KR101360948B1 - Novel 2-aminoquinazolin derivatives and the pharmaceutical composition for treating tumor comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel aminoquinazoline derivative, specifically, the parent nucleus structure of Formula 1 wherein the 8-position of 2-aminoquinazolin is substituted with piperidine 4-oxy and the 2-amino group is substituted with 6-indazole A novel aminoquinazoline compound having a parental nucleus structure. Such compounds can effectively inhibit the activity of extracellular signal-regulated kinase 1/2 (ERK 1/2), and thus can be effectively used for the prevention and / or treatment of cancers in which cell proliferation is not controlled.

Description

Novel 2-aminoquinazolin derivatives and the pharmaceutical composition for treating tumor comprising the same as an active ingredient

The present invention relates to a novel 2-aminoquinazolin derivative having inhibitory activity against extracellular signal-regulated kinase, a novel 2-aminoquinazolin derivative, the 2-aminoquinazolin derivative and And / or extracellular signal-regulated kinase inhibitors containing the pharmaceutically acceptable salts thereof as an active ingredient, and prevention and / or treatment of cancer containing the aminopyridine derivatives and / or pharmaceutically acceptable salts thereof as the active ingredient. It relates to a composition for.

Cells recognize and respond to extracellular stimuli by specific intracellular programs such as signaling systems. This signaling system activates mitogen-activated protein kinase (MAPK). All eukaryotic cells have a MAPK signaling system that cooperates to regulate a variety of cellular activities ranging from gene expression, division, and metabolism to motility, survival and apoptosis, and differentiation. MAPKs so far known in mammals include extracellular signal-regulated kinases (ERKs) 1 and 2 (ERK1 / 2)); c-Jun amino-terminal kinases (JNKs) 1,2, and 3; p38 isoforms a, b, g, and d; ERKs 3 and 4; There are five types of ERK5, among which ERK1 / 2, JNKs, and p38 kinase have been intensively studied.

MAPK is activated by various stimuli, but in general ERK1 / 2 is activated by growth factors and phorbol esters, whereas JNK and p38 kinases are mechanical wear cytokines from osmotic shock and ionizing radiation. It is known to respond to a variety of stress stimuli, ranging from mechanical wear cytokine stimulation.

The ERK1 / 2 signaling system, known as the p42 / p44 MAPK pathway, includes mitogen-activated protein kinase kinase (MAPKKK), A-Raf, B-Raf, and Raf-1; Consists of mitogen-activated protein kinase kinase (MAPKK) and extracellular signal-regulated kinase (ERK) kinase (MEK2) and MAPK, ERK1 and ERK2, which are important determinants of cell growth, differentiation and survival.

This signaling system, which operates downstream of Ras, is frequently upregulated in human carcinomas, making it an attractive target for anticancer drug development. ERK1 and ERK2 have 83% amino acid similarity and are expressed over a wide range in all tissues (ChemMed Chem 2007, 2, 1116-1140).

Ras / Raf / MEK / ERK signaling pathways link many of the proteins involved in apoptosis, as well as linking transcription factors that regulate gene expression from cell surface receptors. Regulate the activity of. This signaling system is activated in chromosomal translocations such as BCR-ABL, mutations in cytokine receptors such as Flt-3, Kit, and Fms, overexpression of receptors such as EGFR (epidermal growth factor receptor), or cancer caused by mutant receptors. . Raf / MEK / ERK signaling pathways are also involved in the regulation of cell death by post-translational phosphorylation of Bad, Bim, Mcl-1, caspase-9 and, arguably, apoptosis regulatory molecules, including Bcl-2. Important influence

This signaling system has a variety of effects that regulate cell cycle progression, apoptosis or differentiation. This signaling system is abnormally activated in cancer and is caused by mutations in the stream membrane receptor, Ras and B-Raf, or by other pathway genes such as PI3K, PTEN, and Akt that regulate Raf activity. Mutations are known to cause.

In addition, the ectopic activiation of Raf in the Raf / MEK / ERK pathway is known to induce resistance to doxorubicin and paclitaxel in breast cancer, thereby affecting chemotherapeutic drug resistance. For this reason, the Raf / MEK / ERK pathway is an important signaling system as a target for therapeutic intervention and Raf and MEK inhibitors have been developed and are currently in clinical practice.

Raf inhibitors are known such as L-779,450, ZM 336372, Bay 43-9006 that competitively inhibits the ATP-binding site of Raf protein. Some Raf inhibitors inhibit only one of the Raf isoforms (e.g., Raf-1), while some Raf inhibitors inhibit all three Raf proteins (Raf-1, A-Raf and B-Raf). Knowing whether a particular Raf gene has been mutated or overexpressed in a particular carcinoma could result in a more sensitive inhibition of the corresponding Raf gene by a therapeutic agent targeting that Raf protein. Inhibition of certain Raf genes may be useful. On the other hand, under certain circumstances, inhibition of other Raf genes may be disadvantageous. Thus, development of characteristic or extensive Raf inhibitors may be useful for treating cancer. Raf activity is regulated by dimerization and is affected by protein relationship inhibitors, proteins such as geldanamycin. Raf isoforms dimerize themselves to activate other Raf isoforms. Coumymycin inhibits Raf dimerization and geldanamycin inhibits the binding of Raf to Hsp90. Another approach to targeting Raf is to inhibit Raf by targeting kinases (e.g., Src, PKC, PKA, PAK or Akt) and phosphorylating agents (e.g., PP2A) included in Raf activity. This may activate or inactivate other proteins or affect cellular physiology.

MEK1 rarely detects mutations in cancer, but abnormal expression of MEK1 is found in many cancers, including upstream kinase (eg BCR-ABL) and growth factor receptors (eg, EGFR) is known to be due to activation of the Raf / MEK / ERK signaling system. Several MEK inhibitors (PD98059, U0126, PD184352 (a.k.a., CI1040), PD-0325901, Array MEK inhibitors [ARRY-142886, etc.)) have been developed. The advantage of targeting the Raf / MEK / ERK signaling system is that it can be done without information about abnormally activated gene mutations. This is important because the nature of important mutations that induce at least 50% or more malignant growth of AML and other cancers is not yet known. The advantage of targeting MEK is that Raf / MEK / ERK signaling can prevent many upstream signaling from MEK inhibition.

ERK inhibitors have not yet been developed to the clinical stage, but ERK is the final stage of the Raf / MEK / ERK signaling system and can phosphorylate many targets (at least 150 such as Rsk, c-Myc, Elk, etc.). ERK inhibitors can be very useful for the prevention or treatment of various forms of cancer. Since the final stage of the Raf / MEK / ERK signaling system directly inhibits the activity of abnormally activated ERK in cancer cells, it is possible to prevent the Raf / MEK / ERK signaling system without information on abnormally activated upper gene mutations. It can be usefully used for prevention and treatment.

On the other hand, the parent nucleus structure in which the second position of quinazoline is substituted with an amine is one of the general chemical structures that have been known for a long time in the invention of pharmaceuticals and is used for kinase inhibitors and shows selective kinase inhibitory activity depending on the structure of each substituent. . (WO8905297, WO2001038315, WO2006039718, WO2007117607, WO2007125405).

Therefore, while studying a substance that can be used as an anticancer agent by regulating a signaling system related to cell growth, a novel compound and its activity were discovered.

WO2007117607 Abstract and claims WO2007125405 Abstract and claims

One embodiment provides novel 2-aminoquinazoline derivatives.

Another embodiment provides a composition for preventing and / or treating cancer, which contains a novel 2-aminoquinazolin derivative and / or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, one embodiment of the present invention relates to a 2-aminoquinazoline derivative of formula 1 below, pharmaceutically acceptable salts, solvates, hydrates, and isomers thereof.

≪ Formula 1 >

Another example relates to extracellular signal-regulated kinase inhibitors containing 2-aminoquinazolin derivatives of Formula 1, pharmaceutically acceptable salts, solvates, hydrates, and isomers thereof as active ingredients.

Another example relates to a composition for the prophylaxis and / or treatment of cancer containing 2-aminoquinazolin derivatives of Formula 1, pharmaceutically acceptable salts, solvates, hydrates, and isomers thereof as active ingredients.

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

One aspect provides a compound of Formula 1 and pharmaceutically acceptable salts, hydrates, solvates, or isomers thereof:

≪ Formula 1 >

Wherein R is hydrogen or substituted or unsubstituted C ₁ to C ₃₀ alkyl, substituted or unsubstituted C ₁ to C ₃₀ alkenyl, substituted or unsubstituted C ₁ to C ₃₀ alkynyl, substituted or unsubstituted Substituted or unsubstituted C ₁ to C ₃₀ cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkenyl, substituted or unsubstituted arylalkynyl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl Alkenyl, substituted or unsubstituted heteroarylalkynyl, carboxylic acid, ester, amide, substituted or unsubstituted C ₁ to C ₃₀ alkylamide, hydroxy, halogen, cyano, substituted or unsubstituted C ₁ to C ₃₀ hydroxyalkyl, substituted or unsubstituted C ₁ ˜C ₃₀ alkoxy, amino, substituted or unsubstituted C ₁ ˜C ₃₀ alkylamino, substituted or unsubstituted phenylamino, substituted or unsubstituted carbamoyl, substituted or unsubstituted oxadiazole, and substituted or unsubstituted Independently and optionally substituted by one or more of the carbamic acids.

The term “substituted” means substitution of one or more hydrogens by any one or any combination of the following substituents: halogen such as fluorine, chlorine, bromine and iodine; Hydroxy; Nitro; Cyano; Oxo (═O); Thioxo (= S); Azido; Nitroso; Amino; Hydrazino; Formyl; Alkyl; Alkoxy; Aryl; Haloalkyl groups such as trifluoromethyl, tribromomethyl, trichloromethyl and the like; Haloalkoxy such as -OCH ₂ Cl, -OCHF ₂ , -OCF ₃ , and the like; Arylalkoxy such as benzyloxy, phenylethoxy and the like; Cycloalkyl; -O-cycloalkyl; Heterocyclyl; Heteroaryl; Alkylamino; -0-CH ₂ -cycloalkyl; -COOR ^a ; -C (0) R ^b ; -C (O) NR ^a R ^b ; -NR ^a C (0) NR ^b R ^c ; -NR ^a C (O) OR ^b ; -NR ^a R ^b ; -NR ^a C (O) R ^b ; -0R ^a ; -0R ^a C (0) 0R ^b ; -C (0) NR ^a R ^b ; -OC (O) R ^a ; -R ^a NR ^b R ^c ; -R ^a 0R ^b ; R ^a , R ^b and R ^c are each independently a hydrogen atom; Alkyl; Alkylene; Aryl; Arylalkyl; Cycloalkyl; Heterocyclyl; A substituted or unsubstituted group selected from heteroaryl and heteroarylalkyl, and R ^a , R ^b and R ^c are also combined to form a ring of 3-7 atoms having 0-2 heteroatoms. The substituent may be optionally further substituted.

"Alkyl" means a straight or branched aliphatic hydrocarbon group having a certain number of carbon atoms attached to the rest of the molecule by a single atom. Preferred alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, and the like.

In this case, "halogen" may be any one selected from fluorine, chlorine, bromine or iodine.

Wherein “alkoxy” is selected from, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.

Herein, "alkenyl" may be any one selected from ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1-butenyl or 2-butenyl It is not limited.

Herein, "alkynyl" includes, but is not limited to, ethynyl, propynyl or butynyl.

Wherein “cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, perhydronaphthyl, adamantyl, crosslinked cyclic groups or spirobicyclic groups It may be selected from, but is not limited thereto.

Wherein "heterocycloalkyl or heteroaryl group" means azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cynolinyl, dioxolanyl, pyridyl, putridinyl , Furinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, pyrrolyl, piperonyl, pyrazinyl, pyrimidinyl, pyri Dazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, decahydroisoquinolyl, benzimidazolyl, indazolyl, phenylpiperidinyl, furyl, tetra Hydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomorpholinyl, piperidonyl, 2-oxopyrerazinyl, 2-oxo Hetero selected from piperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, oxazolidinyl It may be any one selected from the cyclyl group, but is not limited thereto.

In this case, "aryl" may be selected from phenyl, naphthyl, anthracenyl, indanyl or biphenyl, but is not limited thereto.

In this case, "hydroxy alkyl" may be hydroxymethyl or hydroxyethyl, but is not limited thereto.

At this time, "amide group" is substituted or unsubstituted C ₁ ~ C ₃₀ alkylamide, substituted or unsubstituted C ₁ ~ C ₃₀ benzylamide, substituted or unsubstituted C ₁ ~ C ₃₀ halobenzylamide, substituted or unsubstituted Substituted C ₁ to C ₃₀ phenylamide, or substituted or unsubstituted C ₁ to C ₃₀ phenylalkylamide, wherein at least one hydrogen atom of the phenyl group is alkyl, cycloalkyl, alkoxy, cyano, halogen, alkylsulfonyl May be selected independently and optionally substituted by one or more of, alkylthio, -CO ₂ alkyl, -COOH, -CONH ₂ , -CHO, -CH ₂ OH, hydroxyl, haloalkyl, amino, nitro, It is not limited to this.

In this case, "heterocyclylalkyl" may be oxadiazole, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morphonyl, but is not limited thereto. It doesn't happen.

In this case, "heteroarylalkenyl" may be pyridinylethenyl, thienylethenyl, or triazolylethenyl, but is not limited thereto.

In this case, "heteroarylalkenyl" may be selected from pyridinylethynyl or thienylethynyl, but is not limited thereto.

Further, the substituent R is hydrogen, substituted or unsubstituted carboxylic acid methyl ester, substituted or unsubstituted carboxylic acid, substituted or unsubstituted hydroxy methyl, substituted or unsubstituted amino, substituted or unsubstituted N, N-di Methylamide, substituted or unsubstituted methylamide, substituted or unsubstituted benzylamide, chloro, substituted or unsubstituted 4-chlorobenzylamide, substituted or unsubstituted phenylamide, substituted or unsubstituted phenyl phenethylamide, Fruor, substituted or unsubstituted benzylcarbamoyl, substituted or unsubstituted isopropylamide, substituted or unsubstituted 3-methylbutoxy, substituted or unsubstituted methoxy, substituted or unsubstituted 5-methyl- [ 1,3,4] oxadiazol-2-yl, substituted or unsubstituted tert-butylamide, substituted or unsubstituted sec-butylamide, substituted or unsubstituted cyclopentylamide, substituted or Substituted butylamide, substituted or unsubstituted (2-dimethylaminoethyl) -amide, substituted or unsubstituted cyclopropylamide, substituted or unsubstituted cyclohexylamide, substituted or unsubstituted (2-methoxyethyl ) -Amide, substituted or unsubstituted (1-ethylpropyl) -amide, substituted or unsubstituted isobutylamide, substituted or unsubstituted propylamide, substituted or unsubstituted ethylamide, substituted or unsubstituted cyclopropyl Methylamide, substituted or unsubstituted (2-morpholin-4-ylethyl) -amide, substituted or unsubstituted (3-methylbutyl) -amide, substituted or unsubstituted indan-2-ylamide, substituted or Unsubstituted (2,2,2-trifluoroethyl) -amide, substituted or unsubstituted methoxycarbonyl methylamide, substituted or unsubstituted 1 (R) -methoxycarbonyl ethylamide, substituted or unsubstituted Substituted 2-chlorobene Amide, substituted or unsubstituted 3-chlorobenzylamide, substituted or unsubstituted 2,3-dichlorobenzylamide, substituted or unsubstituted 2,5-dichlorobenzylamide, and substituted or unsubstituted 2-chloro It may be any one selected from the group consisting of -4-fluorobenzylamide, but is not limited thereto.

In addition, the substituent R may be any one selected from the group consisting of hydrogen, amine, chlorine, fluorine or the following formula:

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Where the symbol * represents a point of attachment of R to the remainder of Formula 1.

In addition, the compound represented by Formula 1 may preferably be a compound described in Table 1 below.

Compound Name Compound name (Korean) (1H-Indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine (1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid methyl ester 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methyl ester 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid {6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl} -methanol {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -methanol N * 6 *-[8- (Piperidin-4-yloxy) -quinazolin-2-yl] -1H-indazole-4,6-diamine N * 6 *-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -1 H-indazol-4,6-diamine 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid dimethylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid dimethylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid methylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid benzylamide (4-Chloro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine (4-Chloro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 4-chloro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 4-chlorobenzylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid phenylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid phenethyl-amide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenethylamide (4-Fluoro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine (4-Fluoro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 2-Phenyl-N- {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl} -acetamide 2-phenyl-N- {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -aacetamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid isopropylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isopropylamide [4- (3-Methyl-butoxy) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine [4- (3-Methylbutoxy) -1 H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine (4-Methoxy-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine (4-methoxy-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine [4- (5-Methyl- [1,3,4] oxadiazol-2-yl) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine [4- (5-Methyl- [1,3,4] oxadiazol-2-yl) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin -2-yl] -amine 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid tert-butylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid tert-butylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid sec-butylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid sec-butylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid cyclopentylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopentylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid butylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid butylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (2-dimethylamino-ethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-dimethylaminoethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid cyclopropylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopropylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid cyclohexylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclohexylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (2-methoxy-ethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-methoxyethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (1-ethyl-propyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (1-ethylpropyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid isobutyl-amide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isobutylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid propylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid propylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid ethylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid ethylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid cyclopropylmethyl-amide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclopropylmethylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (2-morpholin-4-yl-ethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-morpholin-4-ylethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (3-methyl-butyl) -amide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (3-methylbutyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid indan-2-ylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid indan-2-ylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid (2,2,2-trifluoro-ethyl) -amide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2,2,2-trifluoroethyl) -amide ({6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carbonyl} -amino) -acetic acid methyl ester ({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -acetic acid methylester 2 (R)-({6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carbonyl} -amino) -propionic acid methyl ester 2 (R)-({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -propionic acid methylester 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 2-chloro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chlorobenzylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 3-chloro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 3-chlorobenzylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 2,3-dichloro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,3-dichlorobenzylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 2,5-dichloro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,5-dichlorobenzylamide 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 2-chloro-4-fluoro-benzylamide 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chloro-4-fluorobenzylamide

delete

Another aspect may be provided in a composition comprising a compound of one embodiment, a pharmaceutically acceptable salt, hydrate, solvate, or isomeric form thereof.

The 'pharmaceutically acceptable salts' may be any pharmaceutically acceptable salts derived from inorganic or organic acids or bases. For example, as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, iodide But are not limited to, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, But are not limited to, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Benzoates, phthalates, terephthalates, benzenesulfonates, toluene sulfonates, chlorobenzene sulphates, Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The 'solvate' means herein that the compound molecule of Formula 1 and a pharmaceutically acceptable solvent, such as a lower alcohol molecule having 1 to 4 carbon atoms, form a complex, wherein the 'hydrate' is a compound molecule of Formula 1 Means that it forms a complex with the water molecule.

In addition, the range of the compound of the present invention can be broadened to a form in which a known protecting group introduction or deprotecting group is introduced, and when an optical isomer is present in the compound, the respective enantiomers, diastereomers, , And racemic mixtures.

In one embodiment, the compound of Formula 1 may be prepared by any compound synthesis method commonly known in the art.

In one embodiment, the compound of Formula 1 and the intermediate may be prepared by the preparation process of Scheme 1.

<Reaction Scheme 1>

According to Scheme 1, compound 2 is formed by condensation reaction with urea from commercially available 2-amino-3-methoxybenzoic acid derivative (Compound 1) and Compound 2 is POCl Chlorination by ₃ and the like converts to compound 3 and selective dechlorination to compound 4. Compound 4 is converted to Compound 5 by removing the methyl protecting group and converted to Compound 6 by Mitsunobu reaction with 4-hydroxypiperidine having a protecting group. Compound 6 may synthesize a compound of Formula 1 by substitution with various 6-amino indazole derivatives (8).

Compound (8-1) having an amide substituent in the 6-amino indazole derivative (8) used in Scheme 1 can be prepared by the procedure of Scheme 2.

<Reaction Scheme 2>

According to Scheme 2, compound 8-1 was introduced from a commercially available 2-methyl3-nitrobenzoic acid to introduce a protecting group by esterification, to reduce a nitro group to an amine, to introduce a nitro group, to form a pyrazole ring reaction and to remove an ester protecting group. To Compound 14 through. Compound 14 can synthesize 6-amino indazole (8-1) in which an amide is introduced at position 4 of the indazole by forming a amide by coupling with various amines (R1NH2) and by nitro group reduction.

Compound (8-2) having an alkoxy substituent in the 6-amino indazole derivative (8) used in Scheme 1 may be prepared by the procedure of Scheme 3.

<Reaction Scheme 3>

According to Scheme 3, compound 8-2 can be optionally reduced from two commercially available 2,4,6-trinitrotoluenes (16), reduction of two nitro groups, introduction of amine protecting groups such as phthalimide, 2-methyl 4-hydroxy-6-nitro indazole (by introduction of a protecting group by esterification from 3-nitro benzoic acid, pyrazole cyclization reaction, removal of amine protecting group and introduction of hydroxyl group using Sandmyer reaction) 21). 6-amino indazole 8-2 having an alkoxy group introduced at position 4 of the indazole may be synthesized by introducing a protecting group into the NH of the compound 21, introducing an alkyl group into the hydroxy group, and then reducing the nitro group.

Compound (8-3) having a carbamoyl substituent in the 6-amino indazole derivative (8) used in Scheme 1 can be prepared by the procedure of Scheme 4.

<Reaction Scheme 4>

According to Scheme 4, Compound 8-3 may be synthesized from Compound 20, which is an intermediate of Scheme 3, by amide synthesis by reaction with various acids in the presence of an acid chloride or a coupling agent, followed by reduction of a nitro group to synthesize Compound 8-3. .

Compound (8-4) having a carbamoyl substituent in the 6-amino indazole derivative (8) used in Scheme 1 can be prepared by the procedure of Scheme 5.

<Reaction Scheme 5>

According to Scheme 5, compound 8-4 can synthesize 4-hydroxymethyl-6-amino indazole (8-4) by reducing the nitro group and reducing the ester with alcohol from compound 13, which is an intermediate of Scheme 2. have.

Compound (8-5) having an oxadiazole substituent in the 6-amino indazole derivative (8) used in Scheme 1 may be prepared by the process of Scheme 6.

<Reaction Scheme 6>

According to Scheme 6, compound 8-5 converts an ester group to hydrazide from compound 13, which is an intermediate of Scheme 2, and then reacts with orthoacetate to introduce an oxadiazole substituent, thereby reducing the nitro group to reduce the 4 position of indazole. 6-amino indazole (8-5) substituted with diazoles can be synthesized.

Compound (6-6) having a halogen substituent in the 6-amino indazole derivative (8) used in Scheme 1 can be prepared by the procedure of Scheme 7.

<Reaction Scheme 7>

According to Scheme 7, Compound 8-6 may be synthesized by converting an amino group into a halogen by Sandmeyer reaction from Compound 20, which is an intermediate of Scheme 3, and then reducing the nitro group.

R in Chemical Formula 1 may be converted from the compound of Chemical Formula 1 or an intermediate of the reaction process into a different kind of R by chemical reaction by a known method or a method well known to those skilled in the art.

As a result of measuring the inhibitory activity of the derivative of Formula 1 according to the present invention in ERK1 and ERK2, the inhibitory activity against ERK2 (IC ₅₀ ) is 2 μM or less in all compounds corresponding to Formula 1, Synthesis Examples 103, 105, 106 0.2 to 1 μM or less for compounds of 109, 111, 112, 113, and 116, 0.1 to 0.2 μM for compounds of Synthesis Examples 104, 108, 110, 117, 118, 119, 124, 125, 127, and 129, Synthesis Examples 102, 107, 115, 120, 121, 122, 123, 126, 128 and 130-142 were found to be 0.1 μM or less. In addition, in order to confirm the effect of inhibiting cancer cell proliferation through the inhibition of ERK activity, the results of experiments on human colon cell line COLO-205 cells Synthesis Example 101, 102, 104, 108, 109, 110, 113, 115, 120 to 122 The compounds of, 128, 131, 133 to 135, and 138 to 142 showed an EC50 2-5 μM inhibitory effect on cancer cell proliferation.

On the other hand, the compound of formula (1), which is similar in structure to formula (1) but has a cyclohexyl group instead of piperidine in formula (1) or a pyridine substituent instead of indazole, did not exhibit ERK inhibitory activity (IC ₅₀ ) ( See Comparative Example and Table 5.

(2)

<Formula 3>

Accordingly, the derivative of formula 1 according to the present invention is a compound having a specific structure in which 4-piperidinyl oxy and indazole are bound to a known 2-aminoquinazoline structure, and thus, to the extracellular signal-regulating kinase by the structural characteristics of the compound. Since it shows an effective inhibitory activity, it is not only useful as an inhibitor of extracellular signal-regulated kinase, but also can be effectively used for the prevention or treatment of cancer caused by extracellular signal-regulated kinase activity.

Another aspect therefore relates to the use of the compounds of formula 1, their pharmaceutically acceptable salts, hydrates, solvates, or isomers for the inhibition of extracellular signal-regulated kinase activity.

Specifically, there is provided a composition for inhibiting extracellular signal-regulated kinase activity containing the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. In another aspect, an extracellular signal comprising preparing a biological sample isolated from a living body and applying a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof to the biological sample Methods of inhibiting regulatory kinase activity are provided. The biological sample is a cell, tissue, blood, saliva, other body fluids, etc. derived from a mammal, preferably a human, and means a sample separated from a living body.

Another aspect provides a cancer prophylactic and / or therapeutic composition comprising a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient.

Specifically, there is provided a composition for the prevention and / or treatment of cancer containing the compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. In another aspect, preventing and / or administering a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof to a patient in need thereof, and / or treating the cancer Or a method of treatment is provided. By patient is meant a mammal, preferably a human, an individual in need of and / or prevention of cancer caused by extracellular signal-regulated kinase activity.

The cancer may be any cancer caused by extracellular signal-regulated kinase activity, such as lung cancer, pancreatic cancer, colon cancer (eg colorectal cancer), myeloid leukemia (eg acute lymphocytic leukemia (AML), chronic) Myeloid Leukemia (CML) and Chronic Bone Cell Leukemia (CMML), Thyroid Cancer, Myelodysplastic Syndrome (MDS), Bladder Carcinoma, Epidermal Carcinoma, Melanoma, Breast Cancer, Prostate Cancer, Head and Neck Cancer (e.g. Cancer), ovarian cancer, brain cancer (eg glioma, eg glioblastoma multiforme), cancer of mesenchymal origin (eg fibrosarcoma and rhabdomyosarcoma), sarcoma, teratcarcinomas, neuroblastoma , Renal carcinoma, liver cancer, non-Hodgkin's lymphoma, multiple myeloma, or thyroid undifferentiated cancer, and the like.

The content of the compound of formula 1, a pharmaceutically acceptable salt, solvate, hydrate, and / or isomer thereof as an active ingredient in the composition for inhibiting extracellular signal-regulated kinase activity and the composition for preventing or treating cancer may be It can be appropriately adjusted according to the degree, symptoms, the patient condition to be applied, and the like, for example, 0.0001 to 99.9% by weight, preferably 0.001 to 50% by weight based on the total weight of the composition, but is not limited thereto.

When the composition is used in the form of a pharmaceutical composition, it may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions, powders, granules, tablets, capsules, It may be used in the form of oral dosage forms such as suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injectable solutions.

When the composition is formulated, it is prepared using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient usually used. Solid formulations for oral administration include tablets, pills, powders, powders, granules, capsules and the like, and such solid preparations may contain at least one excipient and / or lubricant. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration include injections, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.

The preferred dose of the composition may be appropriately determined depending on the disease, symptom, body weight of the patient, drug form, administration route and duration. For a more preferable effect, the dosage of the composition of the present invention is preferably 0.01 mg / kg to 1000 mg / kg per day by weight of the active ingredient, preferably 0.1 to 500 mg / kg, but is not limited thereto. no. The administration may be carried out once a day or divided into several doses. The compositions of the present invention may be administered by a variety of routes to mammals or birds, including animals, preferably humans. All modes of administration may be expected, for example, by oral, intravenous, intramuscular, subcutaneous injection, and the like. The pharmaceutical dosage form of the composition of the present invention may be used in the form of a pharmaceutically acceptable salt of the active ingredient, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable combination.

Another aspect provides a method of treating cancer comprising administering to a patient a cancer prophylactic and / or therapeutic composition comprising a compound of Formula 1, a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof as an active ingredient. to provide.

The invention is further understood by reference to the following synthesis examples, for which pure illustration is intended. The present invention is not limited by the illustrated embodiments and any method that is functionally equivalent is within the scope of the present invention.

The 2-aminoquinazolin derivatives according to the present invention effectively inhibit the activity of extracellular signal-regulated kinase 1 and / or extracellular signal-regulated kinase 2 and thus are very useful for the treatment of cancer caused by their activity.

Hereinafter, the present invention will be described in detail by way of synthesis examples.

However, the following synthesis examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following synthesis examples.

To prepare a compound of Synthesis Examples 101 to 144 as shown in Table 2 by the following Preparation Example:

Synthetic example Compound name R 101 (1 H- indazol-6-yl) - [8- (piperidin-4-yloxy) -quinazolin-2-yl] H 102 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methyl ester Carboxylic Acid Methyl Ester 103 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid Carboxylic acid 104 {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -methanol Hydroxy methyl 105 N * 6 *-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -1 H-indazol-4,6-diamine Amino 106 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid dimethylamide N, N-dimethylamide 107 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methylamide Methylamide 108 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid benzylamide Benzylamide 109 (4-Chloro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine Chloro 110 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 4-chlorobenzylamide 4-chlorobenzylamide 111 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenylamide Phenylamide 112 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenethylamide Phenethylamide 113 (4-Fluoro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine Furuor 114 2-phenyl-N- {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -aacetamide Benzylcarbamoyl 115 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isopropylamide Isopropylamide 116 [4- (3-Methylbutoxy) -1 H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 3-methylbutoxy 117 (4-methoxy-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine Methoxy 118 [4- (5-Methyl- [1,3,4] oxadiazol-2-yl) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin -2-yl] -amine 5-methyl- [1,3,4] oxadiazol-2-yl 119 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid tert-butylamide tert-butylamide 120 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid sec-butylamide sec-butylamide 121 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopentylamide Cyclopentylamide 122 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid butylamide Butylamide 123 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-dimethylaminoethyl) -amide (2-dimethylaminoethyl) -amide 124 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopropylamide Cyclopropylamide 125 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclohexylamide Cyclohexylamide 126 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-methoxyethyl) -amide (2-methoxyethyl) -amide 127 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (1-ethylpropyl) -amide (1-ethylpropyl) -amide 128 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isobutylamide Isobutylamide 129 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid propylamide Propyl amide 130 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid ethylamide Ethylamide 131 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclopropylmethylamide Cyclopropylmethylamide 132 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-morpholin-4-ylethyl) -amide (2-morpholin-4-ylethyl) -amide 133 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (3-methylbutyl) -amide (3-methylbutyl) -amide 134 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid indan-2-ylamide Indan-2-ylamide 135 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2,2,2-trifluoroethyl) -amide (2,2,2-trifluoroethyl) -amide 136 ({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -acetic acid methylester Methoxycarbonyl methylamide 137 2 (R)-({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -propionic acid methylester 1 (R) -methoxycarbonyl ethylamide 138 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chlorobenzylamide 2-chlorobenzylamide 139 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 3-chlorobenzylamide 3-chlorobenzylamide 140 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,3-dichlorobenzylamide 2,3-dichlorobenzylamide 141 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,5-dichlorobenzylamide 2,5-dichlorobenzylamide 142 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chloro-4-fluorobenzylamide 2-chloro-4-fluorobenzylamide 143 (Comparative Example) (8-cyclohexyloxy-quinazolin-2-yl)-(1H-indazol-6-yl) -amine - 144 (comparative) [8- (piperidin-4-yloxy) -quinazolin-2-yl] -pyridin-4-yl-amine -

Hereinafter, the preparation process of the above Synthesis Examples 101 to 144 is illustrated by the preparation examples below.

Preparation Example 1 Synthesis of Compound of Formula 1 from 2-Amino-3-methoxy Benzoic Acid

<Scheme 1-1>

(1-1) Synthesis of Compound 2

Compound 1 (6.0 g, 36 mmol), urea (10.8 g, 180 mmol) and NMP (22 ml) were added to the reactor and stirred by heating at 180 ° C. for 1.5 hours. The reaction was cooled to room temperature and poured into water (300 ml), and the resulting solid was filtered and washed with water to obtain compound 2 (3.78 g, yield 55%).

(1-2) Synthesis of Compound 3

Compound 2 (3.70 g, 19.2 mmol) and N, N-dimethylaniline (4 ml) were added to POCl ₃ (25.0 ml), heated to reflux at 120 to 130 ° C. for 2 hours, poured into ice, and the resulting precipitate was extracted with EtOAc. . The organic layer was dried over MgSO ₄ and the solvent was removed under reduced pressure to obtain compound 3 (4.0 g, yield 90%, LC-MS: 229.2, 233.0 [M + H] ⁺ ).

(1-3) Synthesis of Compound 4

To a solution of compound 3 (4.0 g, 17.4 mmol) in EtOAc (200 ml) was added Pd / C (450 mg) and DIPEA (2.7 g, 21.0 mmol), and the mixture was stirred under room temperature hydrogen (1 atm) for 1.5 hours and then passed through Celite. After filtration, the mixture was washed with water and brine and dried over MgSO ₄ . Concentration under reduced pressure and purification by silica gel column chromatography (PE / EA = 4/1) afforded Compound 4 (2.64 g; yield 79%) as a yellow solid.

(1-4) Synthesis of Compound 5

Compound 4 (2 g, 10.3 mmol) was added to DCM (16 ml), and boron tribromide (20.6 ml, 1.0 M DCM solution) was slowly added dropwise at 0 ° C., and the mixture was stirred at 50 ° C. for 6 hours. The reaction was diluted with EtOAc, washed with water and 3N HCl (20 ml), dried over MgSO ₄ and concentrated under reduced pressure. The resulting solid was washed with MeOH and dried to give compound 5 (1.56 g, 82% yield). )

¹ H NMR (300 MHz, DMSO-d 6); [delta] 10.56 (s, IH), 9.51-9.42 (m, IH), 7.62-7.59 (m, 2H), 7.39-7.36 (m, IH).

(1-5) Synthesis of Compound 6

To a mixture of compound 5 (700 mg, 3.88 mmol), triphenylphosphine (1.526 g, 5.82 mmol) and N-BOC-4-hydroxypiperidine (860 mg, 4.27 mmol) in dry THF (16 ml), DIAD ( 1.145 ml) was added dropwise and the reaction was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, dissolved in EtOAc, washed with water, and then the organic layer was dried over MgSO ₄ , concentrated under reduced pressure, and purified by silica ê ”column chromatography (Hex / EtOAc = 4/1) to give a compound 6 (1.24 g, yield 88%). )

1 H NMR (300 MHz, CDCl ₃ ); δ 9.22 (s, 1H), 7.53-7.49 (m, 2H), 7.34-7.31 (m, 1H), 4.73 (quin., J = 4.2 Hz, 1H), 3.87-3.79 (m, 2H), 3.31- 3.23 (m, 2H), 1.92-1.82 (m, 4H), 1.42 (s, 9H).

(1-6) Synthesis of Compound 7

Compound 6 (50mg, 0.14mmol) and 6-amino indazole (Compound 8, 0.14 mmol) substituted at position 4 were added thereto, and the mixture was heated at 150 ° C. for 6-18 hours, cooled to room temperature, followed by DCM (2ml). TFA (1 ml) was added thereto, stirred at 40 ° C. for 10 minutes, the solvent was removed by distillation under reduced pressure, and purified by prep-HPLC (0.1% HCOOH in H ₂ O / CH ₃ CN) to obtain compound 7 (Formula 1).

Compounds corresponding to Compound 7 (Formula 1) preparable by the above method are as described in Table 3 below:

Synthetic example Compound Name ^One H NMR LC / MS 101 (1 H- indazol-6-yl) - [8- (piperidin-4-yloxy) -quinazolin-2-yl] 　 1 H NMR (300 MHz, CD3OD, δ):
9.20 (s, 1H), 8.49 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.56-7.43 (m, 4H), 7.33 (t, J = 7.8 Hz, 1H), 5.06 (s , 1H), 3.54 (m, 2H), 3.23 (m, 2H), 2.19 (m, 4H) 360.0 102 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methyl ester 1 H NMR (300 MHz, DMSO, δ):
10.27 (s, 1H), 9.31 (s, 1H), 9.16 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.45 (d , J = 7.5Hz, 1H), 7.32 (t, J = 7.8Hz, 1H), 4.91 (s, 1H), 3.95 (s, 3H), 3.27 (m, 2H), 2.92 (m, 2H), 2.03 (m, 4H) 419.2 103 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 1 H NMR (300 MHz, DMSO, δ):
9.93 (s, 1H), 9.27 (s, 1H), 8.39-8.35 (m, 2H), 7.94 (s, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.44 (d, J = 7.5Hz , 1H), 7.29 (t, J = 7.5Hz, 1H), 4.93 (s, 1H), 3.33 (m, 2H), 3.02 (m, 2H), 2.04 (m, 4H) 404.1 104 {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -methanol 1 H NMR (300 MHz, DMSO, δ):
10.01 (s, 1H), 9.28 (s, 1H), 8.65 (s, 1H), 8.02 (s, 1H), 7.52 (d, J = 7.8Hz, 1H), 7.45-7.39 (m, 2H), 7.30 (t, J = 7.8 Hz, 1H), 4.91 (s, 1H), 4.77 (s, 2H), 3.27 (m, 2H), 2.96 (m, 2H), 2.03 (m, 4H) 391.1 105 N * 6 *-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -1 H-indazol-4,6-diamine 1 H NMR (300 MHz, DMSO, δ):
10.01 (s, 1H), 9.32 (s, 1H), 8.38-8.32 (m, 2H), 7.91 (s, 1H), 7.52 (d, J = 7.8Hz, 1H), 7.41 (d, J = 7.8Hz , 1H), 7.28 (t, J = 7.5 Hz, 1H), 4.91 (s, 1H), 3.28 (m, 2H), 3.02 (m, 2H), 2.04 (m, 4H) 376.1 106 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid dimethylamide 1 H NMR (300 MHz, DMSO, δ):
10.16 (s, 1H), 9.30 (s, 1H), 8.79 (s, 1H), 7.86 (s, 1H), 7.54-7.51 (m, 2H), 7.45 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 4.89 (m, 1H), 3.27 (m, 2H), 3.07 (m, 2H), 2.91 (s, 6H), 2.03 (m, 4H) 432.2 107 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methylamide 1 H NMR (300 MHz, DMSO, δ):
10.12 (s, 2H), 9.31 (s, 1H), 8.73 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 7.2Hz , 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 4.90 (s, 1H), 3.26 (m, 2H), 2.99 (m, 2H), 2.83 (s, 3H), 2.05 (m, 4H) 418.2 108 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid benzylamide 1 H NMR (300 MHz, DMSO, δ):
10.08-10.05 (m, 2H), 9.29 (s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.34-7.25 (m, 6H), 4.90 (s, 1H), 4.63 (s, 2H), 3.26 (m, 2H), 2.99 ( m, 2H), 2.02 (m, 4H) 494.2 109 (4-Chloro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 1 H NMR (300 MHz, DMSO, δ):
10.18 (s, 1H), 9.28 (s, 1H), 8.41 (s, 1H), 8.00 (s, 1H), 7.68-7.42 (m, 4H), 7.31 (t, J = 8.7 Hz, 1H), 4.95 (s, 1H), 3.27 (m, 2H), 2.95 (m, 2H), 2.08-2.02 (m, 4H) 395.1 110 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 4-chlorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
9.21 (s, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 7.55 (d, J = 8.7Hz, 1H), 7.45-7.26 (m, 7H), 4.99 (s, 1H), 4.63 (s, 2H), 3.54-3.42 (m, 2H), 3.12-3.06 (m, 2H), 2.20-2.08 (m, 4H) 529.1 111 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenylamide 1 H NMR (300 MHz, DMSO, δ):
9.22 (s, 1H), 8.35-8.31 (m, 2H), 7.77 (d, J = 8.7Hz, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.54 (d, J = 8.4Hz, 1H ), 7.43-7.30 (m, 5H), 7.21-7.13 (m, 1H), 4.95 (s, 1H), 3.47-3.39 (m, 2H), 3.10-3.06 (m, 2H), 2.13-2.07 (m) , 4H) 480.1 112 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid phenethylamide 1 H NMR (300 MHz, DMSO, δ):
9.22 (s, 1H), 8.43 (s, 1H), 8.06-7.89 (m, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 7.34-7.25 (m, 5H), 6.93 (s, 1H), 3.72-3.62 (m, 2H), 3.52-3.42 (m, 2H), 3.15-3.10 (m, 2H), 3.01-2.94 (m, 2H), 2.19-2.11 (m, 4H) 508.2 113 (4-Fluoro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 1 H NMR (300 MHz, DMSO, δ):
10.20 (s, 1H), 9.31 (s, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.66-7.41 (m, 4H), 7.32 (t, J = 8.7Hz, 1H), 4.89 (s, 1H), 3.27 (m, 2H), 2.93 (m, 2H), 2.02 (m, 4H) 378.2 114 2-phenyl-N- {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-yl} -acetamide 1 H NMR (300 MHz, DMSO, δ):
9.91 (s, 1H), 9.27 (s, 1H), 8.42-8.35 (m, 2H), 7.51 (d, J = 6.9 Hz, 1H), 7.39-7.26 (m, 8H), 6.91 (s, 1H) , 6.01 (s, 1H), 4.86 (m, 1H), 4.47 (s, 2H), 3.16-3.12 (m, 2H), 2.85 (m, 2H), 1.93-1.90 (m, 4H) 494 115 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isopropylamide 1 H NMR (300 MHz, DMSO, δ):
10.08 (s, 1H), 9.31 (s, 1H), 8.82 (s, 1H), 8.18-8.10 (m, 2H), 7.72 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.8Hz, 1H), 7.31 (t, J = 8.1Hz, 1H), 4.90 (s, 1H), 4.13 (quin., 1H), 3.26 (m, 2H), 2.95 (m, 2H ), 2.01 (m, 4H), 1.20 (d, J = 7.2 Hz, 6H) 446.3 116 [4- (3-Methylbutoxy) -1 H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 1 H NMR (300 MHz, DMSO, δ):
9.95 (s, 1H), 9.26 (s, 1H), 8.43 (s, 1H), 7.91 (s, 1H), 7.49 (d, J = 7.8Hz, 1H), 7.43 (d, J = 6.6Hz, 1H ), 7.30 (t, J = 7.8 Hz, 1H), 7.00 (s, 1H), 4.87 (s, 1H), 3.32-3.26 (m, 4H), 2.97 (m, 2H), 2.02 (m, 4H) , 1.68 (quin., J = 6.9 Hz, 1H), 1.46 (q, J = 7.2 Hz, 2H), 0.93 (d, J = 6.9 Hz, 6H) 447.1 117 (4-methoxy-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine 1 H NMR (300 MHz, DMSO, δ):
9.92 (s, 1H), 9.27 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.49 (d, J = 7.5Hz, 1H), 7.43 (d, J = 6.6Hz, 1H ), 7.30 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.88 (s, 1H), 3.91 (s, 3H), 3.26 (m, 2H), 2.87 (m, 2H), 2.03 -1.91 (m, 4H) 391.1 118 [4- (5-Methyl- [1,3,4] oxadiazol-2-yl) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin -2-yl] -amine 1 H NMR (300 MHz, DMSO, δ):
10.33 (s, 1H), 9.34 (s, 1H), 9.05 (s, 1H), 8.42 (s, 1H), 8.38 (br s, 1H), 8.15 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 4.95 (m, 1H), 3.26 (m, 2H), 2.89 (m, 2H), 2.03 (m, 4H) 443.1 119 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid tert-butylamide 1 H NMR (300 MHz, DMSO, δ):
10.04 (s, 1H), 9.30 (s, 1H), 8.84 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.54-7.42 (m, 1H) , 7.35-7.28 (m, 1H), 4.90 (s, 1H), 3.26 (m, 2H), 2.94 (m, 2H), 2.04 (m, 4H), 1.42 (s, 9H) 460.1 120 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid sec-butylamide 1 H NMR (300 MHz, DMSO, δ):
10.08 (s, 1H), 9.30 (s, 1H), 8.90 (s, 1H), 8.10-8.08 (m, 2H), 7.67 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 4.90 (s, 1H), 3.99-3.95 (m, 1H), 3.27 (m, 2H), 2.96 (m, 2H), 2.05 (m, 4H), 1.59-1.47 (m, 2H), 1.59-1.18 (m, 3H), 0.95-0.90 (m, 3H) 460.1 121 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopentylamide 1 H NMR (300 MHz, DMSO, δ):
10.07 (s, 1H), 9.30 (s, 1H), 8.84 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.53 (d , J = 6.9 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 4.90 (s, 1H), 4.28-4.24 (m, 1H), 3.25 (m, 2H), 2.93 (m, 2H), 2.02-1.90 (m, 6H), 1.76 (m, 2H), 1.55 (m, 4H) 472 122 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid butylamide 1 H NMR (300 MHz, DMSO, δ):
10.11 (s, 1H), 9.30 (s, 1H), 8.88 (s, 1H), 8.33-8.29 (m, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 4.90 (s, 1H), 3.33-3.27 (m, 4H), 2.95 (m, 2H), 2.04 (m, 4H), 1.60-1.50 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H) 460.5 123 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-dimethylaminoethyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.13 (s, 1H), 9.30 (s, 1H), 9.01 (s, 1H), 8.15-8.12 (m, 2H), 7.74 (s, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.43 (d, J = 6.9 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 4.91 (s, 1H), 3.16 (m, 2H), 2.78 (m, 2H), 2.21 (s, 6H) , 1.97-1.85 (m, 4H), 1.22-1.12 (m, 4H) 475.3 124 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopropylamide 1 H NMR (300 MHz, DMSO, δ):
10.07 (s, 1H), 9.30 (s, 1H), 8.87 (s, 1H), 8.41 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.52 (d, J = 7.5Hz , 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 4.89 (s, 1H), 3.26 (m, 2H), 2.91 (m, 2H), 1.99 (m, 4H), 1.20 (m, 1H), 0.72-0.60 (m, 4H) 444.1 125 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclohexylamide 1 H NMR (300 MHz, DMSO, δ):
10.07 (s, 1H), 9.30 (s, 1H), 8.46 (s, 1H), 8.15-8.03 (m, 2H), 7.66 (s, 1H), 7.51 (d, J = 7.5Hz, 1H), 7.43 (d, J = 7.8Hz, 1H), 7.30 (t, J = 7.8Hz, 1H), 4.90 (s, 1H), 3.78 (m, 1H), 3.15 (m, 2H), 2.82 (m, 2H) , 1.96-1.74 (m, 8H), 1.34-1.17 (m, 6H) 486.5 126 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-methoxyethyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.11 (s, 1H), 9.30 (s, 1H), 8.89 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 7.73 (s, 1H), 7.52 (d, J = 8.1Hz , 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 4.90 (s, 1H), 3.51-3.47 (m, 4H), 3.30 (m, 5H) , 2.92 (m, 2 H), 2.02 (m, 4 H) 462.2 127 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (1-ethylpropyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.10 (s, 1H), 9.30 (s, 1H), 9.06 (s, 1H), 8.46 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.44 (d, J = 7.5Hz, 1H), 7.31 (t, J = 8.1Hz, 1H), 4.91 (s, 1H), 3.81 (m, 1H), 3.31 (m, 2H), 2.86 (m, 2H), 1.96 (m, 4H), 1.60-1.45 (m, 4H), 0.94 (t, J = 7.8 Hz, 6H) 474.3 128 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isobutylamide 1 H NMR (300 MHz, DMSO, δ):
10.13 (s, 1H), 9.31 (s, 1H), 8.85 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.54 (d, J = 8.1Hz , 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 4.90 (s, 1H), 3.26 (m, 2H), 3.13 (t, J = 5.7 Hz , 2H), 2.97 (m, 2H), 2.03 (m, 4H), 1.89 (quin., J = 6.9 Hz, 1H). 0.94 (d, J = 6.6 Hz, 6H) 460.1 129 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid propylamide 1 H NMR (300 MHz, DMSO, δ):
10.12 (s, 1H), 9.30 (s, 1H), 8.90 (s, 1H), 8.34 (s, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 7.53 (d, J = 7.8Hz , 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 4.89 (s, 1H), 3.30-3.23 (m, 4H), 2.93 (m, 2H) , 2.03 (m, 4H), 1.57 (q, J = 6.9 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H) 446.1 130 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid ethylamide 1 H NMR (300 MHz, DMSO, δ):
10.12 (s, 1H), 9.31 (s, 1H), 8.91 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H), 7.54 (d, J = 7.5Hz , 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 4.91 (s, 1H), 3.39-3.31 (m, 4H), 2.94 (m, 2H) , 2.04 (m, 4H), 1.18 (t, J = 6.9 Hz, 3H) 432.3 131 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclopropylmethylamide 1 H NMR (300 MHz, DMSO, δ):
10.13 (s, 1H), 9.32 (s, 1H), 8.90 (s, 1H), 8.43 (s, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 7.54 (d, J = 7.8Hz , 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 4.92 (s, 1H), 3.24-3.19 (m, 4H), 2.96 (m, 2H) , 2.05 (m, 4H), 1.10 (quin., 1H), 0.48-0.44 (m, 2H), 0.29-0.26 (m, 2H) 458.2 132 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-morpholin-4-ylethyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.18 (s, 1H), 9.35 (s, 1H), 8.66 (s, 1H), 8.47-8.37 (m, 2H), 8.24 (s, 1H), 7.86 (s, 1H), 7.59 (d, J = 8.1Hz, 1H), 7.48 (d, J = 8.1Hz, 1H), 7.34 (t, J = 7.5Hz, 1H), 4.93 (s, 1H), 3.69 (m, 4H), 3.55 (m, 2H) , 3.12 (m, 2H), 2.76 (m, 2H), 2.08 (m, 4H) 517.3 133 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (3-methylbutyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.12 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.73 (s, 1H), 7.54 (d, J = 7.8Hz , 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 4.91 (s, 1H), 3.36-3.29 (m, 4H), 2.97 (m, 2H) , 2.02 (m, 4H), 1.68 (quin., J = 6.6 Hz, 1H), 1.46 (q, J = 7.2 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6H) 474.2 134 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid indan-2-ylamide 1 H NMR (300 MHz, DMSO, δ):
10.09 (s, 1H), 9.30 (s, 1H), 8.94 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.52 (d , J = 7.8 Hz, 1H, 7.44 (d, J = 7.5 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.28-7.23 (m, 2H), 7.16-7.14 (m, 2H) , 4.90 (s, 1H), 4.76 (q, J = 6.9 Hz, 1H), 3.33-3.25 (m, 4H), 3.04-2.96 (m, 2H), 2.90 (m, 2H), 2.00 (m, 4H ) 520.5 135 6- [8- (Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2,2,2-trifluoroethyl) -amide 1 H NMR (300 MHz, DMSO, δ):
10.18 (s, 1H), 9.31 (s, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 7.54 (d, J = 8.1Hz , 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 4.90 (s, 1H), 4.19-4.08 (m, 2H), 3.28 (m, 2H) , 2.96 (m, 2H), 2.05 (m, 4H) 486.2 136 ({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -acetic acid methylester 1 H NMR (300 MHz, DMSO, δ):
10.17 (s, 1H), 9.31 (s, 1H), 8.83 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.54 (d, J = 8.1Hz , 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 4.90 (s, 1H), 4.08 (d, J = 5.7 Hz, 2H), 3.68 (s , 3H), 3.27 (m, 2H), 3.00 (m, 2H), 2.05 (m, 4H) 476.5 137 2 (R)-({6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -propionic acid methylester 1 H NMR (300 MHz, DMSO, δ):
10.13 (s, 1H), 9.31 (s, 1H), 8.93 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 7.54 (d , J = 8.1Hz, 1H), 7.45 (d, J = 7.5Hz, 1H), 7.31 (t, J = 7.8Hz, 1H), 4.90 (s, 1H), 4.56 (m, 1H), 3.68 (s , 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.03 (m, 4H), 1.42 (d, J = 7.5 Hz, 3H) 490.1 138 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chlorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
10.18 (s, 1H), 9.32 (s, 1H), 8.99-8.94 (m, 2H), 8.39 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.55-7.45 (m, 4H), 7.39-7.30 (m, 4H), 4.92 (m, 1H), 4.61 (d, J = 5.7 Hz, 2H), 3.36 (m, 2H), 2.93 (m, 2H), 2.04 (m, 4H ) 528.1 139 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 3-chlorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
10.15 (s, 1H), 9.32 (s, 1H), 8.99-8.95 (m, 2H), 8.41 (br s, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.47-7.30 (m, 6H), 4.92 (s, 1H), 4.54 (d, J = 5.4 Hz, 2H), 3.30 (m, 2H), 2.95 (m, 2H) 528.1 140 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,3-dichlorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
10.16 (s, 1H), 9.31 (s, 1H), 9.02-8.94 (m, 2H), 8.37 (br s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 7.59-7.52 (m , 3H), 7.46-7.29 (m, 4H), 4.90 (s, 1H), 4.62 (d, J = 5.4 Hz, 2H), 3.28 (m, 2H), 2.93 (m, 2H), 2.02 (m, 4H) 563.3 141 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,5-dichlorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
10.18 (s, 1H), 9.31 (s, 1H), 9.02-8.95 (m, 2H), 8.16 (s, 1H), 7.83 (s, 1H), 7.55-7.50 (m, 3H), 7.46-7.29 ( m, 5H), 4.90 (m, 1H), 4.57 (d, J = 5.4 Hz, 2H), 3.31 (m, 2H), 2.95 (m, 2H), 2.04 (m, 4H) 563.3 142 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2-chloro-4-fluorobenzylamide 1 H NMR (300 MHz, DMSO, δ):
10.17 (s, 1H), 9.32 (s, 1H), 8.99 (s, 1H), 8.41 (br s, 1H), 8.16 (s, 1H), 7.82 (s, 1H), 7.56-7.45 (m, 5H ), 7.35-7.22 (m, 2H), 4.92 (m, 1H), 4.57 (d, J = 5.4 Hz, 2H), 3.31 (m, 2H), 2.95 (m, 2H), 2.06 (m, 4H) 547.1

Preparation Example 2 Synthesis of 6-Amino Indazole (Compound 8-1) Having an Amide Substituent

<Reaction Scheme 2>

(2-1) Synthesis of Compound 10

Thionyl chloride (SOCl ₂ , 3 ml) was added to a 2-methyl-3-nitrobenzoic acid (2 g, 11.04 mmol) solution dissolved in methanol (20 ml), and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM, washed with water, dried over MgSO 4, concentrated under reduced pressure, purified by silica gel column chromatography (n-Hex / EtOAc = 4/1) to give compound 10 (1.91 g, 89% yield). Got it.

1 H NMR (300 MHz, CDCl 3); δ 8.00 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 3.94 (s, 3H), 2.63 (s, 3H) .

(2-2) Synthesis of Compound 11

10% Pd / C (catalyst amount) was added to a methanol (16ml) solution of compound 10 (1.8 g), followed by stirring under room temperature hydrogen (1 atm) for 4 hours, filtered through Celite, and distilled under reduced pressure to remove the solvent, and flash silica gel. Purified by column chromatography to give the compound 11 (1.44g, 95% yield). LCMS (M + 1; 166).

(2-3) Synthesis of Compound 12

Compound 11 (1.15 g, 6.96 mmol) was dissolved in concentrated sulfuric acid (7 ml), cooled to 0 ° C. and slowly added fuming nitric acid (0.32 ml, 7.66 mmol) while maintaining the temperature of the reaction not exceeding 20 ° C. Added dropwise. The reaction was stirred at 10-20 ° C. for 90 minutes, poured into ice water and extracted with EtOAc. The organic layer was washed twice with water, dried over Na ₂ SO ₄ , distilled under reduced pressure to remove the solvent, and the resulting solid was washed with cold EtOAc to give compound 12 (1.03 g, yield 70.5%) as an orange solid.

1 H NMR (300 MHz, CDCl 3); δ 8.84 (s, 1H), 8.68 (s, 1H), 4.01 (s, 3H), 2.75 (s, 3H).

(2-4) Synthesis of Compound 13

A solution of sodium nitrite (NaNO 2, 214 mg, 3.1 mmol) in water (2 ml) was added dropwise to a mixture of compound 12 and glacial acetic acid (16 ml) cooled to 0 ° C., followed by stirring for 1 hour. . The reaction mass was raised to room temperature, distilled under reduced pressure to remove the solvent, and the remaining solid was triturated with water and stirred for 15 minutes while being cooled to 0 ° C. The resulting solid was filtered and washed with water to give compound 13 (469 mg, yield 72%) as a light orange solid.

1 H NMR (300 MHz, DMSO-d 6); δ 14.01 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 3.98 (s, 3H).

(2-5) Synthesis of Compound 14

Compound 13 (560 mg, 2.53 mmol) was dissolved in THF (6 ml) and 3N aq. NaOH solution (4 ml) was added and stirred at 60-70 ° C. for 2 hours. The reaction was cooled to rt, acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with water, dried over MgSO _4, and then solvent was removed by distillation under reduced pressure to obtain compound 14 (470 mg, yield 90%). LCMS (M + 1; 208).

(2-6) Synthesis of Compound 15

Compound 14 (1 equiv), TBTU (1.5 equiv), amine (R1NH2, 1 equiv) and Et3N (2 equiv) were added to DMF, stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure, EtOAc and water were added and mixed. Then separated. The organic layer was dried over MgSO ₄ , distilled under reduced pressure, concentrated, and purified by flash silica gel column chromatography to obtain compound 15.

R 1 is methyl, ethyl, propyl, phenyl, benzyl, 4-chloro benzyl, 2,3-dichlorobenzyl, 2,5-dichlorobenzyl, 2-chloro-5-fluorobenzyl, phenethyl, isopropyl, tert- Butyl, isobutyl, n-butyl, cyclopropyl. Cyclopentyl, cyclohexyl, sec-butyl, dimethylaminoethyl, 1-ethylpropyl, 2-methoxyethyl, cyclopropylmethyl, 2-morpholin-4ylethyl, indan-2yl, 2,2,2- Compound 15 was synthesized by reaction with amines with trifluoroethyl, methoxycarbonylmethyl, and 1 (R) -methoxy carbonyl ethyl substituent, and each compound identified M + 1 by LCMS.

(2-7) Synthesis of Compound 8-1

Compound 15 (1 equiv) was added to EtOH-H2O (4: 1, 1/15 mmol / ml), iron (10 equiv) and ammonium chloride (0.5 equiv) were added, and the reaction was heated to reflux for 0.5 to 1 hour. After the reaction was cooled to room temperature, the insoluble solid was filtered through Celite, washed with ethanol and EtOAc, and the filtrate was concentrated under reduced pressure. Diluted with EtOAc, washed with water, dried over MgSO4, concentrated by distillation under reduced pressure, and purified by flash column chromatography to obtain compound 8-1. Each compound identified M + 1 by LCMS.

Preparation Example 3 Synthesis of 6-amino indazole (Compound 8-2) with Alkoxy Substituents

<Reaction Scheme 3>

(3-1) Synthesis of Compound 17

Methanol, in the compound 16 (300 ml) (TNT, 40g, 264 mmol), FeCl 3 -6H 2 O (1.28g, 4.73 mmol) and hydrazine hydrate activated carbon in methanol (100 ml) to a mixture of (21g) (33.3 ml, 667 mmol) solution 5-10 Slow dropwise addition at 3 ° C. was performed. 15 reactants After stirring for 2.5 hours at ℃ 20-22 The mixture was further stirred for 5 hours. Gradually increase the reaction temperature to 1.5 hours After raising to ℃ and stirred for 1 hour. The hot reaction was filtered through celite and washed three times with hot methanol (200 ml). The combined filtrates were distilled under reduced pressure, concentrated to about 100 ml, and the same amount of water at about 60 ℃ was added while heating to reflux, and then slowly cooled to room temperature. The resulting solid precipitate was filtered and dried in vacuo to give compound 17. The filtrate was concentrated by distillation under reduced pressure and the resulting solid precipitate was filtered and dried to add to the preceding product to give compound 17 (7.37 g, yield 25%) as a red solid.

¹ H NMR (400 MHz, d-DMSO): δ 6.79 (2H, s, ArH); 5.22 (4 H, s, 2 NH ₂ ); _{1.86 (3H, s, CH 3} ).

(3-2) Synthesis of Compound 18

Compound 17 (7.20 g, 43 mmol) and phthalic anhydride (6.38 g, 43 mmol) were added to acetic acid (350 ml), heated to reflux for 4 hours, and cooled to room temperature. The resulting white solid was filtered to give compound 19 (12.30 g). , Yield 96.1%).

(1H, s, ArH), 7.59 (1H, s, ArH), 7.53 (1H, s, ArH). LCMS: 298.2 ([M + H] ⁺ , , 5.88 (2H, s, NH 2), 1.91 (3H, s, CH 3).

(3-3) Synthesis of Compound 19

Compound 18 (12.3 g, 41.4 mmol) and sodium nitrite NaNO ₂ (8.57 g, 124.2 mmol) were added to acetic acid (300 ml) / water (10 ml) and stirred at room temperature for 2 hours, and then the resulting solid was filtered and filtered with water. Washed and dried to synthesize Compound 19 (11.9 g, 93% yield).

LC-MS: 309.2 ([M + H] &lt; ⁺ &gt; 1 H NMR (400 MHz, d-DMSO): δ 8.57 (1H, s, ArH), 8.29 (1H, s, ArH), 8.10 (1H, d, ArH), 8.04 (2H, m, ArH), 7.96 ( 2H, m, ArH).

(3-4) Synthesis of Compound 20

Compound 19 (23 g, 74.6 mmol) and hydrazine hydrate (15 ml) were dissolved in ethanol (800 ml), heated to reflux for 3.5 hours under argon, and stirred at room temperature for 18 hours. The mixture was filtered, washed with water and brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure to synthesize compound 20 (13 g, yield 98%) as a red solid.

(3-5) Synthesis of Compound 21

Compound 20 was added to a hot aqueous sulfuric acid solution (0.3 M, 50 ml), cooled to 5 ° C., and an aqueous solution of sodium nitrite (NaNO ₂ , 5.8 g, 84.6 mmol) dissolved in water (50 ml) was added thereto. The reaction was stirred at 0 ° C. for 5 minutes and then urea (0.01 M, 50 ml) was added while maintaining 5 ° C. or less. In another reactor Na ₂ SO ₄ (17 g, 63.45 mmol) and H ₂ SO ₄ (10 ml) were dissolved in water (10 ml), heated to 135 ° C. and the preceding reaction was added. The reaction was stirred at 105 ° C. for 4 hours, washed with water and brine, dried over Na ₂ SO ₄ and the solvent was removed to give compound 21 (yield 66.7%) as a red liquid.

LCMS: 180 ([M + H] ⁺ , 1 H NMR (400 MHz, d-DMSO): 13.6 (1H, s, NH), 11.1 (1H, s, OH), 8.2 (1H, s, ArH), 7.8 (1H, s, ArH), 7.1 (1H, s, ArH).

(3-6) Synthesis of Compound 22

Compound 21 (500 mg, 2.8 mmol) was dissolved in DCM (16 ml) / DMF (2 ml) and di tert-butyl dicarbonate (560 mg, 2.8 mmol) was added and DMAP (340 mg, 2.8 mmol) was added. After stirring for 5 hours at room temperature, the solvent was removed by distillation under reduced pressure, dissolved in EtOAc, washed with 1 M citric acid, brine, sat. NaHCO 3 and brine in that order, dried over MgSO 4, and the solvent was removed by distillation under reduced pressure to obtain Compound 22 (yield 50). %) Was obtained. LCMS (M + 1; 280)

(3-7) Synthesis of Compound 23

(a) reaction with alkyl halides (R 2 = CH 3); 4-methoxy-6-nitroindazole-1-carboxylic acid-tert-butylester

MeI (54 mg, 0.375 mmol) was added to a solution containing Compound 22 (100 mg, 0.358 mmol) and Cs 2 CO 3 (140 mg, 0.429 mmol) in DMF (5 ml), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with water, dried over MgSO 4, concentrated under reduced pressure, purified by silica gel column chromatography (nHex / EtOAc = 2/1), and the compound 4-methoxy-6-nitroindazole-1. -Carboxylic acid-tert-butyl ester (94 mg, 90% yield) was obtained.

(b) Mitsunobu reaction with alcohol (R 2 = (CH 2) 2 CH (CH 3) 2): 4- (3-methylbutoxy) -6-nitroindazole-1-carboxylic acid-tert-butylester

Compound 22 (100 mg, 0.358 mmol) and PPh 3 (141 mg, 0.537 mmol) were added to anhydrous THF (5 ml), and 3-methyl butanol and DIAD (108 mg) were added slowly, followed by stirring at room temperature for 2 hours. The reaction was distilled under reduced pressure, concentrated, diluted with EtOAc, washed with water and dried over MgSO 4. Concentrated by distillation under reduced pressure, purified by silica gel column chromatography (nHex / EtOAc = 4/1) to give compound 4- (3-methylbutoxy) -6-nitroindazole-1-carboxylic acid-tert-butyl ester (90 mg, yield). 72%). LCMS (M + 1; 350)

(3-8) Synthesis of Compound 8-2

Compound 23 (0.317 mmol) was dissolved in methanol (5 ml), 10% Pd / C (50% wet) was added, stirred under hydrogen (1 atm) for 1 hour, filtered through Celite, and the solvent was removed by distillation under reduced pressure. Compound 8-2 was synthesized and used in the next reaction without further purification.

R 2 = CH 3; LCMS (M + 1; 264)

R 2 = (CH 2) 2 CH (CH 3) 2; LCMS (M + 1; 320)

Preparation Example 4 Synthesis of 6-amino indazole (Compound 8-3) with Carbamoyl Substituent

<Reaction Scheme 4>

(4-1) Synthesis of Compound 24

R3 = CH2Ph

Compound 20 (80 mg, 0.449 mmol), phenylacetic acid (61 mg, 0.449 mmol) and TBTU (210 mg, 0.673 mmol) were added to anhydrous DMF (6 ml), and Et3N (0.093 ml, 0.673 mmol) was added, followed by reaction. The mixture was stirred at room temperature for 3 hours, concentrated under reduced pressure, diluted with EtOAc, washed with water, dried over MgSO 4, and distilled under reduced pressure to remove the solvent. The obtained solid was washed with methanol and dried in vacuo to yield compound 28 (100 mg, yield 76%) as a light yellow solid.

1 H NMR (300 MHz, DMSO-d 6); 8.67 (s, 1H), 7.35-7.26 (m, 5H), 6.87 (s, 2H), 4.51 (s, 2H).

(4-2) Synthesis of Compound 25

R3 = CH2Ph

Compound 24 (100mg, 0.337 mmol) was dissolved in methanol (4 ml), 10% Pd / C (50% wet) was added, stirred for 1 hour under hydrogen (1 atmosphere), filtered through Celite, and then the solvent was evaporated under reduced pressure. Compound 8-2 was synthesized by removal of and used for the next reaction without further purification. LCMS (M + 1; 267)

Preparation Example 5 Synthesis of 6-amino indazole (Compound 8-4) with a hydroxymethyl Substituent

<Reaction Scheme 5>

(5-1) Synthesis of Compound 25

Compound 13 (6.0 g, 27.7 mmol) was added to MeOH / THF = 1/1 (160 ml), and 10% Pd / C (1 g) was added, followed by stirring at room temperature under hydrogen (1 atm) for 18 hours. The reaction was filtered through celite, distilled under reduced pressure, concentrated, and then purified by silica gel column chromatography (DCM / MeOH = 10/1) to give compound 25 (5.221 g, 83%).

(5-2) Synthesis of Compound 8-4

Compound 25 (2.0 g, 10.5 mmol) was added to THF (80 ml), LiAlH ₄ (1.2 g, 31.4 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The reaction was poured into water (20 ml) and 3N NaOH (15 ml) was added and filtered. The filtrate was concentrated and the resulting solid was purified by silica gel column chromatography to synthesize compound 8-4 (0.80 g, yield 47%) as a yellow solid.

LC-MS: 164.3 [M + H] ⁺

1 HNMR (400 Hz DMSO): δ 12.22 (1 H, s, NH); 7.77 (1 H, s, CH); 6.48 (1H, s, ArH); 6.36 (1H, s, ArH); 5.18 (2H, s, NH ₂ ); 5.15 (1H, t, OH); 4.64 (2H, d, CH ₂ ).

Preparation Example 6 Synthesis of 6-amino indazole (Compound 8-5) with Oxadiazole Substitute

<Reaction Scheme 6>

(6-1) Synthesis of Compound 26

Compound 13 (300 mg, 1.34 mmol) was added to n-BuOH (8 ml) and hydrazine hydrate (270 mg, 5.36 mmol) was added, followed by stirring at 110 ° C. for 3 hours. The reaction was diluted with EtOAc, washed with brine, dried over MgSO 4, concentrated by distillation under reduced pressure, and the resulting solid was washed with methanol and dried in vacuo to give compound 26 (200 mg, yield 67%).

(6-2) Synthesis of Compound 27

Compound 26 (200 mg, 0.90 mmol) was added to 1,4-dioxane (4 ml), triethylorthoacetate (0.5 ml) was added, followed by stirring at 110 ° C. for 15 hours. The reaction was diluted with EtOAc, washed with brine, dried over MgSO 4, concentrated under reduced pressure, and purified by silica gel column chromatography (nHex / EtOAc = 4/1) to give compound 27 (176 mg, yield 79%).

(6-3) Synthesis of Compound 8-5

Compound 27 (100mg, 0.408 mmol) was dissolved in methanol (4 ml), 10% Pd / C (50% wet) was added, stirred for 1 hour under hydrogen (1 atmosphere), filtered through Celite, and then the solvent was evaporated under reduced pressure. Compound 8-5 was synthesized by removal of and used for the next reaction without further purification.

Preparation Example 7 Synthesis of 6-amino indazole (Compound 8-6) with Halogen Substituents

<Reaction Scheme 7>

(7-1) Synthesis of Compound 28

X = Cl

Compound 20 (100 mg, 0.57 mmol) was added to 3N HCl (6 ml), NaNO ₂ (42 mg, 0.6 mmol) and CuCl (64 mg, 0.6 mmol) were added, followed by stirring at room temperature for 6 hours. The reaction was diluted with EtOAc, washed with brine, dried over MgSO 4, concentrated by distillation under reduced pressure, and purified by silica gel column chromatography (nHex / EtOAc = 4/1) to synthesize compound 28 (79 mg, yield 70%).

(7-2) Synthesis of Compound 8-6

Compound 28 (79 mg, 0.39 mmol) and iron (111 mg, 1.99 mmol) were added to ethanol (6 ml) and NH 4 Cl aqueous solution (0.1 ml) was added thereto. The reaction was stirred at 80 ° C. for 1 h, filtered through Celite and concentrated by distillation under reduced pressure. Diluted with EtOAc, washed with brine, dried over MgSO 4, removed the solvent by distillation under reduced pressure, and then obtained compound 8-6 (X = Cl) which was used in the next reaction without further purification.

Experimental Example 1 Measurement of Inhibitory Activity of Extracellular Signal Control Kinase (ERK-1 / ERK-2)

Extracellular signal-regulated kinade inhibitory activity of the prepared compounds was determined by Koresawa, M. and Okaba, T. (2004) High-throughput screening with quantitation of ATP concentration: A universal non-radioactove, homogenous assay for protien kinases. Assay Drug Dev. Technol. It measured according to the description in 2, 153-60.

Each compound of Synthesis Examples 101 to 144 obtained in Preparation Examples 1 and 2 was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 12.5 mM to prepare a sample compound. The enzymatic reaction was performed with 20 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid, pH 7.4), 5 mM MgCl ₂ , 0.5 mM ethylene glycol tetraacetic acid (EGTA), 200 mM KCl, 0.05% TritonX-100 and 1 It was performed in buffer containing mM DTT (dithiothreitol). After adding 0.33 mg / ml MBP (Maltose Binding Protein) (Upstate) and 1 μM of ATP to the buffer, ERK-1 activity was evaluated by 20 nM of recombinant ERK-1 enzyme (M84490) and ERK-2 activity. 50 nM of recombinant ERK-2 enzyme (M84489) was added thereto and reacted at 30 ° C. for 1 hour. By adding 25 µl of Kinase glo (promega) to 25 µl of the reaction solution, a reaction by Luciferase, which is the second reaction, was carried out to react with ERK-1 or ERK-2, and the amount of ATP remaining was changed to Fusion a-FP (Packard). It measured using. The enzyme inhibitory ability was evaluated by adding a solution prepared by dissolving the sample compound in dimethyl sulfoxide (DMSO) to within 5% of the total reaction solution. In addition, the enzyme inhibitory ability was expressed as a percentage of the measured value in the presence of the sample compound to the measured value in the absence of the test compound, and the concentration of the compound that inhibited 50% enzymatic activity was determined as an IC ₅₀ (μM) value.

As a result of measuring the inhibitory activity of the derivative of Formula 1 according to the present invention in ERK1 and ERK2, the inhibitory activity against ERK2 (IC ₅₀ ) is 2 μM or less in all compounds corresponding to Formula 1, Synthesis Examples 103, 105, 106 0.2 to 1 μM or less for compounds of 109, 111, 112, 113, and 116, 0.1 to 0.2 μM for compounds of Synthesis Examples 104, 108, 110, 117, 118, 119, 124, 125, 127, and 129, Synthesis Examples 102, 107, 115, 120, 121, 122, 123, 126, 128 and 130-142 were found to be 0.1 μM or less.

Comparative Example

The IC ₅₀ value of the compound of formula 2 having a structure similar to that of formula 1 of the present invention, but having a cyclohexyl substituent on the 2-amino quinazoline parent, but not a piperidine substituent, and a compound of formula 3 having a pyridine substituent instead of indazole is obtained It was compared with the compound of.

Comparative Compound 2 (Synthesis Example 143) is a reaction of Compound 5 with cyclohexanol instead of N-Boc-4-hydroxypiperidine in Scheme 1, and Formula 3 (Synthesis Example 144) is a compound 6 and an indazole derivative. Instead, it could be obtained by reaction of 4-amino pyridine.

Synthetic example Compound name 1H NMR LC / MS 143 (Comparative Example) (8-cyclohexyloxy-quinazolin-2-yl)-(1H-indazol-6-yl) -amine 1 H NMR (300 MHz, CD3OD, δ):
9.15 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.55 (dd, J = 8.7, 1.8 Hz, 1H), 7.45 (dd, J = 7.8, 1.8 Hz, 1H), 7.34 -7.28 (m, 2H), 4.63 (m, 1H), 2.07-2.05 (m, 2H), 1.78-1.72 (m, 2H), 1.58 (m, 1H), 1.48-1.35 (m, 4H) 360.2 144 (comparative) [8- (piperidin-4-yloxy) -quinazolin-2-yl] -pyridin-4-yl-amine 1 H NMR (300 MHz, DMSO, δ):
9.65 (s, 1H), 9.43 (d, J = 7.5Hz, 2H), 7.85-7.82 (m, 1H), 7.77-7.68 (m, 2H), 7.08 (d, J = 7.5Hz, 2H), 5.07 (m, 1H), 3.62-3.54 (m, 2H), 3.31-3.27 (m, 2H), 2.33-2.21 (m, 4H) 322.1

Specifically, IC ₅₀ values were measured using the compounds of Synthesis Example 143 and Synthesis Example 144 in Table 5 below in the same manner as in Experiment 1, and the results were obtained from the compounds of Synthesis Example 101 of the present invention. Together is shown in Table 5 below.

Comparison of ERK Inhibitory Activity According to Compound Structure Synthetic example
rescue
IC50 (μM) ERK1 ERK2


101

0.12


0.11


143 (Comparative Example)

> 10


> 10


144 (comparative)

> 50


> 50

As confirmed in Table 5 above, compounds 143 and 144 have piperidine and indazole-free compounds in 2-amino quinazoline nucleus, even at 10 μM or 50 μM, despite having similar diatoms as the formula of the present invention. ERK inhibitory activity (IC ₅₀ ) was not shown. On the other hand, Synthesis Example 101, which is a corresponding compound having the structure of Formula 1 of the present invention, shows an ERK inhibitory effect. These results indicate that the piperidine oxy substituent and the indazole substituent located in the 2-amino quinazoline parental nucleus in the general formula (1) of the present invention play an important role in the inhibition of kinase activity. It can be seen that not only is novel to the existing 2-amino quinazoline derivative of similar structure, but also has significant kinase inhibitory activity.

In addition, ERK inhibition of FR18204 compound of Astellas Pharma, known as selective ERK inhibitor, showed excellent ERK inhibitory activity in the compounds of 102, 107, 115, 120, 121, 122, 123, 126, 128, and 130 to 142 of less than 0.1 μM. Compared to the activity (IC ₅₀ , ERK1 = 0.37 μM, ERK2 = 0.51 μM), excellent ERK inhibitory activity can be confirmed.

Experimental Example 2: MTS Essay

In order to confirm that the compound prepared in Preparation Example 1 has a cancer cell proliferation inhibitory effect through the inhibition of extracellular signal-regulated kinase activity, Synthesis Examples 101, 102, 104, 107, 108, 109, 110, 111, 113, 115 MTS assay was performed on compounds of 120, 123, 126, 128, 130, 135, and 138-142 (Barltrop, JA et al (1991) 5- (3-carboxymethoxyphenyl) -2- (4,5-dimethylthiazoly). ) -3- (4-sulfophenyl) tetrazolium, inner salt (MTS) and related analog of 3- (4,5-dimethylthiazolyl) -2,5, -diphenyltetrazolium bromide (MTT) reducing to purple water soluble formazans as cell-viability Bioorg.Med. Chem. Lett. 1 , 611-4; Cory, AH et al (1991) Use of an aqueous soluble tertrazolium / formazan assay for cell growth assays in culture.Cancer Comm . 3 , 207-12.)

The following analysis was performed on COLO-205 (ATCC), a human colon cell line.

COLO-205 cells were seeded in 96 well plates containing RPMI1640 medium (GIBCO, invitrogen) containing 5% FBS at a concentration of 5000 cells / well, respectively, and then for 24 hours at 5% CO ₂ and 37 ° C. Incubated. Each well was then treated with compounds of the above synthesis examples at concentrations of 0.2, 1, 5, 25 and 100 μM, respectively, and treated with dimethyl sulfoxide (DMSO) at 0.08% by weight, the same as the percent used for compound treatment. . Each cell was then incubated for 48 hours.

To determine the viability of the cells, MTS (3- (4,5-dimethylthiazol-2-yl) -5 provided in CellTiter 96 AQ _ueous Non-Radioactive Cell Proliferation Assay Kit (Promega) was added to the cultured cells. 20 ul of a mixture of-(3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt) and PMS (phenazine methosulfate) was added and incubated for 1 hour at 37 ℃. The absorbance was then measured at 490 nm. The degree of inhibition of cell proliferation according to the treatment concentration of each compound was calculated based on the absorbance of the control cells not treated with the compound, and the concentration of each compound that inhibits the proliferation of cancer cells by 50% was calculated as an EC 50 (μM) value.

Results of Inhibition of Cancer Cell Proliferation Tests for Compounds of the Present Invention Synthesis Example 50 It showed a very good cancer cell proliferation inhibitory effect of 2 ~ 5 μM.

Claims (9)

A compound of Formula 1 and a pharmaceutically acceptable salt, hydrate, solvate, or optical isomer thereof.
&Lt; Formula 1 >

Wherein R is hydrogen or substituted or unsubstituted C ₁ to C ₃₀ alkyl, substituted or unsubstituted C ₁ to C ₃₀ alkenyl, substituted or unsubstituted C ₁ to C ₃₀ alkynyl, substituted or unsubstituted Substituted or unsubstituted C ₁ to C ₃₀ cycloalkyl, substituted or unsubstituted C ₅ to C ₃₀ aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted arylalkenyl, substituted or unsubstituted aryl Alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or Unsubstituted heteroarylalkenyl, substituted or unsubstituted heteroarylalkynyl, carboxylic acid, ester, amide, substituted or unsubstituted C ₁ to C ₃₀ alkylamide, hydroxy, halogen, cyano, substituted or unsubstituted Substituted C ₁ to C ₃₀ hydroxyalkyl, substituted or unsubstituted Substituted C ₁ to C ₃₀ alkoxy, amino, substituted or unsubstituted C ₁ to C ₃₀ alkylamino, substituted or unsubstituted phenylamino, substituted or unsubstituted carbamoyl, substituted or unsubstituted oxadiazole and substituted or One of the unsubstituted carbamates,
The substitution may include one or more hydrogens with halogen such as fluorine, chlorine, bromine and iodine; Hydroxy; Nitro; Cyano; Oxo (═O); Thioxo (= S); Azido; Nitroso; Amino; Hydrazino; Formyl; Alkyl; Alkoxy; Aryl; Haloalkyl groups such as trifluoromethyl, tribromomethyl, trichloromethyl and the like; Haloalkoxy such as -OCH ₂ Cl, -OCHF ₂ , -OCF ₃ , and the like; Arylalkoxy such as benzyloxy, phenylethoxy and the like; Cycloalkyl; -O-cycloalkyl; Heterocyclyl; Heteroaryl; Alkylamino; -0-CH ₂ -cycloalkyl; -COOR ^a ; -C (0) R ^b ; -C (O) NR ^a R ^b ; -NR ^a C (0) NR ^b R ^c ; -NR ^a C (O) OR ^b ; -NR ^a R ^b ; -NR ^a C (O) R ^b ; -0R ^a ; -0R ^a C (0) 0R ^b ; -C (0) NR ^a R ^b ; -OC (O) R ^a ; -R ^a NR ^b R ^c ; -R as ^a change in 0R ^b, R ^a, R ^b and R ^c are each independently a hydrogen atom; Alkyl; Alkylene; Aryl; Arylalkyl; Cycloalkyl; Heterocyclyl; And a group selected from heteroaryl and heteroarylalkyl, wherein R ^a , R ^b and R ^c are rings of 3 to 7 carbon atoms having 0 to 2 heteroatoms. The compound of claim 1, wherein, when an alkoxy group is present, the alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or t-butoxy; When halogen is present, the halogen is fluorine, chlorine, bromine or iodine; Alkyl Group When present, the alkyl group is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl or substituted thereof; If an alkenyl group is present, the alkenyl group is ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-l-propenyl, 1-butenyl or 2-butenyl ; When an alkynyl group is present, said alkynyl group is ethynyl, propynyl or butynyl; When a cycloalkyl group is present, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cycloheptyl, perhydronaphthyl, adamantyl, crosslinked cyclic groups or spirobicyclic Spirobicyclic groups; Where a heterocycloalkyl or heteroaryl group is present, the heterocycloalkyl or heteroaryl group may be azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cynolinyl, dioxane Solanyl, pyridyl, putridinyl, furinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolinyl, pyrrolyl, piperonyl , Pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, oxazolinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, decahydroisoquinolyl, benzimidazolyl, indazolyl , Phenylpiperidinyl, furyl, tetrahydrofuryl, tetrahydropyranyl, piperazinyl, homopiperazinyl, piperidyl, piperidopiperidyl, morpholinyl, thiomorpholinyl, piperidonyl, 2 Oxopyrerazinyl, 2-oxopiperidinyl, pyrrolidi , 2-oxopyrrolidin pyridinyl, oxazolyl selected from pyridinyl Jolly heterocyclyl group; When an aryl group is present, the aryl group is phenyl, naphthyl, anthracenyl, indanyl or biphenyl; When a hydroxyalkyl group is present, the hydroxyalkyl group is hydroxymethyl or hydroxyethyl; If an amide group is present, the amide group may be substituted or unsubstituted C ₁ to C ₃₀ alkylamide, substituted or unsubstituted C ₁ to C ₃₀ benzylamide, substituted or unsubstituted C ₁ to C ₃₀ halobenzylamide, substituted Or unsubstituted C ₁ to C ₃₀ phenylamide, or substituted or unsubstituted C ₁ to C ₃₀ phenylalkylamide, wherein at least one hydrogen atom of the phenyl group is silver alkyl, cycloalkyl, alkoxy, cyano, halogen, May be independently and optionally substituted by one or more of alkylsulfonyl, alkylthio, -CO ₂ alkyl, -COOH, -CONH ₂ , -CHO, -CH ₂ OH, hydroxyl, haloalkyl, amino, nitro; If a heterocyclylalkyl group is present, the heterocyclylalkyl group is selected from oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, morpholinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morphonyl Become; When a heteroarylalkenyl group is present, said heteroarylalkenyl group is pyridinylethenyl, thienylethenyl or triazolylethenyl; And when a heteroarylalkynyl group is present, the heteroarylalkynyl group is pyridinylethynyl or thienylethynyl and pharmaceutically acceptable salts, hydrates, solvates, or optical isomers thereof. The compound of claim 1, wherein R is hydrogen, substituted or unsubstituted carboxylic acid methyl ester, substituted or unsubstituted carboxylic acid, substituted or unsubstituted hydroxy methyl, substituted or unsubstituted amino, substituted or unsubstituted N, N-dimethylamide, substituted or unsubstituted methylamide, substituted or unsubstituted benzylamide, chloro, substituted or unsubstituted 4-chlorobenzylamide, substituted or unsubstituted phenylamide, substituted or unsubstituted phenyl pen Ethylamide, fluoro, substituted or unsubstituted benzylcarbamoyl, substituted or unsubstituted isopropylamide, substituted or unsubstituted 3-methylbutoxy, substituted or unsubstituted methoxy, substituted or unsubstituted 5- Methyl- [1,3,4] oxadiazol-2-yl, substituted or unsubstituted tert-butylamide, substituted or unsubstituted sec-butylamide, substituted or unsubstituted cyclopentylamide, substituted or Unsubstituted butylamide, substituted or unsubstituted (2-dimethylaminoethyl) -amide, substituted or unsubstituted cyclopropylamide, substituted or unsubstituted cyclohexylamide, substituted or unsubstituted (2-methoxy Ethyl) -amide, substituted or unsubstituted (1-ethylpropyl) -amide, substituted or unsubstituted isobutylamide, substituted or unsubstituted propylamide, substituted or unsubstituted ethylamide, substituted or unsubstituted cyclo Propylmethylamide, substituted or unsubstituted (2-morpholin-4-ylethyl) -amide, substituted or unsubstituted (3-methylbutyl) -amide, substituted or unsubstituted indan-2-ylamide, substituted Or unsubstituted (2,2,2-trifluoroethyl) -amide, substituted or unsubstituted methoxycarbonyl methylamide, substituted or unsubstituted 1 (R) -methoxycarbonyl ethylamide, substituted or Unsubstituted 2-chloro Zylamide, substituted or unsubstituted 3-chlorobenzylamide, substituted or unsubstituted 2,3-dichlorobenzylamide, substituted or unsubstituted 2,5-dichlorobenzylamide, and substituted or unsubstituted 2- A compound and a pharmaceutically acceptable salt, hydrate, solvate, or optical isomer thereof, which is any one selected from the group consisting of chloro-4-fluorobenzylamide. According to claim 1, wherein R is hydrogen, amine, chlorine, fluorine or any one selected from the group consisting of the following formula and a pharmaceutically acceptable salt, hydrate, solvate, or optical isomer thereof, Where the symbol * denotes the point of attachment of R to the remainder of Formula 1:

. The compound of claim 1, wherein the compound is (1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine, 6- [8- ( Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid methyl ester, 6- [8- (piperidin-4-yloxy) -quinazolin-2 -Ylamino] -1H-indazol-4-carboxylic acid, {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl}- Methanol, N * 6 *-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -1H-indazol-4,6-diamine, 6- [8- (piperidine 4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid dimethylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-yl Amino] -1H-indazol-4-carboxylic acid methylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid benzylamide, (4-Chloro-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine, 6- [8- (piperidin-4 -Yloxy) -quinazolin-2-ylamino] -1 H-indazol-4- Carboxylic acid 4-chlorobenzylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid phenylamide, 6- [8- (pi Ferridin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid phenethylamide, (4-fluoro-1H-indazol-6-yl)-[8- (blood Ferridin-4-yloxy) -quinazolin-2-yl] -amine, 2-phenyl-N- {6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl} -acetamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid isopropylamide , [4- (3-Methylbutoxy) -1 H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine, (4-meth Oxy-1H-indazol-6-yl)-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine, [4- (5-methyl- [1,3,4 ] Oxadiazol-2-yl) -1H-indazol-6-yl]-[8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine, 6- [8- ( Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid te rt-butylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid sec-butylamide, 6- [8- (pi Ferridin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid cyclopentylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2 -Ylamino] -1H-indazol-4-carboxylic acid butylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid ( 2-dimethylaminoethyl) -amide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclopropylamide, 6- [ 8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclohexylamide, 6- [8- (piperidin-4-yloxy)- Quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (2-methoxyethyl) -amide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino ] -1H-indazol-4-carboxylic acid (1-ethylpropyl) -amide, 6- [8- ( Ferridin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid isobutylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2 -Ylamino] -1H-indazol-4-carboxylic acid propylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid ethyl Amide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid cyclopropylmethylamide, 6- [8- (piperidine- 4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid (2-morpholin-4-ylethyl) -amide, 6- [8- (piperidin-4-yljade C) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid (3-methylbutyl) -amide, 6- [8- (piperidin-4-yloxy) -quinazolin-2- Monoamino] -1H-indazol-4-carboxylic acid indan-2-ylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4 -Carboxylic acid (2,2,2-trifluoroethyl) -amide, ({6- [8- (piperidin-4-yloxy) -quine Zolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -acetic acid methylester, 2 (R)-({6- [8- (piperidin-4-yloxy) -quina Zolin-2-ylamino] -1H-indazol-4-carbonyl} -amino) -propionic acid methylester, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid 2-chlorobenzylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid 3- Chlorobenzylamide, 6- [8- (piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazole-4-carboxylic acid 2,3-dichlorobenzylamide, 6- [8 -(Piperidin-4-yloxy) -quinazolin-2-ylamino] -1 H-indazol-4-carboxylic acid 2,5-dichlorobenzylamide, and 6- [8- (piperidine-4 -Yloxy) -quinazolin-2-ylamino] -1H-indazol-4-carboxylic acid 2-chloro-4-fluorobenzylamide and a pharmaceutically acceptable compound thereof Salts, hydrates, Solvates, or optical isomers. A pharmaceutical composition for preventing and / or treating cancer comprising the compound of any one of claims 1 to 5, a pharmaceutically acceptable salt, hydrate, solvate, or optical isomer thereof as an active ingredient. The pharmaceutical composition for preventing and / or treating cancer of claim 6, wherein the cancer is a cancer caused by signal kinase activity. The method of claim 6, wherein the cancer is lung cancer, pancreatic cancer, colon cancer (eg colorectal cancer), myeloid leukemia, thyroid cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, Head and neck cancer, ovarian cancer, brain cancer, cancer of mesenchymal origin, sarcoma, teratoma, neuroblastoma, kidney carcinoma, liver cancer, non-Hodgkin's lymphoma, multiple myeloma, and thyroid undifferentiated cancer Pharmaceutical compositions for the prophylaxis and / or treatment of cancer. A method of treating cancer, comprising administering the pharmaceutical composition of claim 6 to a mammal other than a human in need thereof.