KR20140095325A - Aminoquinazoline derivatives having inhibitory activity on lyn kinase - Google Patents

Abstract

The present invention relates to a novel aminoquinazoline derivative and a use thereof. The aminoquinazoline derivative, represented by chemical formula 1, inhibits Lyn kinase, thus can be effectively used for preventing or treating Alzheimer′s disease induced by the activation of Lyn kinase.

Description

TECHNICAL FIELD [0001] The present invention relates to an aminoquinazoline derivative having inhibitory activity against Lyn kinase,

The present invention relates to an aminoquinazoline derivative having inhibitory activity against Lyn kinase or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating Alzheimer's disease comprising the same as an active ingredient.

Degenerative brain disease is a disease that occurs commonly in the world. It refers to a disease in which neurons in the brain are structurally or functionally dead or degenerated, impairing the function of the nervous system, and gradually develops over a long period of time . In addition, degenerative brain disease starts with either cognitive dysfunction such as motor dysfunction or memory depression and dementia, but as the disease progresses, the two dysfunctions become complex and deteriorate. The most common of these degenerative brain diseases is Alzheimer's disease.

Alzheimer's Disease (AD) is currently the fourth leading cause of death in adults and the elderly. More than 12.5% of the world's population is predicted to suffer from Alzheimer's disease. Alzheimer's disease is associated with an increase in the prevalence rate of more than 50% every 5 years with the increase in age, and the number of patients is increasing due to the prolonged life span (Suh G., 2006, Int . J. Ger . Psychi , 21 : 722).

In the brain of patients who die from Alzheimer's disease, senile plaques and neurofibrillary tangles are observed as pathological features, and senescent plaques are formed by accumulated proteins and dead cells outside the cells, main component is the amyloid-beta: the (amyloid-β or less "Aβ" hereinafter) of the peptide (Hardy, J. et al, Nature .. Neurosci ., 1: 355-358, 1998).

Aβ is known to be produced by amyloid precursor protein (hereinafter referred to as "APP") proteolytic cleavage by β-secretase and γ-secretase Craven, R., Nat Rev Neurosci, 2:..... 533, 2001; David, HS et al, Nat Rev. Neurosci ., 2: 595-598, 2001; Yankner, BA, Neuron , 16: 921-932, 1996; Selkoe, DJ, Nature , 399: A23-A31, 1999). Genetic evidence suggests that all Alzheimer's onset dementia genes promote the production of A [beta] peptides, particularly A [beta] 42 peptides, that such A [beta] peptides are chronically increased in the brain, damaging neurons and ultimately causing Alzheimer's disease have.

In this regard, the mainstream of Alzheimer's disease studies to date is focused on the development of substances that modulate the overproduction of A [beta] peptides, particularly A [beta] 42 peptides, or prevent the toxicity of the resulting A [beta] peptides, And protease activity, or complexes with proteases to target proteins involved in the production and degradation of A [beta] peptides.

However, the limitations and competitiveness of each target are emerging. One example is the development of active inhibitors of gamma, beta-secretase (Aβ-producing gamma, beta-secretase) (2008, Keystone AD meeting, Chicago ICAD meeting) In addition to APP, it cleaves a variety of physiologically important substrates, so inhibiting gamma-secretase may cause other side effects. In another example, the recent Selko group has shown that the oligomeric form of Aβ is involved in the toxicity and memory of Aβ in the human demented brain, resulting in the formation of β-sheet of Aβ (2008, Keystone AD meeting, Chicago ICAD meeting) and oligomerization blocker development in addition to the development of a therapeutic agent for inhibiting oligomerization. Since the intracellular protein has a? -Sheet structure, there is a problem in that there is a limit of selectivity to A ?. Another example is amyloid-beta binding alcohol dehydrogenase (ABAD), a gene that mediates mitochondrial dysfunction, one of the representative pathologies observed in Alzheimer's disease (Lustbader JW et al . , Science , 304 (5669): 448-452, 2004) is predicted to bind in the mitochondria with A [beta] entering the cell and regulate signaling or neurotoxicity of intracellular A [beta ] al . , FASEB J., 19: 597-598, 2005), toxic removal inhibitors using this have been developed (Yan SD et al. , Nature , 382: 685-691, 1996), yet the mechanism is unclear.

As a result of confirming apoptosis caused by A [beta] 42 by using AIMP (Amyloid-beta-interacting membrane protein) shRNA (short hairpin RNA) in B103 neurons, the inventors confirmed that apoptosis by A [beta] 42 is mediated by AIMP, AIMP expression was increased in hippocampus, cortex and AD hippocampal tissues of mice. In addition, A [beta] neuropathology was confirmed in AIMP knock-out mice and it was confirmed that memory was maintained (Gwon et < RTI ID = 0.0 > al . , Alzheimer's & Dementia: The Journal of the Alzheimer's Association , vol 8 (4): P940, 2012). These results indicate that AIMP can act as an important mediator involved in neuronal cell death.

Furthermore, LynK phosphorylates the AIMP to activate AIMP, thereby enabling down-signaling of AIMP. Thus, LynK may also be involved in neuronal cell death.

Based on the above findings, the inventors of the present invention confirmed that the novel aminoquinazoline derivatives can be used for the prevention or treatment of Alzheimer's disease by inhibiting Lyn kinase phosphorylating AIMP and completed the present invention.

It is therefore an object of the present invention to provide novel compounds which are capable of effectively inhibiting Lyn kinase.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating Alzheimer's disease comprising the above-mentioned compound as an active ingredient.

To this end, the present invention provides compounds selected from the group consisting of aminoquinazoline derivatives of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof:

(I)

Wherein R1, R2, R3, A, X, Y and Z are as defined herein.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating Alzheimer's disease comprising the compound as an active ingredient.

The novel aminoquinazoline derivatives of the present invention inhibit Lyn kinase, and thus may be useful for the prevention or treatment of Alzheimer's disease caused by activation of Lyn kinase.

Brief Description of the Drawings Fig. 1 is a graph showing the cytotoxic effect of Aβ-induced apoptosis according to the treatment of the compound of Example 9 (left) and the compound of Example 11 (right). In FIG. 1, the first bar (white) represents the positive control treated with DMSO + PBS in the HT22 cell line, the second bar (light gray) represents the negative control treated with 5 μM of the Aβ complex without DMSO and the third bar Black) represents another negative control treated with 5 [mu] M DMSO + A [beta] complex, and the fourth through sixth bars (dark gray) represent the concentration of 5 [mu] M of DMSO + A [beta] complex and the concentrations of the compounds of Examples 9 and 11 .
FIG. 2 is a graph showing the cytotoxic selectivity of the compounds of the present invention. After the compounds of Examples 9 and 11 were treated with etoposide for 24 hours, the number of viable cells was measured by a microscope And the cell death rate was calculated by comparing with the cell number before treating the compound. In the figure, PBS was used as a positive control, and DMSO was used as a negative control.

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

The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

The term " alkyl ", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon residues.

The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to cyclic alkyl including cyclopropyl and the like.

The term " aryl ", as used herein, unless otherwise indicated, refers to an aromatic group including phenyl, naphthyl, and the like.

The term " heterocycloalkyl ", as used herein, unless otherwise indicated, refers to monocyclic or bicyclic-like cyclic aliphatic groups containing at least one, for example one to four heteroatoms selected from O, . Examples of monoheterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar groups no.

The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic above aromatic group containing at least one, for example one to four, heteroatoms selected from O, N and S it means. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine Pyridazinyl, pyrimidinyl, pyrazinyl, and similar groups, but are not limited thereto. Examples of bicyclic heteroaryl include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso But are not limited to, quinolinyl, purine, furopyridinyl and similar groups.

The present invention provides compounds selected from the group consisting of aminoquinazoline derivatives of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof:

(I)

In this formula,

R 1 is selected from the group consisting of hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₇ alkenyl, C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, C ₃ -C ₁₂ cycloalkyl, 5-10 membered heterocycloalkyl Or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl;

Fig, sulfonyl, C ₁ -C ₅ alkyl, C ₂ -C ₇ alkenyl, C ₅ -C ₁₂ R2 and R3 are amino each independently hydrogen, halogen, hydroxy, amino, carboxyl, C ₁ -C ₅ alkyl aryl, heteroaryl of 5 to 13 won, C ₃ -C ₁₂ cycloalkyl or a 5- to 10-membered heterocycloalkyl, and the;

A is hydrogen, halogen, hydroxy, amino, carboxyl or C ₁ -C ₅ alkylamido;

X, Y and Z are each independently carbon or nitrogen;

Said alkyl, C ₂ -C ₇ alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, and C ₁ -C ₅ alkyl amido are each independently selected from halogen, hydroxy, amino, carboxyl, C ₁ -C ₅ alkyl amido, sulfonyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₅ -C ₁₂ aryl, 5 to 13 member heteroaryl, C ₃ -C ₁₂ cycloalkyl, 5-10 membered of Heterocycloalkyl or 5- to 10-membered heterocycloalkyl C ₁ -C ₅ alkyl.

In one embodiment of the invention, R 1 is C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl to be.

In another embodiment of the present invention, R 2 is hydrogen, halogen, C ₁ -C ₃ alkyl, cyano, carboxyl or acetamido.

In another embodiment of the present invention, R < 3 > is hydrogen or halogen.

In another embodiment of the present invention, A is hydrogen or 2-phenylacetamido.

In another embodiment of the present invention, X and Y are nitrogen and Z is carbon.

In a preferred embodiment of the present invention,

R 1 is C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl;

R2 is hydrogen, halogen, C ₁ -C ₃ alkyl, cyano, carboxyl, or an acetamido;

R3 is hydrogen or halogen;

A is hydrogen or 2-phenylacetamido;

X and Y are nitrogen, and Z is carbon.

In another preferred embodiment of the present invention,

R1 is benzimidazole, phenyl, piperidinylmethyl, pyrrolidine, pyridine or piperidine;

R2 is hydrogen, halogen, C ₁ -C ₃ alkyl, cyano, carboxyl, or an acetamido;

R3 is hydrogen or halogen;

A is hydrogen or 2-phenylacetamido;

X and Y are nitrogen, and Z is carbon.

Specific examples of the more preferable aminoquinazoline derivatives of the present invention are as follows, and pharmaceutically acceptable salts, isomers, hydrates or solvates thereof are also included in the scope of the present invention:

1) [8- (3H-Benzoimidazol-5-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;

2) [8- (3-Amino-phenoxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;

3) (lH-Indazol-6-yl) - [8- (piperidin-4-ylmethoxy) -quinazolin-2-yl] -amine;

4) (8- (4-Fluoro-1H-benzoimidazol-5-yloxy) -quinazolin-2-yl) - (1H-indazol-6-yl) -amine;

5) 3-Fluoro-4- [2- (lH-indazol-6-ylamino) -quinazolin-8-yloxy] -benzene-l, 2-diamine;

6) [5-Bromo-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;

7) [6-Bromo-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;

8) (lH-Indazol-6-yl) - [6-methyl-8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine;

9) 2-Phenyl-N- {6 - [(8-piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl} -acetamide;

10) [(6-Chloro-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;

11) (lH-Indazol-6-yl) - [8- (piperidin-4-yloxy) -6-propyl-quinazolin-2-yl] -amine;

12) (lH-Indazol-6-yl) - [8- (pyrrolidin-3-ylmethoxy) -quinazolin-2-yl] -amine;

13) 2- (lH-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-6-carbonitrile;

14) 2- (lH-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-6-carboxylic acid;

15) N- [2- (1H-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazolin-6-yl] -acetamide;

16) (lH-Indazol-6-yl) - [8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine; And

17) (lH-Indazol-6-yl) - [8- (pyridin-4-yloxy) -quinazolin-2-yl] -amine.

The aminoquinazoline derivatives according to the invention can also form pharmaceutically acceptable salts. Such a pharmaceutically acceptable salt is not particularly limited as long as it is an acid which forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion. For example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like; Organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid and maleic acid; Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like. Preferred examples of these include acid addition salts formed by sulfuric acid, methanesulfonic acid or hydrohalic acid.

The present invention also encompasses isomeric compounds of the aminoquinazoline derivatives of formula (I). May exist as an optical isomer, racemic compound, diastereomeric mixture, or individual diastereomer, including R or S isomers, as it may have an asymmetric carbon center, and all these stereoisomers and mixtures may be present in the ≪ / RTI >

In addition, solvates and hydrate forms of the aminoquinazoline derivatives of formula I are also included within the scope of the present invention.

Hereinafter, the production method of the present invention will be described in detail.

In the present invention, an aminoquinazoline derivative in which R2 and R3 are hydrogen can be prepared by the following Reaction Scheme 1.

[Reaction Scheme 1]

In Scheme 1, a commercially available 2-amino-3-methoxybenzoic acid ( 1 ) is condensed with urea to give a 2-hydroxyquinazoline compound ( 2 ), followed by substitution of the hydroxy group of the compound with chlorine To obtain the compound ( 3 ), the compound ( 3 ) is selectively dechlorinated to remove the chlorine at the 4-position to obtain the compound ( 4 ), and then the compound ( 5 ) is synthesized using boron tribromide. Thereafter, the compound ( 5 ) is reacted with R1-OH to give a compound ( 6 ), which is then subjected to a substitution reaction with an amine compound ( 8 ) to synthesize the compound ( 9 ). Alternatively, after the introduction of the amine compound (8) to the compound (5) Synthesis of the compound (7), by this, R1-Br with Cu- coupling reaction can be synthesized in the compound (9).

Furthermore, an aminoquinazoline derivative in which R 2 is hydrogen and R 3 is a substituent other than hydrogen can be produced by selectively brominating the 5-position of the aminoquinazoline ring of the compound ( 5 ) in Scheme 1, introducing the amine compound ( 8 ) Followed by introduction of R < 1 > in a Mitsunobu reaction followed by a Pd-coupling reaction with an R3 substituent and removal of the protecting group.

R3, A, X, Y and Z may be prepared from compounds of formula I or compounds of the reaction scheme by known methods or by methods known to those skilled in the art, Can be converted.

In the present invention, an aminoquinazoline derivative in which R 3 is hydrogen and R 2 is a substituent other than hydrogen can be prepared by the reaction scheme 2.

[Reaction Scheme 2]

In Scheme 2 above, by bromination of commercially available 2-amino-3-methoxybenzoic acid (1) to obtain the compound (10), the acid portion of the compound (10) to compound (11) using a BH ₃ -THF after the reduction in benzyl alcohol, to obtain the aldehyde compound (12) through an oxidation reaction using manganese dioxide therefrom, to a condensation reaction with this urea 2-hydroxy-6-bromo-8-methoxy-quinazoline (13 ). Subsequently, the compound ( 15 ) is synthesized by substituting chlorine for the hydroxy group at the 2-position of the aminoquinazoline ring of the compound ( 13 ), from which boron tribromide is used to synthesize the compound ( 15 ) The final compound ( 19 ) can be synthesized by introducing an amine compound ( 8 ) in sequence, synthesizing a compound ( 18 ) and finally coupling with an R2 substituent.

In the above Reaction Scheme 2, R2, A, X, Y and Z are converted from the compound of formula (I) or the compound of the reaction process into other kinds of R2, A, X, Y and Z by a known method or a method apparent to a person skilled in the art .

On the other hand, examples of the intermediate compound (8) of the above schemes 1 and 2, N- (6- amino -1H- indazol-4-yl) -amide -R4- (wherein, R4 is C ₅ -C ₁₂ Aryl-C ₁ -C ₅ alkyl) can be prepared by the following reaction scheme 3, but the production method is not limited thereto.

 [Reaction Scheme 3]

In Scheme 3, commercially available 2,4,6-trinitrotoluene is selectively reduced to synthesize compound ( 20 ), a protecting group is introduced into one side amine, and then an indazole compound ( 22 ). Then after removing the protecting group using hydrazine from the compound (22), and wherein R4 is by an amide coupling reaction with the substituted carbonyl chloride or R4 is a substituted carboxylic acid Synthesis of the compound 24, reduction of the nitro to an amine compound ( 25 ) can be obtained.

In the above Reaction Scheme 3, R4 may be converted from the compound of formula (I) or the compound of the reaction process to another kind of R4 by a known method or a method apparent to a person skilled in the art.

The compounds of formula I of this invention are further understood by reference to the following examples, which are purely illustrative, but the invention is not to be construed as being limited by the illustrated examples in any way, ≪ / RTI > In addition, the introduction of a protecting group for a certain functional group is not limited to the exemplified embodiment, and can be extended to a generally known method of protecting group introduction or deprotection.

In the case of the starting materials for synthesizing the compounds of the present invention, various synthetic methods are known. When the starting materials are commercially available, they can be purchased from a supplier. The reagent supply sources include, but are not limited to, Aldrich, Sigma, TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, and Fluka.

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. Other process conditions may also be used, unless otherwise noted, under typical or preferred process conditions, such as reaction temperature, time, molar ratio of reactants, solvent, pressure, and the like. The optimum reaction conditions can vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

In addition, the compounds of the present invention may contain one or more chiral centers. Thus, if desired, such compounds may be prepared or separated as pure stereoisomers, i.e. as individual enantiomers or diastereomers, or as stereoisomeric diastereoisomers. Pure stereoisomers and diastereoisomers can be prepared, for example, using optically active starting materials or stereoselective reagents known in the art. On the other hand, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral decomposition, and the like.

The present invention also relates to a pharmaceutical composition for preventing or treating Alzheimer's disease comprising, as an active ingredient, a compound selected from an aminoquinazoline derivative of formula (I) according to the present invention, a pharmaceutically acceptable salt, hydrate, solvate and isomer thereof Gt;

The derivatives of formula (I) according to the present invention are excellent in the inhibitory activity against Lyn kinase (LynK) and thus are useful for the prevention or treatment of Alzheimer's disease caused by Lyn kinase activation. Specifically, the inhibitory activity (IC ₅₀ ) of the compounds of Examples 1 to 17 against LynK was 5 μM or less, and in particular, the compounds of Examples 4, 9, and 11 showed inhibitory activity of 0.3 μM or less. In addition, the compounds of Examples 1 to 17 exhibit the inhibitory effect of A [beta] on neuronal cell death by A [beta], and especially in the case of the compounds of Examples 9 and 11, HT22 neuronal cell death by A [beta] (See Fig. 1). Furthermore, in the experiment of inhibiting cell death by etoposide to confirm whether the neuronal apoptosis-suppressing mechanism is selectively activated, when the compounds of Examples 9 and 11 were treated, no activity was observed, (Fig. 2).

The pharmaceutical composition of the present invention may be formulated according to a conventional method and may be formulated into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions and microemulsions or parenteral administration such as intramuscular, intravenous or subcutaneous administration Can be prepared in a dosage form.

The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier or an additive. When the pharmaceutical composition of the present invention is prepared in the form of an oral formulation, examples of the carrier or additive to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, Calcium stearate, gelatin, talc, a surfactant, a suspending agent, an emulsifying agent and a diluent. When the pharmaceutical composition of the present invention is prepared in the form of an injectable preparation, the carrier or the additive includes water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, , Glyceride, a surfactant, a suspending agent, and an emulsifying agent.

The dosage of the active ingredient, such as an aminoquinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof, of the present invention depends on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. An aminoquinazoline derivative of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient is administered to a mammal including a human in an amount of 0.01 to 200 mg / kg (body weight), preferably 10 to 100 mg / kg The dosage can be administered via the oral or parenteral route once or twice a day or on an on / off schedule. In some cases, dosage values less than the above-mentioned ranges may be more suitable, more doses may be used without causing harmful side effects, and more doses may be administered several times daily / RTI >

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example  1: [8- (3H- Benzoimidazole -5- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

The compound of Example 1 was prepared according to Reaction Scheme 1 through the following 6 steps.

≪ 1-1 > 2 Manufacturing

(10.8 g, 180 mmol) and 1-methyl-2-pyrrolidinone (NMP, 22 ml) were added to a reactor, and the mixture was stirred at 180 ° C for 1.5 hours ≪ / RTI > The reaction mixture was cooled to room temperature, poured into water (300 ml), the resulting solid was filtered, washed with water and dried to obtain Compound 2 (3.78 g, yield 55%).

<1-2> Compound 3 Manufacturing

Compound 2 (3.70 g, 19.2 mmol) and N, N-dimethylaniline (4 ml) were added to POCl ₃ (25.0 ml) and the mixture was refluxed at 120-130 ° C for 2 hours. The mixture was poured into ice, And 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] ⁺ ).

&Lt; 1-3 > 4 Manufacturing

Pd / C (450 mg) and diisopropylethylamine (DIPEA, 2.7 g, 21.0 mmol) were added to a solution of compound 3 (4.0 g, 17.4 mmol) in EtOAc (200 ml) After stirring for 1.5 hours, the mixture was filtered through a Celite filter, and the filtrate was washed with water, brine, and dried over MgSO ₄ . The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography (PE: EtOAc = 4: 1) to obtain a yellow solid compound 4 (2.64 g, yield 79%).

&Lt; 1-4 > 5 Manufacturing

Compound 4 (2 g, 10.3 mmol) was added to dichloromethane (16 ml) and boron tribromide (20.6 ml, 1.0M DCM solution) was slowly added dropwise at 0 ° C and then 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 rinsed with MeOH and dried to give Compound 5 (1.56 g, yield 82% ).

^{1 H NMR (300MHz, 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).

&Lt; 1-5 > 7 Manufacturing

N-BuOH (4 ml) was added to a flask containing compound 5 (50 mg, 0.276 mmol) and 6-amino-1H-indazole (36.8 mg, 0.276 mmol) and the mixture was stirred at 150 ° C for 4 hours. After cooling to room temperature, the precipitated solid is filtered and washed with a small amount of MeOH / DCM. The obtained solid was dried to obtain 2- (1H-indazol-6-ylamino) -quinazolin-8-ol (Compound 7 , pale yellow solid, 65 mg, yield 85%).

&Lt; 1-6 > [8- (3H- Benzoimidazole -5- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

Compound 7 (100 mg, 0.36 mmol) and 6-bromo-1H-benzoimidazole (71 mg, 0.36 mmol) were placed in a microwave tube and dissolved by adding DMF (2 ml). Cu powder (3 mg, 0.03 mmol) and Cs ₂ CO ₃ (250 mg, 0.72 mmol) were added thereto, followed by stirring at 130 ° C for 30 minutes under microwave reaction conditions. Higo dilute the reaction with EtOAc (50 ml), it was washed with water and 1N NaOH (10 ml), then dried over MgSO ₄ and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give the title compound (light brown solid, 28 mg, yield 20%).

^{1 H NMR (300 MHz, DMSO} , δ): 12.4 (br s, 1H), 12.1 (br s, 1H), 9.43 (s, 1H), 9.2 (br s, 1H), 8.24 (s, 1H), (S, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.56-7.49 (m, 4H), 7.29 , &Lt; / RTI &gt; 1H), 6.40 (d, J = 8.4 Hz,

Example  2: [8- (3-Amino- Phenoxy ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

The procedure of Example 1 was repeated except that 3-bromoaniline was used instead of 6-bromo-1H-benzoimidazole in Example 1-6 to obtain the title compound (20 mg, yield 29% ).

¹ H NMR (300 MHz, DMSO,?): 12.1 (br s, 1H), 9.45-9.43 (m, 2H), 8.20 2H), 7.41 (m, 3H), 7.16 (t, J = 7.8 Hz,

Example  3: (1H- Indazole -6-yl) - [8- (piperidin-4- Ylmethoxy ) - Quinazoline Yl] -amine &lt; / RTI &gt;

According to the above Example 1, Compound 5 was synthesized, and then Compound 2 was prepared according to Reaction Scheme 1 as follows.

<3-1> Synthesis of 4- (2- Chloro - Quinazoline -8- 1-oxymethyl ) -Piperidin-l- Carboxylic acid tert -Butyl ester (compound 6) Manufacturing

To a solution of compound 5 (700 mg, 3.88 mmol) and anhydrous THF (16 ml) in which triphenylphosphine (1.526 g, 5.82 mmol) was dissolved N-Boc-4-hydroxymethylpiperidine (920 mg, 4.27 mmol ), Diisopropyl azodicarboxylate (DIAD, 1.145 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, dissolved in EtOAc, and washed with water. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The concentrated reaction product was purified by silica gel column chromatography (Hex: EtOAc = 4: 1) to obtain the title compound (1.29 g, yield 88%).

<3-2> (1H- Indazole -6-yl) - [8- (piperidin-4- Ylmethoxy ) - Quinazoline -2 days]- Amine  Produce

The compound 6 (53 mg, 0.14 mmol) and 6-aminoindazole (18.6 mg, 0.14 mmol) were placed in a flask, and n-BuOH (4 ml) was added thereto and stirred at 150 ° C for 6 hours. The reaction was cooled to room temperature, concentrated, diluted with DCM (2 ml), then trifluoroacetic acid (TFA, 1 ml) was added and the mixture was stirred at 50 ° C for 10 minutes. The reaction was concentrated and then purified by prep HPLC (0.1% HCO ₂ H / CH ₃ CN) to give the pure title compound (an opaque solid, 42 mg, yield 77.5%).

¹ H NMR (300 MHz, DMSO, 6): 10.05 (s, IH), 9.24 (s, IH), 8.72 (s, IH), 8.37 2H), 3.23-3.20 (m, 3H), 2.28-3.42 (m, 2H) , 3.00-2.95 (m, 2H), 2.17-2.11 (m, 2H), 1.88-1.82 (m,

Example  4: (8- (4- Fluoro -1H- Benzoimidazole -5- Sake ) - Quinazoline Yl) - (lH-indazol-6-yl) - Amine  Produce

The procedure of Example 1 was repeated except that 5-bromo-4-fluorobenzimidazole was used instead of 6-bromo-1H-benzoimidazole in Example 1-6 to obtain the title compound (26 mg, yield 23%).

^{1 H NMR (300 MHz, DMSO} , δ): 12.1 (br s, 1H), 11.5 (br s, 1H), 9.44-9.40 (m, 2H), 8.22-8.19 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.57-7.48 (m, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.07 d, J = 8.1 Hz, 1H)

Example  5: 3- Fluoro -4- [2- (1H- Indazole -6- Amino ) - Quinazoline -8- Sake ] -Benzene-l, 2- Diamine  Produce

The procedure of Example 1 was repeated except that 4-bromo-3-fluoro-1,2-diaminobenzene was used instead of 6-bromo-1H-benzoimidazole in < 1-6 & Was repeated to give the title compound (29 mg, yield 25%).

¹ H NMR (300 MHz, DMSO,?): 12.4 (br s, 1H), 9.45-9.43 (m, 2H), 8.22 2H), 6.40 (d, J = 8.1 Hz, 1H), 6.23-5.90 (m, 4H), 5.19 (br s, 2H)

Example  6: [5- Bromo -8- (Piperidin-4- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

The procedure of Example 3 was repeated, except that N-Boc-4-hydroxy-piperidine was used instead of N-Boc-4-hydroxy-methylpiperidine in Example 3 to give the title compound (39 mg , Yield: 79%).

¹ H NMR (300 MHz, DMSO, δ): 12.83 (s, 1H), 10.34 (s, 1H), 9.32 1H), 7.94-7.61 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.38 4H), &lt; / RTI &gt; 2.12-2.10 (m, 4H)

Example  7: [6- Bromo -8- (Piperidin-4- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

The compound of Example 7 was prepared according to Reaction Scheme 2 through the following 8 steps.

&Lt; 7-1 > 10 Synthesis of

2-amino-3-methoxybenzoic acid (2 g, 11.96 mmol) is CHCl ₃ (50 ml) containing, the _{Br 2 (0.66 ml, 12.82 mmol} ) to the reaction at 0 ℃ dissolved in CHCl ₃ (42 ml) The mixture was slowly added dropwise, followed by stirring at room temperature for two days. The precipitated solid was filtered, washed with DCM, and dried to obtain Compound 10 (3.83 g, yield 98%) as a yellow solid.

&Lt; 7-2 > 11 Synthesis of

Compound 10 (3.83 g, 11.73 mmol) and then placed in THF (50 ml), slowly added dropwise _{BH 3 -THF ((1 M,} 35 ml, 35 mmol)) at 0 ℃, and the mixture was stirred at room temperature for 72 hours . EtOH (2 ml) was slowly added dropwise to the reaction at 0 &lt; 0 &gt; C and then stirred for 15 minutes. The reaction was diluted with dichloromethane (DCM) and, after washed with water and brine, then dried over Na ₂ SO ₄ and concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (PE: EA = 1: 1 ) to give compound 11 (1.23 g in , Yield: 44%).

<7-3> Preparation of Compound 12

Manganese dioxide (3.14 g, 31.8 mmol) is added to CHCl ₃ (35 ml) containing compound 11 (1.22 g, 5.3 mmol) and stirred at room temperature for 16 hours. The reaction was filtered through a Celite filter and washed with DCM. The filtrate was concentrated and dried to obtain an orange solid compound 12 (940 mg, yield 77%).

&Lt; 7-4 > 13 Manufacturing

Compound 12 (940 mg, 4.08 mmol) and urea (3.4 g, 57.2 mmol) were stirred at 180 ° C for 1 hour and then water (30 ml) was added to the reaction at room temperature. The precipitated solid was filtered off, washed and dried to obtain yellow compound 13 (500 mg, yield 48%).

&Lt; 7-5 > 14 Manufacturing

POCl ₃ (10 ml) was added to compound 13 (500 mg, 2 mmol), and the mixture was stirred at 110 ° C for 2 hours. After cooling to room temperature, the POCl ₃ was removed, the reaction was diluted with DCM, washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The concentrated solid was washed with DCM and then filtered to obtain a solid yellow solid compound 14 (430 mg, yield 78%).

<7-6> Compound 15 Manufacturing

Compound 14 (500 mg, 1.83 mmol) was dissolved in anhydrous DCM (10 ml), BBr ₃ (1 M in DCM, 7.3 ml) was slowly added dropwise and the reaction was stirred at 60 ° C for 1 hour. The reaction was concentrated, diluted with EtOAc, washed with 3N HCl, and washed once more with brine. The organic layer was dried over MgSO ₄ and concentrated. The resulting solid was washed with MeOH, filtered, and dried to obtain a deep cyan solid compound 15 (332 mg, yield 60%).

&Lt; 7-7 > 17 Manufacturing

To a flask containing Compound 15 (320 mg, 1.053 mmol) and triphenylphosphine (414 mg, 1.579 mmol), THF (anhydrous, 8 ml) was added and tert- butyl-4-hydroxypiperidine- (Compound 16 , 222 mg, 1.105 mmol). After stirring for 5 minutes, diisopropyl azodicarboxylate (DIAD, 319 mg, 1.579 mmol) was slowly added dropwise to the reaction and stirred at room temperature for 2 hours. Higo diluted in EtOAc and the reaction was washed successively with water and brine, the organic layer was dried with MgSO ₄ and concentrated. The concentrated reaction product was separated by silica gel column chromatography (Hexane: EtOAc = 6: 1) to obtain an amorphous solid compound 17 (295 mg, yield 57.5%).

<7-8> [6- Bromo -8- (Piperidin-4- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) -amine &lt; / RTI &gt;

Compound 17 (254 mg, 0.575 mmol) and 6-amino-1H-indazole (77 mg, 0.575 mmol) were placed in a flask and n-butanol (8 ml) was added thereto and stirred at 150 ° C for 3 hours. The reaction mixture was concentrated and then subjected to silica gel column chromatography (DCM: MeOH = 10: 1) to obtain the title compound (207 mg, yield 82%) as a dark blue solid.

¹ H NMR (300 MHz, DMSO, 隆): 10.18 (s, 2H), 9.25 (s, 1H), 8.69 2H, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H) (m, 4H)

Example  8: (1H- Indazole -6-yl) - [6- methyl -8- (Piperidin-4- Sake ) - Quinazoline -2 days]- Amine  Produce

Compound 17 was synthesized according to the above Example 7, and the compound of Example 8 was prepared according to Reaction Scheme 2 through the following two steps.

<8-1> Synthesis of 4- [6- Bromo -2- (1H- Indazole -6- Amino ) - Quinazoline -8- Sake ] - piperidin-1-car Compartment mountain tert - Preparation of butyl esters

Compound 17 (280 mg, 0.575 mmol) and 6-amino-1H-indazole (77 mg, 0.575 mmol) were placed in a flask, n-butanol (7 ml) was added thereto and stirred at 150 ° C for 3 hours , And the solvent was removed. DCM (8 ml) was added to the reaction, triethylamine (0.5 ml) was added thereto, and the mixture was stirred for 5 minutes. Then, (t-Boc) ₂ O (110 mg) was added thereto and stirred at room temperature for 2 hours. Higo dilute the reaction with EtOAc, was washed successively with water and brine, dried over MgSO ₄ and concentrated. The concentrated reaction product was separated by silica gel column chromatography (Hexane: EtOAc = 3: 1) to obtain the title compound (185 mg, yield 60%) as a yellow solid compound.

<8-2> (1H- Indazole -6-yl) - [6- methyl -8- (Piperidin-4- Sake ) - Quinazoline -2 days]- Amine  Produce

Yloxy] -piperidine-l-carboxylic acid tert-butyl ester (80 mg, 0.148 mmol) was reacted with 4- [6-bromo-2- (lH-indazol- _{Pd (PPh 3) 4 (16.7} mg, 0.014 mmol) and Na ₂ CO ₃ placed in the flask a (30 mg, 0.29 mmol), here in an ethanol / toluene (3 ml / 3 ml) was added, followed by trimethylboroxine new ( 36 mg, 0.29 mmol), which was stirred for 8 hours at 90 ° C. The reaction was concentrated, diluted with EtOAc, washed sequentially with water and brine, dried over MgSO ₄ and concentrated. The concentrated reaction product was separated by silica gel column chromatography (DCM: MeOH = 15: 1) to obtain 4- [2- (1H-indazol-6-ylamino) -6-methyl- quinazolin- Piperidine-1-carboxylic acid tert-butyl ester (31 mg, yield 45%).

Yloxy] -piperidine-l-carboxylic acid tert-butyl ester (30 mg, 0.063 mmol) was added to a solution of 4- [2- (lH- indazol-6-ylamino) -6-methyl- quinazolin- After dissolving in DCM (4 ml), trifluoroacetic acid (0.5 ml) was added and the mixture was stirred at 50 ° C for 10 minutes. The reaction was concentrated and then purified by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain the title compound (20 mg, yield 88%) as a dark yellow solid.

^{1 H NMR (300 MHz, DMSO} , δ): 9.97 (s, 2H), 9.19 (s, 1H), 8.69 (s, 1H), 7.93 (s, 1H), 7.62 (d, J = 9.0Hz, 1H ), 7.48 (d, J = 8.1 Hz, 1H), 7.30 (s, 2H), 4.91 (s, 1H), 3.28 (m, 2H), 2.99 (m, 4H)

Example  9: 2- Phenyl -N- {6 - [(8-piperidin-4- Sake ) - Quinazoline -2- Amino ] -1H- Indazole Yl} - Acetamide  Produce

The procedure of Example 3 was repeated, except that in Example 3 N- (6-amino-1H-indazol-4-yl) -2-phenyl-acetamide was used in place of 6-amino- To give the title compound as a yellow solid (41 mg, 61% yield).

LC-MS: 494 ([M + H] +, 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, IH), 7.39-7.26 (m, 8H), 6.91 (s, IH), 6.01 (m, 2H), 2.85 (m, 2H), 1.93 - 1.90 (m, 4H)

Meanwhile, N- (6-amino-1H-indazol-4-yl) -2-phenyl-acetamide used in the above process was prepared according to the following Scheme 3,

&Lt; 9-1 > 20 Synthesis of

MeOH (300 ml) was added to a flask containing ferric chloride (FeCl ₃ -6H ₂ O, 1.28 g, 4.73 mmol) and activated carbon (21 g), and 2,4,6-trinitrotoluene (TNT, 264 mmol) was added dropwise, hydrazine (33.3 ml, 667 mmol) was diluted with MeOH (100 ml) and slowly added dropwise over 3 hours to the reaction between 5-10 ° C. The reaction was stirred at 15 [deg.] C for 3 hours and then at 20-22 [deg.] C. The temperature was gradually raised to 50 ° C over 90 minutes and further stirred for 1 hour. The heated reaction was filtered through a celite filter and rinsed with warm MeOH (200 ml, 3 times) to remove the activated carbon. After the filtrate was concentrated to about 100 ml, 100 ml of warm water (60 ° C) was added and the mixture was cooled to room temperature while stirring. The precipitated solid was filtered, washed with a small amount of EtOAc, and then dried to obtain Compound 20 (reddish brown solid, 7.37 g, yield 25%).

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

&Lt; 9-2 > 21 Synthesis of

Compound 20 (7.20 g, 43 mmol) and phthalic anhydride (6.38 g, 43 mmol) were dissolved in acetic acid (350 ml), and the mixture was heated to reflux at 110 ° C for 4 hours. After the reaction was cooled, the precipitated solid was filtered and dried to obtain Compound 21 (white solid, 12.30 g, yield: 96%).

(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).

&Lt; 9-3 > 22 Synthesis of

Acetic acid (300 ml) / water (10 ml) was added to a flask containing compound 21 (12.30 g, 41.4 mmol) and NaNO ₂ (8.57 g, 124.2 mmol) and the mixture was stirred at room temperature for 2 hours. . The resulting solid was washed with water and then dried to obtain Compound 22 (light yellow solid, 11.9 g, yield 93%).

LC-MS: 309.2 ([M + H] &lt; ⁺ &gt; (1H, s, ArH), 8.10 (1H, d, ArH), 8.04 (2H, m, ArH), 7.96 , m, ArH).

&Lt; 9-4 > 23 Synthesis of

Compound 22 (23 g, 74.6 mmol) and hydrazine monohydrate (15 ml) were added to EtOH (800 ml) and the mixture was refluxed for 3.5 hours, cooled to room temperature, and stirred for 12 hours. The reaction was filtered and the filtrate was concentrated. EtOAc was added to the concentrated reaction mixture, washed with water, and washed once more with brine. The organic layer was dehydrated with MgSO ₄ and concentrated to give 23 (bright reddish brown solid, 13 g, yield 98%).

&Lt; 9-5 > 24 Synthesis of

Compound 23 (80 mg, 0.449 mmol), phenylacetic acid (61 mg, 0.449 mmol) and TBTU (210 mg, 0.673 mmol) were dissolved in DMF (anhydrous, And the mixture was stirred at room temperature for 3 hours. The reaction was concentrated to remove DMF, diluted with EtOAc and washed with water. The organic layer was dehydrated with MgSO4 and concentrated. The concentrated reaction was washed with MeOH and then filtered to give N- (6-nitro-1H-indazol-4-yl) -2-phenyl-acetamide (light yellow solid, 100 mg, yield 76%).

^{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).

<9-6> Synthesis of N- (6-amino-1H- Indazole Yl) -2- Phenyl - Acetamide (Compound 25 )of  Produce

(Compound 24 , 100 mg, 0.337 mmol) was added to MeOH (4 ml), and Pd / C (10%, 50 By weight), and the mixture was stirred for 1 hour under hydrogen balloon (1 atm) and room temperature. The reaction is filtered through celite and washed with MeOH. Subsequently, the filtrate was concentrated and dried to obtain N- (6-amino-1H-indazol-4-yl) -2-phenyl-acetamide (dark yellow solid, 83 mg, yield 92%).

LC-MS: 494 ([M + H] &lt; ⁺ &gt;

Example  10: [(6- Chloro -8- (Piperidin-4- Sake ) - Quinazoline Yl] - (lH- Indazole -6-yl) - Amine  Produce

The procedure of Example 7 was repeated except that Cl was introduced by using N-chlorosuccinimide instead of Br ₂ in Example 7 (7-1) to give the title compound (120 mg, yield 75%) .

^{1 H NMR (300 MHz, DMSO} , δ): 10.18 (s, 1H), 9.25 (s, 1H), 8.71 (s, 1H), 7.94 (s, 1H), 7.66-7.61 (m, 2H), 7.51 2H), 2.03 (m, 4H), 2.28 (m, IH)

Example  11: (1H- Indazole -6-yl) - [8- (piperidin-4- Sake ) -6-propyl- Quinazoline -2 days]- Amine  Produce

Ylamino) -quinazolin-8-yloxy] -piperidine-l-carboxylic acid tert-butyl ester (78 &lt; RTI ID = mg, 0.145 mmol) placed in a sealed tube (sealed tube), Pd (PPh 3) was added to _{4 (16.7 mg, 0.014 mmol)} , CuI (5.5 mg, 0.029 mmol) and anhydrous triethylamine (3 ml), 1-propyne (5.8 mg, 0.145 mmol) was added under nitrogen and -78 ° C, and the mixture was stirred at 80 ° C for 4 hours. The reaction was concentrated to remove the triethylamine, diluted with EtOAc, washed successively with water and brine, dried over MgSO ₄ and concentrated. The concentrated reaction product was separated by silica gel column chromatography (DCM: MeOH = 15: 1) to obtain tert-butyl 4 - ((2 - ((1H-indazol- Yl) quinazolin-8-yl) oxy) piperidine-1-carboxylate (65 mg, yield 90%).

A solution of the tert-butyl 4 - ((2 - ((1H-indazol-6-yl) amino) -6- (1-propyn- 1 -yl) quinazolin- -Carboxylate (65 mg, 0.13 mmol) was dissolved in DCM (6 ml), trifluoroacetic acid (0.8 ml) was added, and the mixture was reacted at 50 ° C for 10 minutes with stirring. The reaction mixture was concentrated, and then the residue was separated by silica gel column chromatography (DCM: MeOH = 10: 1) to obtain a compound in which the protecting group Boc was removed. This compound was dissolved in DCM (6 ml) and stirred under hydrogen gas conditions (1 atm) in the presence of Pd / C for 90 minutes. The reaction was filtered through a celite filter, concentrated, and then purified by prep HPLC (0.1% HCO ₂ H / CH ₃ CN) to give the title compound (24.8 mg, 47.3% yield) as a light yellow solid.

^{1 H NMR (300 MHz, DMSO} , δ): 9.96 (s, 1H), 9.21 (s, 1H), 8.73 (s, 1H), 7.93 (s, 1H), 7.62 (d, J = 8.4Hz, 1H 2H), 2.64 (m, 2H), 2.66 (t, J = 8.1 Hz), 7.48 (d, J = 8.1 Hz, 1H), 7.35-7.30 J = 7.5 Hz, 2H), 1.99 (m, 4H), 1.67 (q,

Example  12: (1H- Indazole -6-yl) - [8- ( Pyrrolidine -3- Ylmethoxy ) - Quinazoline -2 days]- Amine  Produce

The procedure of Example 3 was repeated except that N-Boc-3-hydroxymethylpyrrolidine was used instead of N-Boc-4-hydroxymethylpiperidine in Example 3 to give the title compound (35 mg, Yield 68%).

1H NMR (300 MHz, DMSO,?): 10.07 (s, IH), 9.29 (s, IH), 8.72 (s, IH), 8.38 (m, 3H), 3.48-3.42 (m, 1H), 3.23-3.21 (m, 3H) 3.00-2.98 (m, 1 H), 2.17-2.13 (m, 1 H), 1.88-1.82 (m, 1 H)

Example  13: 2- (1H- Indazole -6- Amino ) -8- (Piperidin-4- Sake ) - Quinazoline -6- Carbonitrile  Produce

Ylamino) -quinazolin-8-yloxy] -piperidine-l-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) and then dissolved in DMF (1.5 ml), Zn ( CN) 2 (4 eq.), PdCl ₂ (dppf) (microwave reaction 0.2 equivalents) and added DIPEA (10 eq.) for 20 minutes at 120 ℃ Respectively. Higo dilute the reaction in EtOAc, washed with water, and dried and concentrated the organic layer with MgSO _4. DCM (2 ml) was added to the concentrated reaction mixture, and trifluoroacetic acid (1 ml) was added thereto, followed by stirring at 50 ° C for 10 minutes. The reaction was cooled to room temperature, concentrated, and then purified by prep HPLC (0.1% HCO ₂ H / CH ₃ CN) to give the title compound (42 mg, yield 79%).

^{1 H NMR (300 MHz, DMSO} , δ): 9.26 (s, 1H), 8.46 (s, 1H), 8.00 (s, 2H), 7.73 (d, J = 8.7Hz, 1H), 7.60 (s, 1H 2H), 3.22-3.18 (m, 2H), 2.24-2.18 (m, 4H), 7.51 (d, J = 8.7 Hz,

Example  14: 2- (1H- Indazole -6- Amino ) -8- (Piperidin-4- Sake ) - Quinazoline -6- Carboxylic  Produce

(Piperidin-4-yloxy) -quinazoline-6-carbonitrile (30 mg, 0.061 mmol) prepared in Example 13 was dissolved in THF / MeOH (2 ml / 2 ml), 3N NaOH (1 ml) was added thereto, and the mixture was stirred at 60 ° C for 2 hours. The reaction was concentrated, washed with MeOH (10 ml) and filtered. The filtrate was concentrated and then purified by prep HPLC (water / CH ₃ CN) to give the title compound (yellowish solid, 17 mg, yield 55%).

¹ H NMR (300 MHz, DMSO, 隆): 9.21 (s, 1H), 8.51 (s, 1H), 8.16 ), 7.54 (d, J = 8.1 Hz, 1H), 7.49-7.42 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H) (m, 2H), 2.35-2.03 (m, 4H)

Example  15: N- [2- (1H- Indazole -6- Amino ) -8- (Piperidin-4- Sake ) - Quinazoline -6-yl] - Acetamide  Produce

To a microwave tube was added 4- [6-bromo-2- (1H-indazol-6-ylamino) -quinazolin-8-yloxy] -piperidine-l- After adding butyl ester (50 mg, 0.093 mmol), acetamide (0.19 mmol), xantphos (0.04 eq.), Pd ₂ (dba) ₃ (0.02 eq.) And K ₃ PO ₄ (1.2 eq. (4 ml) and potassium t-butoxide (t-BuOK, 1 M in THF, 1 eq.) Were added to the reaction mixture. The reaction was microwaved at 150 ° C for 20 minutes, then diluted with EtOAc and washed with water The organic layer was dried over MgSO ₄ and concentrated, and then the reaction mixture was dissolved in DCM (2 ml), trifluoroacetic acid (1 ml) was added, and the mixture was stirred for 10 minutes at 50 ° C. The reaction mixture was cooled to room temperature, purification by _{prep HPLC (0.1% HCO 2 H} / CH 3 CN) to give the title compound (dark yellow solid, 24.8 mg, yield 47.3%).

^{1 H NMR (300 MHz, DMSO} , δ): 10.13 (s, 1H), 9.96 (s, 1H), 9.23 (s, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.93 (s 1H), 7.87 (s, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.51-7.47 (m, 2H), 4.79 2H), 2.07 (s, 3H), 1.96 (m, 4H)

Example  16: (1H- Indazole -6-yl) - [8- (piperidin-4- Sake ) - Quinazoline -2 days]- Amine  Produce

The procedure of Example 3 was repeated except that N-Boc-4-hydroxypiperidine was used instead of N-Boc-4-hydroxymethylpiperidine in Example 3 to give the title compound (50 mg, yield 88%).

^{1 H NMR (300 MHz, CD3OD} , δ): 9.20 (s, 1H), 8.49 (s, 1H), 7.71 (d, J = 9.0Hz, 1H), 7.56-7.43 (m, 4H), 7.33 (t 2H, J = 7.8 Hz, 1H), 5.06 (s, IH), 3.54 (m, 2H), 3.23

Example  17: (1H- Indazole -6-yl) - [8- (pyridin-4- Sake ) - Quinazoline -2 days]- Amine  Produce

The procedure of Example 1 was repeated except that 4-bromopyridine was used instead of 6-bromo-1H-benzoimidazole in Example 1 to obtain the title compound (6 mg, yield 7%).

^{1 H NMR (300 MHz, CD3OD} , δ): 9.25 (s, 1H), 8.32 (d, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.85 (d, 1H), 7.70 (d 1H), 7.47-7.42 (m, 2H), 7.14 (d, 1H), 7.00 (d, 2H).

The structural formulas of the compounds obtained in Examples 1 to 17 are shown in Table 1 below.

Example Name rescue One [8- (3H-benzoimidazol-5-yloxy) -quinazolin-2-yl] - (lH-indazol-

2 [8- (3-Amino-phenoxy) -quinazolin-2-yl] - (1H-indazol-

3 (1 H- indazol-6-yl) - [8- (piperidin-4-ylmethoxy) -quinazolin- 2-yl]

4 (8- (4-fluoro-lH-benzoimidazol-5-yloxy) -quinazolin-2-yl) - (lH-indazol-

5 Fluoro-4- [2- (lH-indazol-6-ylamino) -quinazolin-8-yloxy] -benzene- l, 2-diamine

6 (Piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl)

7 (6-Bromo-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (lH-indazol-

8 - (6-methyl-8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine

9 2-phenyl-N- {6 - [(8-piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-

10 [(6-Chloro-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-

11 (1 H- indazol-6-yl) - [8- (piperidin-4-yloxy) -6-propyl-quinazolin-

12 (LH-indazol-6-yl) - [8- (pyrrolidin-3- ylmethoxy) - quinazolin-

13 2- (1H-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-

14 2- (1H-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-6-

15 N- [2- (lH-indazol-6-ylamino) -8- (piperidin-4- yloxy) -quinazolin-6- yl] -acetamide

16 (1 H- indazol-6-yl) - [8- (piperidin-4-yloxy) -quinazolin-2-yl]

17 (1 H- indazol-6-yl) - [8- (pyridin-4-yloxy) -quinazolin-

The compounds produced in the above Examples were subjected to the bioassay test as follows.

Experimental Example  1: Compound of the present invention Lyn Kinase  Evaluation of activity inhibition

In order to evaluate the activity of the compounds of the present invention as Lyn inhibitors, Lyn protein was overexpressed in Sf21 insect cells by gene recombination and then purified to perform the enzymatic reaction. Specifically, a reaction buffer (15 mM Tris-HCl (pH 7.5), 10 mM MgCl ₂ , 0.01% Tween-20, 2 mM DTT) and 250 nM biotin-glucose substrate peptide acting as a substrate with 0.2 nM of Lyn enzyme and The test compound was added to a 96-well plate coated with streptavidin and reacted at 30 DEG C for 1 hour. After the reaction was completed, the plate was washed four times with a washing solution [50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.02% Tween-20] 0.02% Tween-20, 0.1% BSA] was added, and the cells were allowed to stand for 30 minutes, followed by treatment with anti-pTyr antibody (pY20) for 30 minutes. Then, color development was performed with a solution of TMB (3,3 ', 5,5'-tetramethylbenzidine) coupled with phosphotyrosine and the absorbance at 450 nm was measured to confirm the enzyme activity of LynK. The absorbance value of the sample not treated with the compound was set as a control, and the absorbance of the sample treated with the compound to be tested was measured to evaluate the activity of the LynK inhibitor as a percentage of the residual activity relative to the control. The LynK inhibitory activity of the compound is shown in Table 2 below as the IC ₅₀ value, which is the concentration of the compound showing 50% inhibition of LynK enzyme activity as compared to the control.

Example IC ₅₀ ([mu] M) Example IC ₅₀ ([mu] M) One 0.39 10 0.7 2 0.83 11 0.15 3 0.54 12 0.37 4 0.18 13 > 1.0 5 0.32 14 > 1.0 6 0.37 15 > 1.0 7 0.46 16 > 1.0 8 > 1.0 17 > 1.0 9 0.29

Experimental Example  2: Compound of the present invention HT22 cell Whether it is dead or not  Measurement experiment

In order to confirm whether the compounds of the present invention inhibit the apoptosis induced by A [beta] peptide by inhibiting LynK activity, it was analyzed by the cell count method. For this analysis, HT22, a cell line derived from mouse brain cells, was used. Aβ peptides (complexes) that kill brain cells were prepared by dissolving Aβ peptide (monosaccharide; Sigma-Aldrich) in a mixed buffer of dimethylsulfoxide (DMSO) and PBS using a vibrator at room temperature for 30 minutes, Day, and the prepared complex was dispensed and stored in a -80 ° C freezer until use.

Specifically, DMEM medium containing the cell line HT22 was added 10% FBS is then (GIBCO, Invitrogen) containing the frequency divider at each concentration of 5,000 cells / well in 96-well plates, for 24 hours in a 5% CO ₂ and 37 ℃ conditions Lt; / RTI &gt; Subsequently, in the case of the experimental group, 5 μM of the Aβ complex was treated, and the compounds of Examples 9 and 11 were added at concentrations of 0.01, 0.1, 0.5 and 5 μM, respectively, for 36 hours. On the other hand, in the case of the positive control, dimethylsulfoxide (DMSO) was pretreated for 30 minutes at a concentration of 0.08% by weight, which was the same as that used for compound treatment, and then treated with the same 1% by weight PBS buffer and cultured for 36 hours. In the case of the negative control, dimethylsulfoxide (DMSO) was pretreated for 30 minutes at a concentration of 0.08% by weight, which was the same as that used for compound treatment, and treated with 5 μM of Aβ complex and cultured for 36 hours. For another negative control, 5 μM of Aβ complex was treated without DMSO and incubated for 36 hours.

After the incubation, in order to confirm the survival rate of the cells, the appearance of the cells in each well was observed using a microscope to count the number of dead cells and living cells. The degree of cell proliferation according to the treatment concentration of each compound was calculated based on the number of living cells in the negative control group and expressed as a cell death ratio (FIG. 1).

As a result of the above experiment, the cell death rate of the negative control group was about 40 to 55%, and the cell death rate of the positive control group was less than about 20%, while the compounds of Examples 9 and 11 were about 30% Apoptotic cell death. This shows that the compounds of the present invention (compounds of Examples 9 and 11) inhibit brain cell death by A [beta] peptide (complex).

In order to evaluate the cell death selectivity of the compounds of Examples 9 and 11, compound (0.5 μM) and etoposide (10 uM), a topoisomerase inhibitor, were administered to HT22, a cell line derived from mouse hippocampus, for 24 hours After that, viable cell number was measured by a microscope through the cell outer shape, and the cell death ratio was calculated based on the cell number before treating the compound . In this experiment, PBS was used as a positive control and DMSO was used as a negative control.

As a result, as shown in FIG. 2, the compound of the present invention did not inhibit the cell death by ethoposide. The results show that the compounds of the present invention selectively act on A [beta] -related signal transduction to lower A [beta] -induced cell death.

Claims (10)

A compound selected from the group consisting of aminoquinazoline derivatives of formula (I), pharmaceutically acceptable salts, hydrates, solvates and isomers thereof:
(I)

In this formula,
R 1 is selected from the group consisting of hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₇ alkenyl, C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, C ₃ -C ₁₂ cycloalkyl, 5-10 membered heterocycloalkyl Or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl;
Fig, sulfonyl, C ₁ -C ₅ alkyl, C ₂ -C ₇ alkenyl, C ₅ -C ₁₂ R2 and R3 are amino each independently hydrogen, halogen, hydroxy, amino, carboxyl, C ₁ -C ₅ alkyl aryl, heteroaryl of 5 to 13 won, C ₃ -C ₁₂ cycloalkyl or a 5- to 10-membered heterocycloalkyl, and the;
A is hydrogen, halogen, hydroxy, amino, carboxyl or C ₁ -C ₅ alkylamido;
X, Y and Z are each independently carbon or nitrogen;
Said alkyl, C ₂ -C ₇ alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, and C ₁ -C ₅ alkyl amido are each independently selected from halogen, hydroxy, amino, carboxyl, C ₁ -C ₅ alkyl amido, sulfonyl, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₅ -C ₁₂ aryl, 5 to 13 member heteroaryl, C ₃ -C ₁₂ cycloalkyl, 5-10 membered of Heterocycloalkyl or 5- to 10-membered heterocycloalkyl C ₁ -C ₅ alkyl.
The compound according to claim 1, wherein R 1 is C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl &Lt; / RTI &gt;
The method of claim 1, wherein the compound, characterized in that the R2 is hydrogen, halogen, C ₁ -C ₃ alkyl, cyano, carboxyl, or an acetamido.
2. A compound according to claim 1, wherein R &lt; 3 &gt; is hydrogen or halogen.
2. A compound according to claim 1, wherein A is hydrogen or 2-phenylacetamido.
2. The compound of claim 1, wherein X and Y are nitrogen and Z is carbon.
The method according to claim 1,
R <1> is C ₅ -C ₁₂ aryl, 5 to 13 membered heteroaryl, 5 to 10 membered heterocycloalkyl or 5 to 10 membered heterocycloalkyl C ₁ -C ₅ alkyl;
R2 is hydrogen, halogen, C1-C3 alkyl, cyano, carboxyl or acetamido;
R3 is hydrogen or halogen;
A is hydrogen or 2-phenylacetamido;
X and Y are nitrogen and Z is carbon.
The method according to claim 1,
R1 is benzoimidazole, phenyl, piperidinylmethyl, pyrrolidine, pyridine or piperidine;
R2 is hydrogen, halogen, C ₁ -C ₃ alkyl, cyano, carboxyl, or an acetamido;
R3 is hydrogen or halogen;
A is hydrogen or 2-phenylacetamido;
X and Y are nitrogen and Z is carbon.
A compound according to claim 1, which is selected from the group consisting of:
1) [8- (3H-Benzoimidazol-5-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;
2) [8- (3-Amino-phenoxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;
3) (lH-Indazol-6-yl) - [8- (piperidin-4-ylmethoxy) -quinazolin-2-yl] -amine;
4) (8- (4-Fluoro-1H-benzoimidazol-5-yloxy) -quinazolin-2-yl) - (1H-indazol-6-yl) -amine;
5) 3-Fluoro-4- [2- (lH-indazol-6-ylamino) -quinazolin-8-yloxy] -benzene-l, 2-diamine;
6) [5-Bromo-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;
7) [6-Bromo-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;
8) (lH-Indazol-6-yl) - [6-methyl-8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine;
9) 2-Phenyl-N- {6 - [(8-piperidin-4-yloxy) -quinazolin-2-ylamino] -1H-indazol-4-yl} -acetamide;
10) [(6-Chloro-8- (piperidin-4-yloxy) -quinazolin-2-yl] - (1H-indazol-6-yl) -amine;
11) (lH-Indazol-6-yl) - [8- (piperidin-4-yloxy) -6-propyl-quinazolin-2-yl] -amine;
12) (lH-Indazol-6-yl) - [8- (pyrrolidin-3-ylmethoxy) -quinazolin-2-yl] -amine;
13) 2- (lH-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-6-carbonitrile;
14) 2- (lH-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazoline-6-carboxylic acid;
15) N- [2- (1H-Indazol-6-ylamino) -8- (piperidin-4-yloxy) -quinazolin-6-yl] -acetamide;
16) (lH-Indazol-6-yl) - [8- (piperidin-4-yloxy) -quinazolin-2-yl] -amine; And
17) (lH-Indazol-6-yl) - [8- (pyridin-4-yloxy) -quinazolin-2-yl] -amine.
A pharmaceutical composition for preventing or treating Alzheimer's disease comprising the compound of claim 1 as an active ingredient.

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