51, 140.73, 133.18, 128.74, 125.36, 123.79, 122.15, 121.28, 119.85, 110.95, 97.52, 57.54, 56.85, 55.51, 55.38, 54.11, 53.70, 37.06, 11.51. MS (ESI) m / z for C 24 H 24 N8O [M +Calculated value: 440.5; Experimental value: 441.5 [M] + + H + ].

[0470] 2-Methyl-1-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)propane-1-one (2-methyl-1-(5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)propane-1-one H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)propan-1-one) (27c) Compound 2p (80 mg, 0.31 mmol) and compound 18c (57 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 110 °C for 2 days. The solvent was evaporated, and the mixture was purified by column chromatography (DCM:MeOH:H2O = 79:9:1) to prepare a white solid, compound 27c (81 mg, 68%). 1 H NMR (300 MHz, DMSO-d6) δ12.12 (s, 1H), 10.06 (s, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.55 (t, J = 8.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.56 (s, 1H), 5.11-4.67 (m,2H), 3.79-3.38 (m, 4H), 2.89-2.74 (m, 1H), 2.28 (s, 3H), 2.08-1.82 (m, 2H),1.10-0.91 (m, 4H), 0.84 (d, J = 6.1 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 174.54, 174.43, 157.85, 157.65, 152.62, 133.14, 125.43, 123.78, 121.28, 97.47, 57.91, 56.37, 55.63, 55.13, 36.25, 31.59, 31.20, 20.14, 19.57, 19.39, 19.19, 11.51. MS (ESI) m / z For C 21 H 25 N7O [M + Calculated value: 391.5; Experimental value: 392.5 [M] + + H + ].

[0471] (5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone ((5-(4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone H -Synthesis of -pyrazol-3-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(phenyl)methanone) (27d) Compound 2p (80 mg, 0.31 mmol) and compound 18d (75 mg, 0.37 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated overnight at 110 °C. The solid was filtered and washed with ethyl acetate to provide compound 27d (60 mg, 46%) as a white solid product. 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.54-11.16 (m, 1H), 8.75-8.53 (m, 1H), 8.10-7.74 (m, 2H), 7.67-7.29 (m, 6H), 6.70-6.34 (m, 1H), 5.63-5.06 (m, 1H), 5.05-4.47 (m, 1H), 4.04-3.67 (m, 3H), 3.67-3.49 (m, 1H), 2.40-2.25 (m, 3H), 2.25-2.00 (m, 2H). 13C NMR (101 MHz, DMSO) δ 169.27, 168.60, 136.87, 136.21, 133.26, 130.78, 130.46, 129.73, 128.98, 128.73, 127.79, 127.58, 123.34, 122.24, 111.08, 60.38, 57.03, 56.88, 56.03, 55.38, 54.99, 37.99, 36.28. MS (ESI) m / z for C 24 H 23 N7O [M + Calculated value: 425.5; Experimental value: 426.5 [M] + + H + ].

[0472] 2-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N -(5-methyl-1 H Synthesis of pyrazol-3-yl)quinazolin-4-amine(27e) Compound 2p (80 mg, 0.31 mmol) and compound 18e (57 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 110 °C for 4 days. The solvent was evaporated and purified by column chromatography (5% DCM / MeOH) to prepare a bright brown solid, compound 27e (79 mg, 68%). 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s,1H), 10.16 (s, 1H), 8.92 (d, J = 81.0 Hz, 1H), 8.41 (d, J = 7.4 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.57 (d, J=52.6 Hz, 1H), 5.11-4.28 (m, 2H), 4.28-3.48 (m, 4H), 3.24-2.78 (m, 2H), 2.47-2.22 (m, 4H), 2.12-1.68 (m, 2H), 0.92 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 158.58, 158.27, 157.66, 157.10, 133.33, 125.03, 123.87, 121.59, 119.27, 116.28, 111.06, 111.04, 97.57, 60.82, 53.74, 42.05, 20.95, 20.85, 12.79, 11.51. MS (ESI) m / z for C 21 H 27 N7[M + Calculated value: 377.5; Experimental value: 378.5 [M] + + H + ].

[0473] 2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N -(5-methyl-1 H Synthesis of pyrazol-3-yl)quinazolin-4-amine)(27f Compound 2p (70 mg, 0.31 mmol) and compound 18f (70 mg, 0.37 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 110 °C for 3 days. The solvent was evaporated, and the mixture was purified by column chromatography (3% DCM / MeOH) to give compound 27f (66 mg, 52%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 12.16 (s,1H), 10.17 (s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.52-7.17(m, 6H), 7.13 (t, J= 7.7 Hz, 1H), 6.77-6.34 (m, 1H), 4.86 (s, 1H), 4.14-3.42(m, 5H), 3.24-3.05 (m, 1H), 2.95 (s, 1H), 2.26 (s, 3H), 2.11-1.68 (m, 2H). 13 CNMR (101 MHz, DMSO) δ 158.58, 158.27, 157.52, 156.98, 133.35, 129.96, 129.64, 128.84, 127.95, 124.69, 123.87, 121.54, 110.93, 97.51, 59.82, 58.03, 53.78, 51.29, 42.08, 14.44, 12.81, 11.51. MS (ESI) m / z for C 24 H 25 N7[M + Calculated value: 411.5; Experimental value: 412.5 [M] + + H + ].

[0474] 5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-N-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-N-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide H -pyrazol-4-yl)amino)quinazolin-2-yl)- N Synthesis of 2,5-isopropyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (28a) Compound 2f (70 mg, 0.29 mmol) and compound 18a (63 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated overnight at 110 °C. The solvent was evaporated, and the mixture was purified by column chromatography (9% DCM / MeOH) to give compound 28a as a white solid (81 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 12.80 (s,1H), 10.48 (s, 1H), 8.34 (s, 1H), 8.24-7.81 (m, 2H), 7.81-7.59 (m, 1H), 7.62-7.43 (m, 1H), 7.32 (s, 1H), 6.17-5.90 (m, 1H), 5.04 (s, 1H), 4.76-4.56 (m,1H), 3.85-3.52 (m, 3H), 3.52-3.39 (m, 1H), 2.07-1.88 (m, 2H), 1.03 (dd, J =6.6, 5.0 Hz, 6H). 13 C NMR (101 MHz, DMSO) δ 159.17, 158.86, 158.55, 123.80, 122.13, 121.72, 121.40, 119.15, 116.17, 110.77, 58.70, 57.46, 56.21, 55.70, 53.96, 53.36, 42.23, 41.98, 37.27, 37.02, 23.50, 23.31, 12.79. MS (ESI) m / z for C 20 H 24 N8O [M + Calculated value: 392.5; Experimental value: 393.5 [M] + + H + ].

[0475] 5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-N-phenyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxamide H -pyrazol-4-yl)amino)quinazolin-2-yl)- N Synthesis of 2,5-diazabicyclo[2.2.1]heptane-2-carboxamide (28b) Compound 2f (60 mg, 0.24 mmol) and compound 18b (58 mg, 0.27 mmol) were dissolved in ethanol (2 mL). The reaction mixture was heated overnight at 110 °C. The solvent was evaporated, and the mixture was purified by column chromatography (7% DCM / MeOH) to give compound 28b as a white solid (33 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 12.69 (s,1H), 10.02 (s, 1H), 8.37-8.17 (m, 2H), 8.03 (s, 2H), 7.61 (t, J = 7.4 Hz, 1H),7.54-7.33 (m, 3H), 7.29-7.06 (m, 3H), 6.96-6.81 (m, 1H), 5.05 (s, 1H), 4.80(s, 1H), 3.92-3.45 (m, 4H), 2.03 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 156.95, 154.37, 140.74, 133.47, 128.74, 123.51, 122.15, 119.81, 110.96, 58.11, 57.05, 56.78, 55.93, 55.72, 53.85, 42.13, 37.13, 12.80. MS (ESI) m / z for C 23 H 22 N8O [M + Calculated value: 426.5; Experimental value: 427.5 [M] + + H + ].

[0476] 1-(5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-methylpropane-1-one (1-(5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-2-methylpropane-1-one H -Synthesis of -pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-methylpropan-1-one) (28c) Compound 2f (70 mg, 0.29 mmol) and compound 18c (63 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated overnight at 110 °C. The solvent was evaporated, and the mixture was purified by column chromatography (7% DCM / MeOH) to give compound 28c (87 mg, 81%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s,1H), 10.14 (s, 1H), 8.28 (d, J= 8.1 Hz, 1H), 8.21-7.72 (m, 2H), 7.62 (t, J = 8.2Hz, 1H), 7.54-7.33 (m, 1H), 7.33-7.13 (m, 1H), 5.06 (d, J = 32.0 Hz, 1H), 4.83(s, 1H), 3.89-3.36 (m, 4H), 2.91-2.76 (m, 1H), 2.11-1.88 (m, 2H), 1.09-0.92(m, 4H), 0.87 (d, J = 6.7 Hz, 2H). 13 C NMR (101 MHz, DMSO) δ 174.67, 174.44, 158.60, 158.29, 156.82, 133.61, 123.56, 110.97, 57.76, 56.66, 55.44, 55.38, 53.52, 49.07, 37.89, 36.27, 31.60, 31.26, 20.15, 19.59, 19.42, 19.16. MS(ESI) m / z for C 20 H 23 N7O [M + Calculated value: 377.5; Experimental value: 378.5 [M] + + H + ].

[0477] (5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone ((5-(4-((1H-pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-yl)(phenyl)methyl ketone H -Synthesis of -pyrazol-4-yl)amino)quinazolin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(phenyl)methanone) (28d) Compound 2f (70 mg, 0.29 mmol) and compound 18d (69 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated overnight at 110 °C. The solvent was evaporated, and the mixture was purified by column chromatography (7% DCM / MeOH) to prepare a white solid, compound 28d (84 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s,1H), 9.93 (s, 1H), 8.24 (dd, J = 15.2, 8.2 Hz, 1H), 8.15-7.74 (m, 2H), 7.71-7.46 (m, 5H), 7.39 (p, J = 7.0 Hz, 2H), 7.19 (t, J = 8.1 Hz, 1H), 5.16-4.40 (m,2H), 3.75 (q, J = 19.3 Hz, 3H), 3.50 (d, J = 11.0 Hz, 1H), 2.22-1.87 (m, 2H). 13 CNMR (101 MHz, DMSO) δ 174.56, 174.44, 157.82, 157.66, 152.64, 133.14, 125.42, 123.80, 121.25, 57.93, 56.34, 55.65, 55.00, 53.19, 37.85, 36.25, 31.60, 31.21, 20.11, 19.57, 19.38, 19.20, 8.47, 8.42, 7.65. MS (ESI) m / z for C 23 H 21 N7O[M + Calculated value: 411.5; Experimental value: 412.5 [M] + + H + ].

[0478] 2-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(1H-pyrazol-4-yl)quinazolin-4-amine (2-(5-isobutyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N -(1 H Synthesis of pyrazol-4-yl)quinazolin-4-amine(28e) Compound 2f (70 mg, 0.29 mmol) and compound 18e (53 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated overnight at 110 °C. The solvent was evaporated, and the mixture was purified by column chromatography (11% DCM / MeOH) to give ivory-colored solid compound 28e (95 mg, 92%).1 H NMR (300 MHz, DMSO-d6) δ 12.71 (s,1H), 10.05 (s, 1H), 9.42 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.02 (s, 2H), 7.60(t, J = 7.7 Hz, 1H), 7.52-7.31 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 4.97 (s, 1H), 4.72-3.45 (m, 4H), 3.28-2.74 (m, 2H), 2.41-1.51 (m, 3H), 0.94 (s, 6H). 13 C NMR (101 MHz, DMSO) δ 158.84, 158.53, 157.07, 152.98, 133.30, 123.78, 122.25, 121.75, 119.21, 116.23, 111.26, 60.83, 26.16, 21.01, 20.94. MS (ESI) m / z for C 20 H 25 N7[M + Calculated value: 363.5; Experimental value: 364.5 [M] + + H + ].

[0479] 2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(1H-pyrazol-4-yl)quinazolin-4-amine (2-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)- N -(1 H Synthesis of pyrazol-4-yl)quinazolin-4-amine)(28f Compound 2f (70 mg, 0.29 mmol) and compound 18f (64 mg, 0.34 mmol) were dissolved in ethanol (3 mL). The reaction mixture was heated at 110 °C for 3 days. The solvent was evaporated and purified by column chromatography (7% DCM / MeOH) to give compound 28f as a white solid (71 mg, 62%). 1 H NMR (300 MHz, DMSO-d6) δ 12.70 (s,1H), 10.03 (s, 1H), 8.30 (d, J= 8.2 Hz, 1H), 7.99 (s, 2H), 7.72-6.89 (m, 8H), 4.96 (s, 1H), 4.73-3.48 (m, 6H), 3.17 (d, J = 4.7 Hz, 1H), 2.04 (s, 2H). 13 C NMR (101 MHz, DMSO) δ 158.63, 158.32, 156.91, 135.07, 133.53, 129.96, 129.63, 128.93, 123.57, 116.28, 111.09, 59.80, 53.83, 40.58, 40.37, 40.16, 39.95, 39.74, 39.53, 39.32, 31.43, 22.53, 14.44. MS (ESI) m / z for C 23 H 23 N7[M + Calculated value: 397.5; Experimental value: 398.5 [M] + + H + ].

[0480] Example 1.1. HTRF Analysis Recombinant GST-tag-MASTL (Thermo Fisher Scientific, MA, USA) is used for HTRF-based kinase assays. Use the HTRF Kin EASE Assay Kit (CisBio, MA, USA) according to the manufacturer's instructions.

[0481] 1.2. In vitro kinase analysis Two recombinant GST-tag-MASTL (Thermo Fisher Scientific) and His-tag-ENSA (Sino Biological Inc., Beijing, China) were used for in vitro kinase analysis. In vitro kinase analysis was performed as described in the literature [Front Oncol 2020, 10, 571601, 39-202021-10-20 doi:10.3389 / fonc.2020.571601.].

[0482] 1.3. Cell viability analysis MCF7 breast cancer cell line and MCF10A normal breast cell line were treated with serially diluted solutions of the compounds of the present invention, ranging from 1 μM to 15.63 nM, for 72 hours. Cell viability was measured by WST-8 assay (Cyto XTM Cell Viability Assay Kit, LPS solution, Daejeon, Korea) according to the manufacturer's instructions.

[0483] The analysis results are shown in Table 1 below.

[0484] [Table 1]

[0485]

[0486]

[0487]

[0488]

[0489] In Table 1, a Concentration = 1.25 μM b Concentration = 10 μM c Concentration = 3.3 μM d Concentration = 1.1 μM. IC50 was calculated based on the results in Table 1. 50 The values ​​are shown in Table 2 below.

[0490] [Table 2] Phophorylated ENSA (pENSA) is activated by MASTL phosphorylation.

[0491]

[0492]

[0493] It can be expected that the activity of phosphorylated ENSA (pENSA), which is activated by MASTL phosphorylation, will be inhibited with the inhibition of MASTL, and therefore can be used as a biomarker. In the cell viability assay, MCF7 represents a breast cancer cell line, and MCF10A represents a normal breast cancer cell line. As shown in Tables 1 and 2 above, it was confirmed that the compounds 4d and 4j of the present invention selectively inhibit breast cancer cells only in terms of cell viability in both breast cancer cells and normal cells. For 4d, the IC50 in MCF7 breast cancer cells was [not specified]. 50 The value was 176 nM, confirming its excellent inhibitory effect on breast cancer cells.

[0494] As a result, the compounds of the present invention were confirmed to have excellent MASTL inhibitory activity and could effectively inhibit breast cancer cells. This confirmed that the compounds of the present invention have the effect of inhibiting MASTL and can therefore be applied to the prevention, improvement or treatment of cancer.

[0495] The above description is merely illustrative of the invention. Those skilled in the art can make various modifications without departing from the essential characteristics of the invention. Therefore, the embodiments disclosed in this specification are not intended to limit the invention, but rather to illustrate it. The concept and scope of the invention are not limited to these embodiments. The scope of protection of this invention should be interpreted according to the scope of the claims, and should be interpreted as including all technologies within the same scope as those claims.

[0496] [Industrial Applicability] The compounds of this invention have MASTL inhibitory effects, are effective as medicines, and can be used for cancer prevention or treatment.

Claims

1. A compound, its stereoisomer, its hydrate, its solvate, or its salt represented by the following chemical formula 1: Chemical Formula 1 In the chemical formula 1, L 1 It is a single bond; -NH-; or a C2~C bond containing at least one N. 30 heterocyclic group, Ar 1 Choose free hydrogen; C1~C 30 Alkyl groups; C1~C 30 Hydroxyalkyl; C6-C 30 aryl; C7-C 30 Aryl alkyl group; C2~C containing at least one N 30 The Ar group consists of heterocyclic groups; -S(=O)2-R'; and -C(=O)-NH-R'. 1 Can be arbitrarily assigned to more than one R 1 replace, Ring A is C6-C 30 aryl; -(CH2)n-aryl; or C2~C containing at least one N. 30 The heterocyclic group, wherein the A ring can optionally be composed of one or more R groups. 2 replace, n is an integer from 1 to 10. R' is C1~C 30 Alkyl groups; C3~C 30 cycloalkyl; C7-C 30 Aryl groups; C6-C 30 aryl; or C2~C 30 heterocyclic group, The R 1 The elements are independently selected from hydrogen, halogen, hydroxyl group, oxo group, -(CH2)n-cyano group, and C3~C. 30 Cycloalkyl groups; C1-C6 groups substituted with or unsubstituted with halogens. 30 Alkyl groups; C1~C 30 alkoxy group; -L'-C2~C 30 Heterocyclic groups; -L'-C(=O)-NH2; -L'-C(=O)OR a ;-L'-S(=O)2-R a ; and -S(=O)2-NR b R c The group formed The R 2 The elements are independently selected from hydrogen, halogen, hydroxyl group, amino group, oxo group, and C3~C. 30 cycloalkyl; C1~C 30 Alkyl groups; C2~C 30 alkenyl group; C1~C 30 alkoxy group; -NH-C(=O)OR d ;-S(=O)2-R d ;-S(=O)2-NR e R f ; and -O-C7~C 30 A group consisting of aralkyl groups, or multiple adjacent R groups. 2 They can combine to form a ring. L' represents a single bond; or C1~C 10 alkylene, R a R b R c R d R e and R f Each of them is independently hydrogen; C1~C 10 Alkyl groups; C3~C 30 Cycloalkyl groups; C6~C6 groups, substituted or unsubstituted with halogens. 12 aryl group; C2~C containing at least one N 30 Heterocyclic groups; or C1~C 10 Hydroxyalkyl groups}.

2. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, The chemical formula 1 is represented by the following chemical formula 1-1: Chemical Formula 1-1 In the aforementioned chemical formula 1-1, Ring A is represented by any one of the following chemical formulas A-1 to A-5. In the chemical formulas A-1 to A-5, This refers to the binding site. R 2 The same as the content defined in claim 1, a is an integer from 0 to 3, b is an integer from 0 to 2, and c is an integer from 0 to 5.

3. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, Chemical Formula 1 is represented by the following Chemical Formula 2-1: Chemical formula 2-1 In the chemical formula 2-1, R 3 With R in claim 1 1 The definitions are the same. But excluding the aforementioned R 3 In the case where all atoms are hydrogen, d is an integer from 0 to 5.

4. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, Chemical Formula 1 is represented by any one of the following Chemical Formulas 2-2 to 2-6: {In the chemical formulas 2-2 to 2-6, R 1 The same as the content defined in claim 1, e is an integer from 0 to 3, f is an integer from 0 to 5, g is an integer from 0 to 4, and h is an integer from 0 to 6.

5. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, The chemical formula 1 is represented by any one of the following chemical formulas 3-1 to 3-9: {In the chemical formulas 3-1 to 3-9, Ar' chooses freely from C1 to C. 30 Hydroxyalkyl; C6-C 30 aryl; C7-C 30 Aryl alkyl group; C2~C containing at least one N 30 The group consisting of heterocyclic groups; -S(=O)2-R'; and -C(=O)-NH-R', wherein the Ar' can optionally be surrounded by more than one R 1 replace, Ar 1 R 1 And R' is the same as the content defined in claim 1.

6. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, Chemical Formula 1 is represented by any one of the following compounds: 。 7. The compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1, characterized in that, The compound, its stereoisomers, its hydrates, its solvates, or its salts inhibit microtubule-associated serine / threonine kinase-like (MASTL) activity.

8. A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of claim 1, its stereoisomer, its hydrate, its solvate, or its salt as an active ingredient.

9. The pharmaceutical composition for the prevention or treatment of cancer according to claim 8, characterized in that, The composition inhibits microtubule-associated serine / threonine kinase-like (MASTL) kinases.

10. The pharmaceutical composition for the prevention or treatment of cancer according to claim 8, characterized in that, The cancers mentioned include stomach cancer, breast cancer, uterine cancer, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, liver cancer, or prostate cancer.

11. A method of preventing or treating cancer, comprising administering to a mammal the composition according to any one of claims 8 to 10.

12. A health-functional food composition for preventing or improving cancer, comprising the compound, its stereoisomer, its hydrate, its solvate, or its salt as an active ingredient according to claim 1.

13. Use of a compound, its stereoisomer, its hydrate, its solvate, or its salt according to claim 1 in the preparation of a medicament for the prevention or treatment of cancer.

Images