Benzenesulfonamide derivative, method for preparing same, and pharmaceutical composition for preventing or treating cancer containing same as active ingredient

Abstract

The present invention relates to: benzenesulfonamide derivatives; a preparation method thereof; and a pharmaceutical composition for preventing or treating cancer, containing the same as an active ingredient. The compound represented by chemical formula 1 disclosed in the specification exhibits an excellent inhibitory effect on kinases associated with integrated stress response (ISR), and thus is expected to be used in the treatment of cancer.

Description

Technical Field

[0001] The present invention relates to a benzenesulfonamide derivative, a preparation method thereof and a pharmaceutical composition containing the benzenesulfonamide derivative as an active ingredient for preventing or treating cancer. Background Art

[0002] Millions of people worldwide die from various cancers, including bone cancer, bladder cancer, blood cancer (leukemia), brain cancer, breast cancer, colon cancer, cervical cancer, esophageal cancer, intestinal cancer, kidney cancer, lung cancer, liver cancer, oral cancer, nasal cancer, nerve cancer, ovarian cancer, pancreatic cancer, skin cancer, stomach cancer, prostate cancer, laryngeal cancer, uterine cancer and vaginal cancer. Over the years, a variety of methods including radiotherapy and chemotherapy have been used to treat cancer, but the number of cancer patients is still increasing, and there are also frequent reports of side effects of radiotherapy and chemotherapy causing some patients to become ill or even die.

[0003] One of the most fundamental characteristics of cancer cells is their adaptability to cellular stress. Dysregulation of the integrated stress response (ISR) is associated with a variety of diseases, including cancer. In addition, four specialized kinases (PERK, GCN2, PKR, and HRI) can sense various stresses, which work together to phosphorylate serine 51 in eIF2α. Therefore, pharmacological regulation of the ISR is known to be closely related to cancer therapy (Tian, ​​Xiaobing, et al. Frontiers in Pharmacology (2021): 2621). PERK is an anticancer target protein that can induce cancer survival, growth, and metastasis, and is also known to be associated with anticancer drug resistance (Bu, Yiwen et al. Journal of cellular physiology 231.10 (2016): 2088-2096). In addition, the expression of GCN is correlated with the prognosis of cancer patients and is known to play a vital role in the survival and proliferation of cancer cells (Ge Liyuan et al. Cancer Biomarkers 22.3 (2018): 395-403).

[0004] Therefore, the present inventors have found that benzenesulfonamide derivatives inhibit kinase signaling involved in ISR and thus have use as anticancer agents, thereby completing the present invention. Summary of the invention Technical Challenges

[0005] An object of the present invention is to provide a novel benzenesulfonamide derivative.

[0006] Another object of the present invention is to provide a method for preparing a novel benzenesulfonamide derivative.

[0007] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer.

[0008] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases associated with ISR (integrated stress response).

[0009] Another object of the present invention is to provide a health functional food for preventing or improving cancer. Means of solving the problem

[0010] In order to achieve the above objectives,

[0011] In one aspect of the present invention, the present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0012] [Formula 1]

[0013]

[0014] In formula 1,

[0015] A is

[0016] or

[0017] R 1 is hydrogen or C1-C10 alkyl;

[0018] R 2 is hydrogen, halogen, unsubstituted or halogen- or hydroxy-substituted C1-C10 alkyl, or C3-C10 cycloalkyl;

[0019] R 3 and R 4 are independently halogen;

[0020] R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group,

[0021] Wherein, the substituted C6-C10 aryl and the substituted 5-10 membered heteroaryl are independently substituted by at least one selected from the group consisting of: C1-C10 alkyl, C1-C10 alkoxy, halogen and cyano, which are unsubstituted or substituted by halogen or hydroxyl, or two adjacent atoms thereof are substituted to form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains at least one N and is unsubstituted or substituted by at least one selected from C1-C10 alkyl and oxo.

[0022] In another aspect of the present invention, the present invention is as shown in the following reaction formula 1:

[0023] The present invention provides a method for preparing a compound of Formula 1, comprising the step of reacting a compound of Formula 2 with a compound of Formula 3 to prepare a compound of Formula 1, as shown in the following Reaction Formula 1.

[0024] [Reaction 1]

[0025]

[0026] In reaction formula 1,

[0027] A.R 1 , R 2 , R 3 , R 4 and R 5 As defined in Formula 1 above.

[0028] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by Formula 1 disclosed in this specification, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

[0029] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating a disease caused by overactivation of a kinase involved in ISR (Integrated stress response), comprising a compound represented by Formula 1 disclosed in the present specification, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0030] In another aspect of the present invention, the present invention provides a health functional food for preventing or improving cancer, which comprises the compound represented by Formula 1 disclosed in this specification, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient. Beneficial Effects

[0031] The compound represented by Chemical Formula 1 disclosed in the present specification exhibits excellent inhibitory effects on kinases related to integrated stress response (ISR), and thus is expected to be used in the treatment of cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a set of photographs confirming the protein mechanism of response after ISR activation, in which the numbers correspond to the example numbers of the present invention. DETAILED DESCRIPTION

[0033] The present invention is described in detail below.

[0034] The embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. It should be understood by those skilled in the art with average knowledge that the embodiments of the present invention are given to more accurately explain the present invention.

[0035] In addition, unless explicitly stated otherwise, “including / comprising” an element throughout the specification does not exclude other elements but may include other elements.

[0036] Unless otherwise indicated, the term "alkylene", "alkenyl" or "alkyl" includes straight or branched hydrocarbon residues. For example, "C1-C5 alkyl" refers to an alkyl group having a backbone of 1 to 5 carbons. Specifically, C1-C5 alkyl can include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, sec-pentyl, neopentyl, etc.

[0037] Unless otherwise indicated, the term "cycloalkyl" includes carbocyclic groups containing carbon atoms. For example, "C3-C8 cycloalkyl" refers to a cycloalkyl group having a backbone of 3 to 8 carbons. Specifically, C3-C8 cycloalkyl can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0038] The term "aryl" refers to a functional group formed by removing a hydrogen atom from an aromatic hydrocarbon, including monocyclic and bicyclic or polycyclic condensed aromatic hydrocarbon functional groups. For example, C6-C10 aryl refers to a fully unsaturated hydrocarbon monocyclic or condensed bicyclic compound having 6 to 10 carbon atoms and satisfying Huckel's rule, including phenyl and naphthyl.

[0039] The term "heterocycle" includes fully saturated heterocycloalkyl or partially unsaturated heterocycloalkyl and heteroaryl.

[0040] Unless otherwise specified, the term "heterocycloalkyl" includes monovalent saturated residues consisting of 1 to 3 rings, which contain 1, 2, 3 or 4 heteroatoms selected from N, O or S. Two or three rings may contain bridged, fused or spirocyclic heterocycloalkyl. Among them, 5-6 membered heterocycloalkyl refers to heterocycloalkyl with 5 or 6 ring atoms.

[0041] Unless otherwise specified, the term "heteroaryl" may include a monocyclic or bicyclic or tricyclic fused aromatic group, wherein one or more aromatic rings contain 1, 2 or 3 ring heteroatoms selected from N, O or S. Also, a 5-6 membered heteroaryl group refers to a heteroaryl group having 5 or 6 ring atoms.

[0042] The term "halogen" refers to a monovalent substituent including F, Cl, Br and I.

[0044] In one embodiment of the present invention,

[0045] The present invention provides a compound represented by the following Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[0046] [Formula 1]

[0047]

[0048] In formula 1,

[0049] A is

[0050] or

[0051] R 1 is hydrogen or C1-C10 alkyl;

[0052] R 2 is hydrogen, halogen, unsubstituted or halogen- or hydroxy-substituted C1-C10 alkyl, or C3-C10 cycloalkyl;

[0053] R 3 and R 4 are independently halogen;

[0054] R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group,

[0055] Wherein, the substituted C6-C10 aryl and the substituted 5-10 membered heteroaryl are independently substituted by at least one selected from the group consisting of: C1-C10 alkyl, C1-C10 alkoxy, halogen and cyano, which are unsubstituted or substituted by halogen or hydroxyl, or two adjacent atoms thereof are substituted to form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains at least one N and is unsubstituted or substituted by at least one selected from C1-C10 alkyl and oxo.

[0056] In one embodiment of the present invention,

[0057] The present invention provides a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0058] R 1 is hydrogen or C1-C6 alkyl;

[0059] R 2 is hydrogen, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1 to 3 halogens or hydroxy groups, or C3-C8 cycloalkyl;

[0060] R 3 and R4 are independently halogen;

[0061] R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-9 membered heteroaryl group,

[0062] Wherein, the substituted C6-C10 aryl and the substituted 5-9 membered heteroaryl are independently substituted by 1-3 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano, which are unsubstituted or substituted by 1-3 halogens or hydroxyls, or two adjacent atoms thereof are substituted to form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains at least one N and is unsubstituted or substituted by 1-3 substituents selected from C1-C6 alkyl and oxo.

[0063] In one embodiment of the present invention,

[0064] The present invention provides a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0065] R 1 is hydrogen or C1-C4 alkyl;

[0066] R 2 is hydrogen, halogen, C1-C4 alkyl which is unsubstituted or substituted by 1 to 3 halogens or hydroxy groups, or C3-C6 cycloalkyl;

[0067] R 3 and R 4 are independently halogen;

[0068] R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-9 membered heteroaryl group,

[0069] wherein the substituted C6-C10 aryl and the substituted 5-9 membered heteroaryl are independently substituted by 1-3 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br and cyano which are unsubstituted or substituted by 1-3 F or hydroxyl groups, or two adjacent atoms thereof are substituted to form a 5-membered non-aromatic heterocycle, wherein the 5-membered heterocycle contains at least one N and is unsubstituted or substituted by 1-2 substituents selected from C1-C4 alkyl and oxo.

[0070] In one embodiment of the present invention,

[0071] The present invention provides a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0072] R 1is hydrogen or methyl;

[0073] R 2 is hydrogen, halogen, methyl which is unsubstituted or substituted by 1 to 3 fluorine or hydroxy groups, or cyclopropyl;

[0074] R 3 and R 4 Independently, F;

[0075] R 5 is substituted phenyl, naphthyl, substituted pyridyl, substituted pyrazolyl, substituted isoxazolyl, substituted thienyl, substituted indolyl or substituted imidazothiazolyl,

[0076] wherein the substituted phenyl, substituted pyridyl, substituted pyrazolyl, substituted isoxazolyl, substituted thienyl, substituted indolyl and substituted imidazothiazolyl are independently substituted with 1 to 3 substituents selected from the group consisting of methyl, ethyl, methoxy, F, Cl, Br, oxo and cyano which are unsubstituted or substituted with 1 to 3 F or hydroxyl groups, or two adjacent atoms thereof are substituted to form a 5-membered non-aromatic heterocyclic ring, wherein the 5-membered heterocyclic ring contains at least one N and is substituted with 1 to 2 substituents selected from methyl and oxo.

[0077] In one embodiment of the present invention,

[0078] The present invention provides a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof, wherein:

[0079] R 1 is hydrogen or methyl;

[0080] R 2 For hydrogen, or

[0081] R 5 for

[0082]

[0083]

[0085] In one embodiment of the present invention,

[0086] The present invention provides a compound of formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof,

[0087] The compound represented by the above formula 1 is one selected from the following compound groups.

[0088] <1> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazole-4-sulfonamide;

[0089] <2> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;

[0090] <3> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide;

[0091] <4> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0092] <5> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide;

[0093] <6> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-6-chloropyridine-3-sulfonamide;

[0094] <7> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-methyl-1H-indole-4-sulfonamide;

[0095] <8> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide;

[0096] <9> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3-chloro-1,5-dimethyl-1H-pyrazole-4-sulfonamide;

[0097] <10> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazole-4-sulfonamide;

[0098] <11> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-chloropyridine-3-sulfonamide;

[0099] <12> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide;

[0100] <13> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3,5-dimethylisoxazole-4-sulfonamide;

[0101] <14> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0102] <15> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide;

[0103] <16> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0104] <17> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide;

[0105] <18> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide;

[0106] <19> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide;

[0107] <20> 2,5-Dichloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide;

[0108] <21> N-(3-(2-amino-8-methyl-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0109] <22> N-(3-(2-amino-8-(difluoromethyl)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0110] <23> N-(3-(2-amino-8-hydroxymethyl)-5-oxopyrido[4,3-d]pyrimidine-6(5H)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0111] <24> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0112] <25> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxypyridine-3-sulfonamide;

[0113] <26> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0114] <27> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichloropyridine-3-sulfonamide;

[0115] <28> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-cyano-2-methoxypyridine-3-sulfonamide;

[0116] <29> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0117] <30> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;

[0118] <31> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide;

[0119] <32> 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide;

[0120] <33> N-(3-(2-amino-8-bromo-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0121] <34> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0122] <35> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide;

[0123] <36> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-3-chloro-1,5-dimethyl-1H-pyrazole-4-sulfonamide;

[0124] <37> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide;

[0125] <38> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0126] <39> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0127] <40> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0128] <41> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0129] <42> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0130] <43> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0131] <44> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0132] <45> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0133] <46> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxypyridine-3-sulfonamide;

[0134] <47> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-cyano-2-methoxypyridine-3-sulfonamide;

[0135] <48> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide;

[0136] <49> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide;

[0137] <50> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide;

[0138] <51> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxybenzenesulfonamide;

[0139] <52> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methylbenzenesulfonamide;

[0140] <53> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1-methyl-2-oxoindole-5-sulfonamide;

[0141] <54> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide;

[0142] <55> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-2,4-dichlorobenzenesulfonamide;

[0143] <56> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1-methyl-1H-pyrazole-4-sulfonamide;

[0144] <57> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichloropyridine-3-sulfonamide;

[0145] <58> 5-Chloro-N-(2,4-difluoro-3-(1-methyl-7-(methylamino)-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide;

[0146] <59> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0147] <60> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide;

[0148] <61> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0149] <62> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide;

[0150] <63> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide;

[0151] <64> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide;

[0152] <65> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; and

[0153] <66> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide.

[0155] In one embodiment of the present invention,

[0156] The present invention provides a method for preparing a compound represented by formula 1.

[0157] The method comprises reacting the compound represented by Formula 2 with the compound represented by Formula 3 to prepare the compound represented by Formula 1, as shown in the following Reaction Formula 1.

[0158] [Reaction 1]

[0159]

[0160] In reaction formula 1,

[0161] A.R 1 , R 2 , R 3 , R 4 and R 5 As defined in Formula 1 above.

[0162] The coupling reaction can be carried out in the presence of a base in an organic solvent such as dichloromethane, THF, ethyl acetate or ether. A tertiary amine such as pyridine or a trialkylamine can be used as a base, and the reaction can be carried out in the range of 0°C to 40°C, and can also be carried out at room temperature.

[0164] In another embodiment of the present invention,

[0165] The present invention provides a method for preparing the compound represented by Formula 1, comprising the following steps, as shown in the following Reaction Formula 2:

[0166] The step of reacting the compound represented by Formula 2' with the compound represented by Formula 3 to prepare the compound represented by Formula 4;

[0167] The step of reacting the compound represented by Formula 4 with the compound represented by Formula 5 to prepare the compound represented by Formula 1.

[0168] [Reaction 2]

[0169]

[0170] In reaction formula 2,

[0171] A' is formed by replacing -NH-R in the above formula 1 Replaced with -SCH3, and

[0172] A.R 1 , R 2 , R 3 , R 4 and R 5 As defined in Formula 1 above.

[0173] The first step in the above reaction formula 2 can be carried out under the same conditions as the coupling reaction in reaction formula 1.

[0174] The second step is to oxidize S in CH3S and then perform an amine substitution reaction. The reaction is carried out in an organic solvent at a temperature range of -20°C to 20°C using a peroxide such as mCPBA (meta-chloroperbezoic acid), and then adding an amine to the organic solvent for substitution. 1 When it is hydrogen, Formula 5 corresponds to ammonia (NH3), in which case Formula 5 can be provided as ammonium hydroxide (NH4OH) to carry out a substitution reaction in an organic solvent. The substitution reaction can be carried out in a polar organic solvent, such as a lower alcohol such as ethanol or dioxane. The substitution reaction can be carried out by heating, and the heating can be carried out in the range of 30°C to 100°C.

[0175] In one embodiment of the present invention,

[0176] The present invention provides a pharmaceutical composition for preventing or treating cancer, comprising the compound represented by the above formula 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

[0177] The cancer can be leukemia, lymphoma, multiple myeloma, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, prostate cancer or skin cancer.

[0178] In one embodiment of the present invention,

[0179] The present invention provides a pharmaceutical composition for preventing or treating a disease caused by excessive activation of a kinase involved in ISR (Integrated stress response), comprising the compound represented by the above formula 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

[0180] The kinase involved in the ISR can be one or more selected from the group consisting of HRI (Heme-regulated initiation factor-2akinase), PKR (dsRNA-activated protein kinase), PERK (PKR-like endoplasmic reticulum kinase) and GCN2 (General control nonderepressible 2).

[0181] In the present invention, "comprising... as an active ingredient" means containing within a dosage range that prevents, ameliorates or treats cancer, wherein the dosage range may vary depending on the severity and dosage form, and the number of uses may also vary depending on the age, weight and constitution of the subject.

[0182] The pharmaceutical composition of the present invention is administered at a pharmaceutically effective dose.

[0183] In the present invention, the term "pharmaceutical effective dose" refers to an amount sufficient to treat a disease and having a reasonable benefit / risk ratio suitable for medical treatment or improvement. The effective dose level depends on factors including subject type and severity, age, sex, drug activity, sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, concomitant drugs, and other factors well known in the medical field. For example, 0.001 mg / kg to 100 mg / kg, 0.01 mg / kg to 10 mg / kg, or 0.1 mg / kg to 1 mg / kg are all included in the effective dose. Those skilled in the art can select the upper limit of the dosage of the pharmaceutical composition of the present invention within an appropriate range.

[0184] The pharmaceutical composition of the present invention may contain a pharmaceutically effective dose of the compound of Formula 1 alone or together with one or more pharmaceutically acceptable carriers, excipients or diluents.

[0185] Pharmaceutically acceptable carrier, excipient or diluent as described herein refer to physiologically acceptable substances, do not cause any allergic reaction or allergic-like reaction, such as gastrointestinal disturbance and dizziness.Carrier, excipient and diluent are for example including lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talcum, magnesium stearate and mineral oil, but are not always limited to this.In addition, filler, anti-aggregating agent, lubricant, wetting agent, flavoring agent, emulsifier and preservative can also be included.

[0186] The compound shown in Formula 1 or its pharmaceutically acceptable salt can be administered in various oral and parenteral dosage forms during clinical administration. Orally administered solid dosage forms include tablets, pills, powders, granules and capsules. These solid dosage forms are made by mixing one or more compounds with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to the above-mentioned simple excipients, lubricants such as magnesium stearate, talc, etc. can also be used. Orally administered liquid dosage forms include suspensions, solutions, emulsions and syrups, and the above dosage forms may contain various excipients such as wetting agents, sweeteners, fragrances and preservatives in addition to commonly used simple diluents such as water and liquid paraffin. The dosage forms for parenteral administration include sterile aqueous solutions, water-insoluble excipients, suspensions and emulsions. In addition to containing one or more active compounds, water-insoluble excipients and suspensions may also contain propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), injectable esters (such as glycolic acid esters), etc.

[0187] The pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, including subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

[0188] At this time, in order to prepare the compound shown in Formula 1 or its pharmaceutically acceptable salt into a preparation for parenteral administration, the compound shown in Formula 1 or its pharmaceutically acceptable salt is mixed with a stabilizer or a buffer in water to prepare a solution or suspension, and then prepared into an ampoule or a vial. The composition here can be sterile and also contain a preservative, a stabilizer, a wettable powder or an emulsifier, a salt and / or a buffer for adjusting the osmotic pressure, and other therapeutic substances, and the composition can be prepared by conventional mixing, granulation or coating methods.

[0189] In the present invention, the term "prevention" refers to inhibiting or blocking the symptoms of cancer by administering, ingesting or applying the pharmaceutical composition or health functional food of the present invention to a subject who does not suffer from cancer, thereby preventing the occurrence of cancer symptoms in advance.

[0190] In the present invention, the term "treatment" includes complete cure of cancer symptoms as well as partial cure, improvement and alleviation of cancer symptoms as a result of administering the pharmaceutical composition of the present invention to a subject suffering from cancer.

[0191] Furthermore, the compound represented by the above formula 1 can be used not only in the form of its pharmaceutically acceptable salt but also in the form of isomers, solvates, hydrates, etc. prepared therefrom.

[0192] The term "isomer" refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but being different in structure or space. These isomers include structural isomers, such as tautomers and stereoisomers. Such stereoisomers include enantiomers, diastereomers and geometric isomers (trans, cis) with an asymmetric carbon center. In the present invention, all stereoisomers of the compound shown in the above formula 1 and mixtures thereof are also included within the scope of the present invention.

[0193] The term "hydrate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate of the compound of Formula 1 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain 1 equivalent or more of water, preferably 1 to 5 equivalents of water. The hydrate may be prepared by crystallizing the compound of Formula 1, its isomer, or a pharmaceutically acceptable salt thereof from water or an aqueous solvent.

[0194] The term "solvate" refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Thus, preferred solvents include those that are volatile, non-toxic and / or suitable for administration to the human body.

[0195] The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed from a pharmaceutically acceptable free acid. The acid addition salt herein can be obtained from an inorganic acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid; a non-toxic organic acid such as aliphatic mono / dicarboxylic acid salts, phenyl-substituted alkanoates, hydroxyalkanoates, alkanedioates, aromatic acids and aliphatic / aromatic sulfonic acids; or an organic acid such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid and fumaric acid. Pharmaceutically nontoxic salts include, for example, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, decanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, carbarates, fumarates, malates, butyne-1,4-dioates , hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and glycolate.

[0196] The acid addition salt according to the present invention can be prepared by conventional methods known to those skilled in the art. For example, the derivative shown in Formula 1 is dissolved in an organic solvent such as methanol, ethanol, acetone, dichloromethane and acetonitrile, and an organic acid or an inorganic acid is added to induce precipitation. The precipitate is then filtered and dried to obtain a salt. Alternatively, the solvent and excess acid are distilled off under reduced pressure and dried to obtain a salt. Alternatively, the precipitate is crystallized in an organic solvent to obtain a salt.

[0197] In addition, the pharmaceutical composition for preventing or treating cancer containing the compound represented by the above formula 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient can be administered as a single therapeutic agent, or can be used in combination with other therapeutic agents, and the therapeutic effect can be enhanced by combined administration.

[0198] In one embodiment of the present invention,

[0199] The present invention provides a health functional food for preventing or improving cancer, which comprises the compound represented by the above formula 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

[0200] In the present invention, the term "improvement" means to reduce or alleviate cancer symptoms by administering, ingesting or applying the pharmaceutical composition or food composition of the present invention to a subject suffering from cancer.

[0201] The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients having functional properties useful to the human body in accordance with the Health Functional Food Act. The term "functional" food refers to a food consumed in order to regulate the nutritional components of the structure and function of the human body or to obtain an effect (e.g., physiological effect) that is beneficial to health. The health functional food or health supplement of the present invention obtained in this way is very useful because it can be consumed every day.

[0202] There is no specific restriction on the types of food; all foods with health functions in the usual sense are included.

[0203] The matters described in the pharmaceutical composition and health functional food of the present invention are equally applicable unless they conflict with each other.

[0204] In one embodiment of the present invention, the present invention provides a method for preventing or treating cancer, comprising the step of administering to a subject in need thereof a compound of Formula 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof disclosed in this specification.

[0205] In one embodiment of the present invention, the present invention provides the use of the compound represented by Formula 1 disclosed in this specification, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt in the preparation of a drug for preventing or treating cancer.

[0206] In the above methods or uses, the above detailed description of the pharmaceutical composition can be applied.

[0207] Hereinafter, the present invention is described in detail through the following preparation examples, embodiments and experimental examples.

[0208] However, the following preparation examples, embodiments and experimental examples are only used to illustrate the present invention, and the contents of the present invention are not limited thereto.

[0210] <Preparation Example>

[0211] The compounds of Preparative Examples 1 and 2 were prepared as shown in the following schemes.

[0212]

[0213] <Preparation Example 1> 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0214] 4-(Methylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (5.46mmol, 1g), methyl-2-(3-amino-2,6-difluorophenyl)acetate (6.55mmol, 1.31g), potassium carbonate (13.67mmol, 2.26g) were dissolved in 13mL DMF and reacted at 100°C for 18 hours. The reaction was terminated by adding NH4Cl aqueous solution, and the solvent was removed by extraction with ethyl acetate. The target compound (900mg, yield: 49%) was obtained by separation using a silica gel column (ethyl acetate, hexane) as a white solid.

[0215] 1 H NMR (400MHz, DMSO-d6) δ9.72 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 6.78-6.59 (m, 2H), 3.74 (s, 3H), 3.61 (s, 2H), 3.14 (d, J = 5.0Hz, 3H).

[0216] <Preparation Example 2> 2-amino-6-(3-amino-2,6-difluorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one

[0217] After adjusting the temperature of a solution of 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.8mmol, 290mg) in 5mL DCM to 0°C, mCPBA (2.3mmol, 410mg) was slowly added thereto and reacted at room temperature for 2.5 hours. After confirming the completion of the reaction by TLC, the reaction was terminated with water and the organic layer was separated to remove the solvent. The mixture was dissolved in 5mL dioxane, the reaction vessel was adjusted to 0°C, ammonium hydroxide (7.9mmol, 0.3mL) was added, sealed and allowed to react for 18 hours. Ethyl acetate was added to the reactant, the organic solvent was removed by separation from water, and a silica gel column (ethyl acetate, hexane) was used for separation. As a result, the target compound (200mg, yield: 83%) was obtained as a white solid.

[0218] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),7.83(s,1H),7.42(s,2H),7.03-6.64(m,2H),5.02(s,2H),3.55(s,3H). C 14 H 11 FWf + m / z calculated for [M+H]: 303.2 found: 305.1.

[0219] <Preparation Example 3> 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0220]

[0221] Step 1: Synthesis of methyl 4-ethyl-2-(methylthio)pyrimidine-5-carboxylate

[0222] 1,1-Dimethoxy-N,N-dimethylmethylamine (5.72mL, 43.1mmol) and methyl 3-oxopentanoate (4.67g, 35.9mmol) were added to a 500mL round-bottom flask and reacted at 80°C for 10 minutes. Methylcarbamate sulfate (5.0g, 35.9mmol) was added thereto, and then reacted at 110°C for 16 hours. The reactant was cooled to room temperature, dissolved in EtOAc (80mL) and transferred to a separatory funnel. The organic layer was washed with saturated NaHCO3 (aqueous solution) (1×80mL), water (1×80mL) and brine (1×80mL), dried over MgSO4, filtered and concentrated. The concentrate was purified by silica gel column chromatography (0-30% EtOAc) to obtain the target compound (4.19g, 52%) as a white solid.

[0223] 1 H NMR (300MHz, CDCl3-d) δ8.92 (s, 1H), 4.38 (q, J = 7.1, 2H), 3.14 ( q, J = 7.5, 2H), 2.60 ( s, 3H), 1.40 ( t, J = 7.1, 3H), 1.29 ( t, J = 7.5, 3H).

[0224] Step 2: Synthesis of 4-ethyl-2-(methylthio)pyrimidine-5-carboxylic acid

[0225] In a 500 mL round-bottom flask, methyl 4-ethyl-2-(methylthio)pyrimidine-5-carboxylate (4.75 g, 22.38 mmol) was dissolved in THF / MeOH / H2O 1:1:1 (54 mL), and NaOH (2.69 g, 67.1 mmol) was added. The mixture was reacted at room temperature for 16 hours. The mixture was then concentrated under reduced pressure to remove THF and MeOH. 1N HCl (aqueous solution) was added to acidify the concentrate (pH = 2). The resulting solid was filtered to obtain the title compound (4.21 g, 95%) as a white solid.

[0226] 1 H NMR (400MHz, DMSO-d6) δ8.89 (s, 1H), 3.07 (q, J = 7.4Hz, 2H), 2.55 (s, 3H), 1.20 (t, J = 7.5Hz, 3H).

[0227] Step 3: Synthesis of N-(2,6-difluorophenyl)-4-ethyl-2-(methylthio)pyrimidine-5-carboxamide

[0228] In a 500 mL round-bottom flask, 4-ethyl-2-(methylthio)pyrimidine-5-carboxylic acid (2.00 g, 10.09 mmol) was dissolved in benzene (25 mL) in a sealed tube. 2,6-difluoroaniline (1.63 mL, 15.13 mmol) and trichlorophosphine (3.53 mL, 40.04 mmol) were added thereto, and then reacted at 130°C for 16 hours. After quenching with saturated NaHCO3 (aqueous solution) (40 mL), the reactant was dissolved in DCM (20 mL) and transferred to a separatory funnel. After extraction with DCM (3×40 mL), the mixture was dried over MgSO4 and concentrated under reduced pressure. The concentrate was dissolved in DCM (MeOH) and solidified with hexane to obtain the target compound (1.23 g, 40%) as a yellow solid.

[0229] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.72(s,1H),7.43(t,J=7.4Hz,1H),7.2 4(t,J=8.2Hz,2H), 2.91(q,J=7.6Hz,2H), 2.58(s,3H), 1.23(t,J=7.4Hz,3H).

[0230] Step 4: Synthesis of 6-(2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0231] In a 100mL round-bottom flask, N-(2,6-difluorophenyl)-4-ethyl-2-methylthiopyrimidine-5-carboxamide (0.698 g, 2.256 mmol) obtained in step 3 was dissolved in DMF (6 mL), 1,1-dimethoxy-N,N-dimethylmethylamine (0.9 mL, 6.77 mmol) was added, and then reacted at 150°C for 3 hours. The reactant was dissolved in DCM (15 mL) and transferred to a separatory funnel. The organic layer was washed with H2O (3×10 mL) and brine (1×10 mL), dried over MgSO4, and concentrated. The concentrate was purified by silica gel column chromatography (0-40% EtOAc) to obtain the target compound (0.263 g, 37%) as a yellow solid.

[0232] 1H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 7.96 (s, 1H), 7.73–7.62 (m, 1H), 7.41 (t, J = 8.5Hz, 2H), 2.66 (s, 3H), 2.23 (s, 3H).

[0233] Step 5: Synthesis of 6-(2,6-difluoro-3-nitrophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0234] 6-(2,6-Difluorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (0.298 g, 0.933 mmol) was dissolved in H2SO4 (1.5 mL) for 1.5 hours. The mixture was cooled to 0°C, magnesium nitrate hexahydrate (0.083 g, 0.560 mmol) was added in portions, and then reacted for 16 hours. The reaction was terminated by adding ice. The reactant was dissolved in EtOAc (10 mL), transferred to a separatory funnel, and extracted with EtOAc (3×15 mL). The extract was dried over MgSO4, concentrated under reduced pressure, and then used as a yellow solid for the next reaction without further purification.

[0235] Step 6: Synthesis of 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0236] The reaction mixture of step 5 (0.272 g, 0.933 mmol), Fe powder (0.167 g, 2.99 mmol), and NH4Cl (0.160 g, 2.99 mmol) were dissolved in THF / MeOH / H2O 2:2:1 (1.5 mL), and then reacted at 70°C for 16 hours. The reactant was filtered through celite and concentrated under reduced pressure. The concentrate was dissolved in EtOAc (7 mL) and transferred to a separatory funnel. Washed with H2O (1×7 mL) and brine (1×7 mL), dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-50% EtOAc) to obtain the target compound (0.0508 g, 20%) as a yellow solid.

[0237] 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.91(s,1H),7.10–7.01(m,1H),6.96–6.87(m,1H),5.34(s,2H),2.65(s,3H),2.23(s,3H).

[0238] <Preparation Example 4> Synthesis of 6-(3-amino-2,6-difluorophenyl)-8-(difluoromethyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0239]

[0240] Step 1: Synthesis of 6-(2,6-difluorophenyl)-2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbaldehyde

[0241] RBF (50 mL) was dried in an oven under vacuum and purged with Ar (g). Distilled DMF (3 mL) was added to the mixture, and then POCl3 (0.470 mL, 5.04 mmol) was added after the mixture was cooled in an ice / water bath. After activation for 30 minutes while maintaining temperature, N-(2,6-difluorophenyl)-4-methyl-2-(methylthio)pyrimidine-5-carboxamide (425 mg, 1.44 mmol) was dissolved in 2 mL DMF and added dropwise to the mixture. The mixture was heated to 60 ° C and reacted overnight. After the reaction was terminated by adding ice, saturated NaHCO3 (aqueous solution) (10 mL) was slowly added. After the reaction mixture was stirred at room temperature for 2 hours, the solid was filtered. The filtrate was transferred to a separatory funnel, and EtOAc (100 mL) was added thereto. The organic layer was washed with saturated NaHCO3 (aqueous solution) (100 mL) and brine (100 mL), and the reactant was dried over MgSO4 and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (0-30% EtOAc / Hex) to give the title compound (73 mg, 16%) as a white solid.

[0242] 1 H NMR (400MHz, CDCl3) δ10.77(d,J=1.6Hz,1H),9.42(d,J=1.6Hz,1H),8.25(s,1H),7.59–7.51(m,1H),7.18(t,J=8.7Hz,2H),2.74–2.65(m,3H).

[0243] Step 2: Synthesis of 8-(difluoromethyl)-6-(2,6-difluorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0244] After 6-(2,6-difluorophenyl)-2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carbaldehyde (70 mg, 0.210 mmol) was placed in a 20 mL vial, DAST (0.111 mL, 0.840 mmol) was added. The mixture was reacted at room temperature for 3 hours, and then the reaction was terminated by adding saturated NaHCO3 (aqueous solution) (5 mL). The reactants were transferred to a separatory funnel and extracted with DCM (15 mL x 3). The extract was dried over MgSO4 and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (0-40% EtOAc / Hex) to obtain the target compound (61 mg, 82%) as a white solid.

[0245] 1 H NMR (400MHz, CDCl3) δ9.40 (d, J=1.8Hz, 1H), 7.78 (s, 1H), 7.52 (ddd, J=8.4, 6.4, 2.2 Hz, 1H), 7.25 (t, J = 55.0 Hz, 1H), 7.16 (td, J = 8.9, 1.6 Hz, 2H), 2.67 (d, J = 1.8 Hz, 3H).

[0246] Step 3: Synthesis of 6-(2,6-difluoro-3-nitrophenyl)-8-(difluoromethyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0247] After dissolving 8-(difluoromethyl)-6-(2,6-difluorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (77 mg, 0.217 mmol) in H2SO4 (2 mL), the temperature was lowered to 0°C. Mg(NO3)2·6H2O (32 mg, 0.127 mmol) was added to the above mixture and allowed to react for 3 hours. The reaction was terminated by adding water (2 mL) and the reactant was transferred to a separatory funnel. The reactant was completely dissolved in EtOAc (100 mL) and then washed with water (50 mL), saturated NaHCO3 (aqueous solution) (50 mL) and brine (50 mL). The reactant was dried over MgSO4 and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (0-30% EtOAc / Hex) to obtain the target compound (39 mg, 45%) as a light yellow foam.

[0248] 1H NMR (300MHz, CDCl3) δ9.39 (s, 1H), 8.37 (ddd, J = 9.5, 8.1, 5.5Hz, 1H), 7.73 (s ,1H),7.32(ddd,J=9.7,7.9,2.1Hz,1H),7.23(t,J=73.1Hz,1H),2.67(s,3H).

[0249] Step 4: Synthesis of 6-(3-amino-2,6-difluorophenyl)-8-(difluoromethyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0250] After 6-(2,6-difluoro-3-nitrophenyl)-8-(difluoromethyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (35 mg, 0.087 mmol) was placed in a 20 mL vial, Fe (49 mg, 0.874 mmol) and NH4Cl (47 mg, 0.874 mmol) were added. THF / MeOH / H2O 1:1:1 (15 mL) was added to the above mixture and reacted at 70°C for 15 hours. After the temperature was lowered to room temperature, the reaction mixture was filtered through diatomaceous earth. The filtrate was washed with EtOAc (100 mL) and transferred to a separatory funnel. The organic layer was washed with water (50 mL x1) and brine (50 mL x1), and then dried over MgSO4.

[0251] <Preparation Example 5> Synthesis of (6-(3-amino-2,6-difluorophenyl)-2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-8-yl)methyl acetate

[0252]

[0253] In a manner similar to Preparation 4, (6-(3-amino-2,6-difluorophenyl)-2-(methylthio)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-8-yl)methyl acetate was prepared.

[0254] <Preparation Example 6> Synthesis of 6-(3-amino-2,6-difluorophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one

[0255]

[0256] It was prepared in a similar manner to Preparation 3. Step 4 of the above scheme, ie, the process for preparing 6-(2,6-difluoro-3-nitrophenyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one, is as follows.

[0257] In a 50mL round-bottom flask, sulfuric acid (200μL, 4.12mmol) was added to the compound (110mg, 0.34mmol) obtained in step 3, and the reaction vessel was adjusted to 0°C. Nitric acid (30μL, 0.66mmol) was added thereto, and the reaction was allowed to react at room temperature for 16 hours. Ice water (1mL) was added to the reactant to obtain the obtained solid, which was then subjected to the next step of reaction without purification.

[0258] 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.52 (dt, J = 9.3, 4.5Hz, 1H), 8.07 (d, J = 7.7Hz, 1H), 7.72 (t, J = 9.3Hz, 1H), 6.79 (d, J = 7.7Hz, 1H), 2.64 (s, 3H).

[0259] <Preparation Example 7> Synthesis of 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrimido[4,5-d]pyridazin-5(6H)-one

[0260]

[0261] Step 1: Synthesis of ethyl 4-(1-ethoxyvinyl)-2-(methylthio)pyrimidine-5-carboxylate

[0262] In a 100mL round-bottom flask, 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1g, 4.3mmol), tributyl(1-ethoxyvinyl)stannane (1.8g, 5.1mmol), bis(triphenylphosphine)palladium dichloride (60mg, 8mol%) were dissolved in 10mL N,N-dimethylformamide and reacted at 70°C for 1h. After the reaction mixture was cooled to room temperature, a solution of KF (1.5g) dissolved in 3mL of water was added to the reaction vessel and stirred for 18h. The reactants were filtered through diatomaceous earth to remove solids and extracted with ether. After the solvent was evaporated under reduced pressure, the target compound (830mg, 72%) was obtained as a white product by MPLC.

[0263] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.69 (s, 1H), 5.22 (d, J = 2.5 Hz, 1H), 4.54 (d, J = 2.6 Hz, 1H), 4.38 (dq, J = 14.3, 7.1 Hz, 2H), 3.92 (q, J = 7.0 Hz, 2H), 2.63 (s, 3H), 1.47–1.31 (m, 6H).

[0264] Step 2: Synthesis of ethyl 4-acetyl-2-(methylthio)pyrimidine-5-carboxylate

[0265] In a 100mL round-bottom flask, ethyl 4-(1-ethoxyvinyl)-2-(methylthio)pyrimidine-5-carboxylate (830mg, 3.0mmol) was dissolved in 8mL of ethanol, 10% HCl solution (1.8mL, 6mmol) was added thereto, and the reaction was carried out at 50°C for 18 hours. After the reaction was confirmed to be terminated by TLC, the solvent was removed under reduced pressure. After the reactant was dissolved in EtOAc (7mL), the organic layer was washed with water (1×7mL) and collected. The next step of the reaction was carried out without purification. The target compound (661mg, 89%) was obtained as a white solid.

[0266] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.99 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.63 (d, J = 1.8 Hz, 6H), 1.38 (t, J = 7.1 Hz, 3H).

[0267] Step 3: Synthesis of 6-(2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrimido[4,5-d]pyridazin-5(6H)-one

[0268] In a 100 mL round-bottom flask, 2,6-(difluorophenyl)hydrazine (300 mg, 2.0 mmol) and ethyl 4-(1-ethoxyvinyl)-2-(methylthio)pyrimidine-5-carboxylate (500 mg, 2.0 mmol) were dissolved in 10 mL of 2,2,2-trifluoroethanol and reacted at 80°C for 18 hours. Water was added to terminate the reaction to obtain the target compound (250 mg, 38%) as a yellow solid.

[0269] 1 H NMR (300MHz, DMSO-d6) δ9.48 (s, 1H), 7.68 (tt, J = 8.5, 6.4Hz, 1H), 7.40 (t, J = 8.3Hz, 2H), 2.70 (s, 3H), 2.56 (s, 3H).

[0270] Step 4: Synthesis of 6-(2,6-difluoro-3-nitrophenyl)-8-methyl-2-(methylthio)pyrimido[4,5-d]pyridazin-5(6H)-one

[0271] In a 50mL round-bottom flask, sulfuric acid (220μL, 4.12mmol) was added to the compound obtained in step 3 (110mg, 0.34mmol), and the reaction vessel was adjusted to 0°C. Nitric acid (30μL, 0.68mmol) was added thereto and reacted at room temperature for 18 hours. Ice water (1mL) was added to obtain the resulting solid. Then, the process was similar to step 6 of preparation example 3 to obtain a pyrimidine compound. Then, the process was similar to step 6 of preparation example 3 to obtain 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrimido[4,5-d]pyridazine-5(6H)-one.

[0272] 1 H NMR (400MHz, DMSO-d6) δ9.50 (s, 1H), 8.59–8.46 (m, 1H), 7.70 (t, J = 9.3Hz, 1H), 2.70 (s, 3H), 2.57 (s, 3H).

[0273] <Preparation Example 8> Synthesis of 3-(3-amino-2,6-difluorophenyl)-1-methyl-7-(methylthio)-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one

[0274]

[0275] 4-Chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (1.0 g, 4.30 mmol) was dissolved in THF (22 mL), and triethylamine (1.20 mL, 8.60 mmol) and methylamine (33 wt.% ethanol solution, 0.78 mL, 6.45 mmol) were added thereto in sequence at room temperature. Then, the temperature of the mixture was raised to 55°C for 2 h. After the reaction was confirmed to be complete by TLC (EtOAc / HEX=1 / 4), the reaction temperature was adjusted to room temperature. The mixture was diluted with H2O and extracted with EtOAc. The extracted organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / HEX=1 / 4, v / v) to obtain 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (976 mg, yield: 99%) as a white solid.

[0276] 1 H-NMR (400MHz, CDCl3) δ8.60 (s, 1H), 8.16 (br, 1H), 4.31 (q, J = 7.2Hz, 2H), 3.07 (d, J = 4.9Hz, 3H), 2.54 (s, 3H), 1.36 (t, J = 7.1Hz, 3H)

[0277] After that, a reaction similar to steps 2, 3, and 6 of Preparation Example 3 was performed. Regarding the synthesis of 3-(3-amino-2,6-difluorophenyl)-1-methyl-7-(methylthio)-2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-one, N-(3-amino-2,6-difluorophenyl)-4-(methylamino)-2-(methylthio)pyrimidine-5-carboxamide (680 mg, 2.09 mmol) was dissolved in MeCN (10 mL), and then dibromomethane (0.44 mL, 6.27 mmol) and cesium carbonate (2.72 g, 8.36 mmol) were added in sequence at room temperature. Then, the temperature of the mixture was raised to 80°C and reacted for 15 hours. After the reaction was confirmed to be complete by TLC (EtOAc / HEX=2 / 3), the reactant was adjusted to room temperature. The reactant was diluted with H2O and extracted with EtOAc. The extracted organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc / HEX=2 / 3, v / v) to obtain the target compound (390 mg, yield 55%) as a white solid.

[0278] <Preparation Example 9> Synthesis of 3-(3-amino-2,6-difluorophenyl)-1-cyclopropyl-7-(methylthio)-2,3-dihydropyrimido[4,5-di]pyrimidin-4(1H)-one

[0279]

[0280] 3-(3-Amino-2,6-difluorophenyl)-1-cyclopropyl-7-(methylthio)-2,3-dihydropyrimido[4,5-di]pyrimidin-4(1H)-one was prepared by a method similar to that described in Preparation 8.

[0281] <Preparation Example 10> Synthesis of 3-(3-amino-2,6-difluorophenyl)-1-methyl-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione

[0282]

[0283] 3-(3-Amino-2,6-difluorophenyl)-1-methyl-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione was prepared by a method similar to that described in Preparation 8.

[0284] 1 H NMR (500MHz, DMSO) δ9.02 (s, 1H), 7.01 (t, J = 9.2, 9.2Hz, 1H), 6.91 (t, J = 7.9, 7.9Hz, 1H), 5.26 (s, 2H), 3.56 (s, 3H), 2.65 (s, 3H).

[0285] <Preparation Example 11> Synthesis of 3-(3-amino-2,6-difluorophenyl)-1-cyclopropyl-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione

[0286]

[0287] 3-(3-Amino-2,6-difluorophenyl)-1-cyclopropyl-7-(methylthio)pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione was prepared by a method similar to that described in Preparation 8.

[0289] Example 1: N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazole-4-sulfonamide

[0290] 2-amino-6-(3-amino-2,6-difluorophenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.06mmol, 20mg) prepared in Preparation Example 1 was dissolved in 1mL of dichloromethane, pyridine (0.65mmol, 53μL) and 1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride (0.09mmol, 26mg) were added thereto, and then reacted at room temperature for 3 hours. After the reaction solution was evaporated, the reactant was purified by silica gel column using ethyl acetate and hexane to obtain the target compound (15mg, 43%) as a light brown solid.

[0291] 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (s, 1H), 7.64 (td, J = 9.0, 5.8 Hz, 1H), 7.53 (s, 1H), 7.03 (td, J = 8.7, 1.7 Hz, 1H), 5.46 (s, 3H), 3.88 (s, 3H), 3.73 (d, J = 2.9 Hz, 3H), 3.67 (s, 3H).

[0292] The compounds of Examples 2 to 19 were prepared according to the method of Example 1.

[0293]

Table 1

[0294]

[0295]

[0296]

[0297]

[0298] <Example 20> 2,5-dichloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide

[0299]

[0300] After reacting in a manner similar to Example 1, 2,5-dichloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide (47 mg, 0.086 mmol) was dissolved in dichloromethane, and mCPBA (16 mg, 1.1 mmol) was slowly added at 0°C. The reaction was terminated by adding water, the reactant was extracted with dichloromethane, and the organic solvent was evaporated. The mixture was dissolved in ethanol, 0.1 mL of methylamine was added thereto, and then reacted at 90°C for 3 hours. After evaporating the solvent, the reactant was purified by silica gel column using ethyl acetate / hexane to obtain the target compound (33 mg, 73%).

[0301] 1 H NMR (500 MHz, chloroform-d) δ 8.47 (s, 1H), 8.10-7.95 (m, 1H), 7.62-7.51 (m, 2H), 7.51-7.41 (m, 2H), 6.96 (td, J = 8.8, 1.7 Hz, 1H), 5.92 (s, 1H), 3.75 (s, 3H), 3.13 (d, J = 5.1 Hz, 3H). m / z calculated: C 21 H 15 Cl2F2N5O3S + [M+H]: 526.3 Measured value: 526.5

[0302] Example 21 N-(3-(2-amino-8-methyl-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0303]

[0304] Step 1: Synthesis of 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide

[0305] 6-(3-amino-2,6-difluorophenyl)-8-methyl-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one (0.0508 g, 0.152 mmol) prepared in Preparation Example 3 was dissolved in DCM (1 mL), cooled to 0°C, 5-chloro-2-methoxypyridine-3-sulfonyl chloride (0.044 g, 0.182 mmol) and pyridine (0.037 mL, 0.456 mmol) were added thereto, and then reacted at 0°C for 2 hours. H2O was added to terminate the reaction, and the reactant was dissolved in DCM (7 mL) and transferred to a separatory funnel. The reactant was extracted with DCM (3×7 mL), dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-35% EtOAc) to obtain the target compound (0.046 g, 56%) as a yellow oil.

[0306] 1 H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.25(s,1H),8.52(s,1H),8.11(s,1H),7.86(s,1 H), 7.49 (d, J = 7.6Hz, 1H), 7.37 (q, J = 9.1Hz, 1H), 3.92 (s, 3H), 2.65 (s, 3H), 2.21 (s, 3H).

[0307] Step 2: Synthesis of N-(3-(2-amino-8-methyl-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0308] After 5-chloro-N-(2,4-difluoro-3-(8-methyl-2-(methylthio)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide (0.046 g, 0.085 mmol) was dissolved in DCM (1 mL), mCPBA (0.037 g, 0.213 mmol) was added thereto and reacted at 0°C for 1 hour. H2O (7 mL) was added to terminate the reaction, and the reactant was dissolved in DCM (7 mL) and transferred to a separatory funnel. The reactant was extracted with DCM (3×7 mL), dried over MgSO4, and concentrated under reduced pressure. The reaction mixture was dissolved in 1,4-dioxane (1 mL), NH4OH (0.030 g, 0.850 mmol) was added thereto, and then reacted at 90°C for 1 hour. The reactant was dissolved in EtOAc (7 mL), transferred to a separatory funnel, and washed with H2O (1×7 mL) and brine (1×7 mL). The reactant was dried over MgSO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0-5% MeOH) and concentrated under reduced pressure. The concentrate was dissolved in DCM (MeOH) and solidified with hexane to obtain the target compound (5 mg, 12%) as a white solid.

[0309] 1 H NMR (400MHz, CDCl3-d) δ9.31 (s, 1H), 8.45 (s, 1H), 8.30 (d, J = 2.5Hz, 1H), 8.11 (d, J = 2. 6Hz,1H),7.73–7.62(m,1H),7.11–7.01(m,2H),5.81(s,2H),4.04(s,3H),2.20(s,3H).

[0310] Example 22: N-(3-(2-amino-8-(difluoromethyl)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0311] N-(3-(2-amino-8-(difluoromethyl)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide was prepared by a method analogous to that described in Example 21.

[0312] 1 H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 8.32 (d, J = 2.4Hz, 1H), 8.10 (d, J = 2.5Hz, 1H), 7.74(s,1H),7.64(s,1H),7.24–6.96(m,2H),5.71(s,2H),4.10(d,J=2.0Hz,3H).

[0313] Example 23 N-(3-(2-amino-8-hydroxymethyl)-5-oxopyrido[4,3-d]pyrimidine-6(5H)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide

[0314]

[0315] After preparing the compound protected with acetyl group in a manner similar to the method described in Example 21, the target compound was prepared in the following manner.

[0316] In a 10 mL vial, (2-amino-6-(3-((5-chloro-2-methoxypyridine)-3-sulfonamido)-2,6-difluorophenyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidin-8-yl)methyl acetate (20 mg, 0.035 mmol) obtained in step 2 was dissolved in 1 mL of MeOH, K2CO3 (10 mg, 0.07 mmol) was added thereto, and then reacted for 2 hours. After the completion of the reaction was confirmed by TLC, the pH of the reactant was adjusted to 6-7 with 1N HCl, and the reactant was extracted with EtOAc. The extract was purified by MPLC to obtain the target compound (5 mg, 27%) as a white solid.

[0317] 1 H NMR (400MHz, chloroform-d) δ9.28(s,1H),8.31(d,J=2.5Hz,1H),8.09(d,J=2.4Hz,1H),7.72(t,J=7.7Hz,1H),7.57( d,J=17.9Hz,1H),7.17(s,1H),7.09(t,J=9.0Hz,1H),5.69(s,2H),4.81–4.57(m,2H),4.11(d,J=1.7Hz,3H).

[0318] The compounds of Examples 24 to 36 were prepared according to the method of Example 21.

[0319] Example 37 N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide

[0320]

[0321] The compound (ethyl-3-(N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)sulfamoyl)-2,5-dichlorobenzoic acid) substituted with ethyl acetate was prepared in a manner similar to the method of Example 21. In a 50 mL round-bottom flask, the compound (50 mg, 0.09 mmol) was dissolved in 1 mL of THF, 1 M LiAlH4 (171 μL, 0.17 mmol) was added thereto at 0° C., and then reacted for 30 minutes. Water was added to terminate the reaction, and the reactant was extracted with EA. The extract was purified by MPLC to obtain the target compound (15 mg, 32%).

[0322] The compounds of Examples 38 to 66 were prepared according to the method of Example 21.

[0323] The compounds of Examples 24 to 66 are as follows.

[0324]

Table 2

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334] The structures of the compounds of Examples 1 to 66 are shown in Table 3 below.

[0335]

Table 3

[0336]

[0337]

[0338]

[0339]

[0340] <Experimental Example 1> Evaluation of PKR-like endoplasmic reticulum kinase (PERK) inhibitory ability

[0341] Recombinant human PERK protein was mixed with the compound in a reaction solution (8mM MOPS pH 7.0, 0.2mM EDTA, 300uM RSRSRSRSRSRSR, 10mM magnesium acetate, 15uM [γ-33P-ATP]) and reacted at room temperature for 40 minutes. Then, phosphoric acid (0.5%) was added to the reaction mixture to terminate the reaction, and 10ul of the reaction solution was dropped onto the P30 filter. The filter was washed 4 times in 0.425% phosphoric acid solution for 4 minutes, then washed once in methanol, dried, and PERK activity was determined by scintillation counting. The activity value obtained in the group without the compound was set to 100% of the control, and the degree of inhibition of the compound on PERK was calculated. The compound was diluted 1 / 3 from the highest concentration of 1uM and treated with a total of 9 concentrations to evaluate the degree of inhibition. The concentration that produces 50% inhibition is defined as IC 50 The values ​​are summarized in Table 3.

[0342] <Experimental Example 2> Evaluation of the inhibitory ability of general control non-inhibitory 2 (GCN2)

[0343] The recombinant human GCN2 protein was mixed with the compound in a reaction solution (20mM Tris / HCl pH8.5, 0.2mMEDTA, 0.1% Tween, 100mM NaCl, 300uM RSRSRSRSRSRSR, 10mM magnesium acetate, 70uM [γ-33P-ATP]) and reacted at room temperature for 40 minutes. Phosphoric acid (0.5%) was then added to the reaction mixture to terminate the reaction, and 10ul of the reaction solution was dropped onto the P30 filter. The filter was washed 4 times in a 0.425% phosphoric acid solution for 4 minutes, then washed once in methanol, dried, and the GCN2 activity was determined by scintillation counting. The activity value obtained in the group without the compound was set to 100% of the control, and the degree of inhibition of the compound on GCN2 was calculated. The compound was diluted 1 / 3 from the highest concentration of 1uM and treated with a total of 9 concentrations to evaluate the degree of inhibition. The concentration that produces 50% inhibition is defined as IC 50 The values ​​are summarized in Table 3.

[0344] <Experimental Example 3> Evaluation of the inhibitory ability of eIF2-α kinase heme-regulated inhibitor (HRI)

[0345] The recombinant human HRI protein was mixed with the compound in a reaction solution (50mM Tris / HCl pH 7.5, 0.04mMEDTA, 300uM RSRSRSRSRSRSR, 10mM magnesium acetate, 45uM [γ-33P-ATP]) and reacted at room temperature for 40 minutes. Phosphoric acid (0.5%) was then added to the reaction mixture to terminate the reaction, and 10ul of the reaction solution was dropped onto a P30 filter. The filter was washed 4 times in a 0.425% phosphoric acid solution for 4 minutes, then washed once in methanol, dried, and the HRI activity was determined by scintillation counting. The activity value obtained in the group without the compound was set to 100% of the control to calculate the degree of inhibition of the compound on HRI. The compound was diluted 1 / 3 from the highest concentration of 1uM and treated with a total of 9 concentrations to evaluate the degree of inhibition. The concentration that produces 50% inhibition is defined as IC 50 The values ​​are summarized in Table 3.

[0346] <Experimental Example 4> Evaluation of protein kinase R (PKR) inhibitory ability

[0347] Recombinant human PKR protein was mixed with the compound in a reaction solution (8mM MOPS pH 7.0, 0.2mM EDTA, 20uMRSRSRSRSRSRSRSR, 10mM magnesium acetate, 15uM [γ-33P-ATP]), reacted at room temperature for 40 minutes, then phosphoric acid (0.5%) was added to the reaction mixture to terminate the reaction, and 10ul of the reaction solution was dropped onto the P30 filter. The filter was washed 4 times in 0.425% phosphoric acid solution for 4 minutes, then washed once in methanol, dried, and PKR activity was determined by scintillation counting. The activity value obtained in the group without the compound was set to 100% of the control, and the degree of inhibition of the compound on PKR was calculated. The compound was diluted 1 / 3 from the highest concentration of 1uM and treated with a total of 9 concentrations to evaluate the degree of inhibition. The concentration that produces 50% inhibition is defined as IC 50 The values ​​are summarized in Table 4.

[0348] The results of the experiments 1 to 4 are summarized in Table 4 below (IC 50 Values: +++<100 nM; ++100-300 nM; +300-1,000 nM; ->1,000 nM).

[0349]

Table 4

[0350] <Experimental Example 5> Western blotting was used to evaluate the inhibitory effect of ISR-related kinase GCN2 under amino acid deficiency conditions. Human fibrosarcoma cell line HT-1080 cells were cultured in RPMI-1640 medium supplemented with 10% FBS, penicillin (100 IU / ml), and streptomycin (100 μg / ml). Cells (1×10 6 Cells / ml) were seeded on 100 mm plates (polypropylene tissue culture plates) and cultured in a 37°C, 5% CO2 incubator for 24 hours before use in experiments.

[0351] The following method was used to achieve amino acid deficiency in the cells. After 24 hours of cell culture, the cells were cultured in RPMI-1640 medium without amino acids and L-glutamine, and 10% FBS, penicillin (100 IU / ml), and streptomycin (100 μg / ml) were added to the medium. After the cells were cultured in RPMI-1640 without amino acids and L-glutamine for 24 hours, the compound prepared at a concentration of 50 nM was dispensed onto each plate and cultured in a 37°C, 5% CO2 incubator for 24 hours.

[0352] In order to measure the signal transduction inhibitory effect of GCN in the ISR-related kinase according to the present invention, the following experiment was performed using SDS-PAGE. The fibrosarcoma cell line HT-1080 cells cultured on the plate as described above were removed from the culture medium and washed with PBS. After removing the PBS, a radioimmunoprecipitation assay buffer (RIPA buffer) containing 50mM Tris (pH 7.4), 150mM NaCl, 1% NP-40, 0.5% sodium deoxycholate, 2mM sodium fluoride, 2mM EDTA, 0.1% SDS and a mixture of protease / phosphatase inhibitors was added to the plate to lyse the cells. After centrifugation at 4°C, 13000×g for 15 minutes, the upper layer of protein was collected and the protein concentration was determined at 562nm using a BCA (bicinchoninic acid) reagent. The amount of protein in all samples was prepared to be 20-50μg.

[0353] After making the total volume equal with the sample buffer and RIPA buffer, heat at 97°C for 5 minutes. Then perform electrophoresis at 80V for 30 minutes on 8% or 12% SDS-PAGE and at 160V for 1 hour and 30 minutes. After electrophoresis, transfer the SDS-PAGE gel to a NC membrane (nitrocellulose membrane) and perform at 90V for 2 hours. Place the NC membrane in TBST (tris buffered saline Tween-20; 20mM tris, 137mM sodium chloride, 0.1% Tween-20, pH 8.0) containing 5% skim milk, place on a shaker, and react at room temperature for 1 hour.

[0354] Each primary antibody was diluted with TBST containing 5% skim milk, poured onto the NC membrane, and reacted at 4°C for 24 hours. The membrane was washed three times with TBST, each time for 10 minutes. The secondary antibody (anti-rabbit IgG and anti-mouse IgG labeled with horseradish peroxidase (HRP)) was diluted in TBST containing 5% skim milk and reacted with the membrane for 1 hour at room temperature. After the reaction was completed, the membrane was washed three times with TBST, each time for 10 minutes. After the ECL solution reacted with the NC membrane, the protein expression band was detected using a chemiluminescence image analyzer (Image Quant LAS 500).

[0355] GCN2 is a key kinase of the integrated stress response (ISR) and is phosphorylated due to amino acid deficiency. Therefore, when the inhibitory effect on phosphorylated GCN2 was confirmed in the compound treatment, the compound (Examples 25, 26, 27, 29, 32, 36, 43, 44, 46, 51, 63, 64 and 65) showed excellent inhibitory effect on phosphorylated GCN2 (Table 5).

[0356] Figure 1 It is a set of photographs confirming the protein mechanism that reacts after ISR activation, in which the numbers correspond to the example numbers of the present invention. The four main specialized kinases of ISR (PERK, GCN2, PKR and HRI) jointly phosphorylate serine 52 of eIF2α in stress response, leading to an increase in certain transcription factors (especially ATF4). They are also known to have the effect of increasing the expression of CHOP (GADD153), the most downstream factor of this mechanism. The compounds synthesized in the above examples (Examples 22, 25, 29, 43, 44, 46 and 51) not only showed excellent inhibitory effects on GCN2, but also on ATF4, a downstream factor of the main kinase of the integrated stress response ( Figure 1 ). Therefore, in addition to activation of the ISR by amino acid deprivation, one would expect that mechanisms inhibiting the activity of the ISR-associated kinase PERK would also have a significant effect due to the ER stress response.

[0357]

Table 5

Claims

1. A compound represented by the following formula 1, its stereoisomer, its solvate, its hydrate, or its pharmaceutically acceptable salt: [Formula 1] In formula 1, A is R 1 is hydrogen or C1-C10 alkyl; R 2 is hydrogen, halogen, unsubstituted or halogen- or hydroxy-substituted C1-C10 alkyl, or C3-C10 cycloalkyl; R 3 and R 4 are independently halogen; R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-10 membered heteroaryl group, in, The substituted C6-C10 aryl and the substituted 5-10 membered heteroaryl are independently substituted by at least one selected from the group consisting of: C1-C10 alkyl, C1-C10 alkoxy, halogen and cyano, which are unsubstituted or substituted with halogen or hydroxyl, or two adjacent atoms thereof are substituted to form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains at least one N and is unsubstituted or substituted by at least one selected from C1-C10 alkyl and oxo.

2. The compound according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt, wherein: R 1 is hydrogen or C1-C6 alkyl; R 2 is hydrogen, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1 to 3 halogens or hydroxy groups, or C3-C8 cycloalkyl; R 3 and R 4 are independently halogen; R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-9 membered heteroaryl group, wherein the substituted C6-C10 aryl and the substituted 5-9 membered heteroaryl are independently substituted by 1-3 substituents selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen and cyano, which are unsubstituted or substituted by 1-3 halogens or hydroxyls, or two adjacent atoms thereof are substituted to form a 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains at least one N and is unsubstituted or substituted by 1-3 substituents selected from C1-C6 alkyl and oxo.

3. The compound according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt, wherein: R 1 is hydrogen or C1-C4 alkyl; R 2 is hydrogen, halogen, C1-C4 alkyl which is unsubstituted or substituted by 1 to 3 halogens or hydroxy groups, or C3-C6 cycloalkyl; R 3 and R 4 are independently halogen; R 5 is an unsubstituted or substituted C6-C10 aryl group, or an unsubstituted or substituted 5-9 membered heteroaryl group, wherein the substituted C6-C10 aryl and the substituted 5-9 membered heteroaryl are independently substituted by 1-3 substituents selected from the group consisting of: C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br and cyano, which are unsubstituted or substituted by 1-3 F or hydroxyl groups, or two adjacent atoms thereof are substituted to form a 5-membered non-aromatic heterocycle, wherein the 5-membered heterocycle contains at least one N and is unsubstituted or substituted by 1-2 substituents selected from C1-C4 alkyl and oxo.

4. The compound according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt, wherein: R 1 is hydrogen or methyl; R 2 is hydrogen, halogen, methyl which is unsubstituted or substituted by 1 to 3 fluorine or hydroxy groups, or cyclopropyl; R 3 and R 4 Independently, F; R 5 is substituted phenyl, naphthyl, substituted pyridyl, substituted pyrazolyl, substituted isoxazolyl, substituted thienyl, substituted indolyl or substituted imidazothiazolyl, wherein the substituted phenyl, substituted pyridyl, substituted pyrazolyl, substituted isoxazolyl, substituted thienyl, substituted indolyl and substituted imidazothiazolyl are independently substituted with 1 to 3 substituents selected from the group consisting of: methyl, ethyl, methoxy, F, Cl, Br, oxo and cyano which are unsubstituted or substituted with 1 to 3 F or hydroxyl groups, or two adjacent atoms thereof are substituted to form a 5-membered non-aromatic heterocyclic ring, wherein the 5-membered heterocyclic ring contains at least one N and is substituted with 1 to 2 substituents selected from methyl and oxo.

5. The compound according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt, wherein: R 1 is hydrogen or methyl; R 2 For hydrogen, or R 5 for 6. The compound according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of the following compounds: <1> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazole-4-sulfonamide; <2> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; <3> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide; <4> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <5> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide; <6> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-6-chloropyridine-3-sulfonamide; <7> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-methyl-1H-indole-4-sulfonamide; <8> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonamide; <9> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3-chloro-1,5-dimethyl-1H-pyrazole-4-sulfonamide; <10> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3-(hydroxymethyl)-1,5-dimethyl-1H-pyrazole-4-sulfonamide; <11> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-chloropyridine-3-sulfonamide; <12> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide; <13> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-3,5-dimethylisoxazole-4-sulfonamide; <14> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <15> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-6-chloroimidazo[2,1-b]thiazole-5-sulfonamide; <16> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <17> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide; <18> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide; <19> N-(3-(2-amino-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide; <20> 2,5-Dichloro-N-(2,4-difluoro-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)benzenesulfonamide; <21> N-(3-(2-amino-8-methyl-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <22> N-(3-(2-amino-8-(difluoromethyl)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <23> N-(3-(2-amino-8-hydroxymethyl)-5-oxopyrido[4,3-d]pyrimidine-6(5H)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <24> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <25> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxypyridine-3-sulfonamide; <26> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <27> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichloropyridine-3-sulfonamide; <28> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-cyano-2-methoxypyridine-3-sulfonamide; <29> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <30> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; <31> N-(3-(2-amino-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide; <32> 5-Chloro-N-(2,4-difluoro-3-(2-(methylamino)-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide; <33> N-(3-(2-amino-8-bromo-5-oxopyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <34> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <35> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonamide; <36> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-3-chloro-1,5-dimethyl-1H-pyrazole-4-sulfonamide; <37> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-2,5-dichloro-3-(hydroxymethyl)benzenesulfonamide; <38> N-(3-(2-amino-8-methyl-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <39> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <40> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <41> N-(3-(7-amino-1-methyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <42> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <43> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <44> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <45> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <46> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxypyridine-3-sulfonamide; <47> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-cyano-2-methoxypyridine-3-sulfonamide; <48> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide; <49> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-2-chloro-5-(trifluoromethyl)benzenesulfonamide; <50> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chlorothiophene-2-sulfonamide; <51> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-5-bromo-2-methoxybenzenesulfonamide; <52> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methylbenzenesulfonamide; <53> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1-methyl-2-oxoindole-5-sulfonamide; <54> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide; <55> N-(3-(7-amino-1-methyl-2,4-dioxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2,4-difluorophenyl)-2,4-dichlorobenzenesulfonamide; <56> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-1-methyl-1H-pyrazole-4-sulfonamide; <57> N-(3-(7-amino-1-methyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichloropyridine-3-sulfonamide; <58> 5-Chloro-N-(2,4-difluoro-3-(1-methyl-7-(methylamino)-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-methoxypyridine-3-sulfonamide; <59> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <60> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; <61> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <62> N-(3-(7-amino-1-cyclopropyl-4-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; <63> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-2,5-dichlorobenzenesulfonamide; <64> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)naphthalene-1-sulfonamide; <65> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-2-methoxypyridine-3-sulfonamide; and <66> N-(3-(7-amino-1-cyclopropyl-2,4-dioxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)-2,4-difluorophenyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide.

7. A method for preparing a compound of formula 1, comprising the step of reacting a compound of formula 2 with a compound of formula 3 to prepare a compound of formula 1, as shown in the following reaction formula 1: [Reaction 1] In reaction formula 1, A.R 1 , R 2 , R 3 , R 4 and R 5 As defined in formula 1 of claim 1.

8. A pharmaceutical composition for preventing or treating cancer, comprising the compound represented by formula 1 according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

9. A pharmaceutical composition for preventing or treating a disease caused by overactivation of kinases involved in ISR (integrated stress response), comprising the compound of formula 1 according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

10. A pharmaceutical composition for inhibiting one or more signal transductions selected from the group consisting of HRI (heme-regulated initiation factor-2a kinase), PKR (dsRNA-activated protein kinase), PERK (PKR-like endoplasmic reticulum kinase) and GCN2 (generally controlled non-inhibitory 2), comprising a compound of formula 1 according to claim 1, a stereoisomer thereof, a solvate thereof, a hydrate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

11. The pharmaceutical composition of claim 8, wherein the cancer is leukemia, lymphoma, multiple myeloma, bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer or skin cancer.

12. A health functional food for preventing or alleviating cancer, comprising the compound represented by formula 1 according to claim 1, its stereoisomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient.

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