TW201406758A - Tricyclic compounds - Google Patents

Abstract

This invention provides a useful novel compound to inhibit GSK3 and cure GSK-associated diseases. This invention provides a compound represented by the following general formula. A compound or the salts thereof represented by [wherein R1, R2, R3, R4, X1, X2 each represents the same meaning as defined in the specification].

Description

Tricyclic compound

The present invention relates to a tricyclic 5-aminoquinolone derivative having a glyco-synthetase kinase 3 (GSK3) inhibitory activity or a salt thereof.

Glyco-synthetase kinase 3 (GSK3) was discovered as a phosphoric acid/threonine which phosphorylates glycogen synthase (Non-Patent Document 1), and it is known that α and β2 subtypes exist. . In view of the lethality of the GSK3β gene-deficient mouse embryo (Non-Patent Document 2), its function is important for the survival of cells, and there are reports of Akt signals (Non-Patent Document 3) and Wnt signals that are closely related to cancer (Non-Patent Document 3). The important signals of Non-Patent Document 4) play a wide range of roles. On the other hand, it has been reported that the GSK3α gene-deficient mouse is not embryonic lethal (Non-Patent Document 5), and a part of the function related to glucose metabolism is different from normal. However, the functions are basically complementary to each other, and in the case where a gene defect of both GSKα and β is reported, strong signal suppression is observed (Non-Patent Document 6).

The target of GSK3, in addition to glycogen synthase, covers a variety of starch-like proteins, Presenilin, β-catenin, cyclin D1, etc. (Non-Patent Document 7), and as a therapeutic target in various The disease is valued.

In the field of cancer, the phosphorylation of β-catenin by GSK3 is responsible for the breakdown of β-catenin in the intracellular system, which results in inhibition of the gene expression of the transcription factor Tcf, and its status as an inhibitor of colorectal cancer. It is widely accepted (Non-Patent Document 4).

However, in recent years, anti-tumor activity by GSK3 inhibition has been reported for leukemia such as MLL leukemia and CML (Non-Patent Documents 8 and 9), and clinical trials for acute leukemia using the GSK3 inhibitor LY2090314 are also underway.

A variety of skeletons have been reported as compounds for inhibiting GSK3 (Non-Patent Document 10), and maleimide derivatives (Patent Document 1, Non-Patent Document 11) and pyrimidine derivatives (Patent Document 2, Non-Phase) have been reported. Patent Document 12), pyrimidinone derivative (Patent Document 3), pyridine derivative (Patent Document 4), azole derivative (Non-Patent Document 13), quinolinone derivative (Patent Document 5, Non-Patent Document 14), and the like .

On the other hand, as a compound having a tricyclic aminoquinolinone structure, a compound group which inhibits P2Y12 has been reported (Patent Document 6).

Prior technical literature Patent literature

Patent Document 1 WO2003/076398

Patent Document 2 WO2003/070729

Patent Document 3 WO2003/072579

Patent Document 4 WO2003/068773

Patent Document 5 WO2007/106537

Patent Document 6 EP1650192

Non-patent literature

Non-Patent Document 1 Eur. J. Biochem. 107 519-527 (1980)

Non-Patent Document 2 Nature 406 86-90 (2000)

Non-Patent Document 3 Nature 378 785-789 (1995)

Non-Patent Document 4 Science 272 1023-1026 (1996)

Non-Patent Document 5 Cell Metab. 6 329-337 (2007)

Non-Patent Document 6 Dev Cell. 12 957-971 (2007)

Non-Patent Document 7 Int. J. Alzheimers Dis. 2011 Article ID: 505607 (2011)

Non-Patent Document 8 Nature 455 1205-1209 (2008)

Non-Patent Document 9 Blood 119 2335-2345 (2012)

Non-Patent Document 10 Expert Opin. Ther. Patents 15 1315-1331 (2005)

Non-Patent Document 11 Bioorg. Med. Chem. Lett. 15 899-903 (2005)

Non-Patent Document 12 Bioorg. Med. Chem. Lett. 14 2127-2130 (2004)

Non-Patent Document 13 J. Med. Chem 46 3333-3341 (2003)

Non-Patent Document 14 Bioorg. Med. Chem. 20 1188-1200 (2012)

The present invention provides novel GSK3 inhibitory compounds. Further, the present invention provides a medicament containing a GSK3 inhibitory compound, such as an anticancer agent.

As a result of intensive studies by the inventors of the present invention, it has been found that a compound having a structure represented by the following formula (1) or a salt thereof has a strong GSK-3 inhibitory activity, and the present invention has been completed.

That is, the present invention is

[1] A compound represented by the formula (1) or a salt thereof;

Wherein R ₁ represents a carboxyl group, an amine carbenyl group or a cyano group, R ₂ represents a methyl group or a hydrogen atom, R ₃ represents a halogen atom, and R ₄ represents a piperidine which may also have a substituent selected from the following Group A; And a cyclohexyl group or a hydrogen atom which may have a substituent selected from the following group A, and X ₁ represents CH, CF or N, X. ₂ represents CH ₂ , NH or S]

Group A: C ₁ -C ₆ alkyl, ethyl sulfonyl, methylsulfonyl, or hydroxy group which may be substituted by 1 to 3 halogen atoms, a hydroxyl group or a methoxy group.

[2] The compound of [1] or a salt thereof, wherein R ₁ is a carboxyl group or a cyano group.

[3] a compound or a salt thereof, which is selected from the group consisting of:

[4] A hepatose synthase kinase 3 (GSK3) inhibitor, which comprises the compound according to any one of [1] to [3] or a salt thereof.

[5] A pharmaceutical composition according to any one of [1] to [3] or a salt thereof as an active ingredient.

[6] An anticancer agent, which comprises the compound according to any one of [1] to [3] or a salt thereof as an active ingredient.

[7] A pharmaceutical composition comprising the compound according to any one of [1] to [3] or a salt thereof, and a pharmaceutically acceptable carrier.

[8] A method for treating a cancer, which comprises administering a compound according to any one of [1] to [3] or a salt thereof.

[9] The anticancer agent according to [6], wherein the cancer is blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendic cancer, colon cancer, anal cancer, Cholecystectomy, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, uterine body cancer, cervical cancer , ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, kidney cancer, bladder cancer or testicular cancer.

[10] The treatment method of cancer according to [8], wherein cancerous blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, gastric cancer, appendix cancer, colon cancer, anal cancer, Cholecystectomy, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, uterine body cancer, cervical cancer , ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, kidney cancer, bladder cancer or testicular cancer.

According to the present invention, a novel tricyclic compound represented by the above formula (1) having GSK3 inhibitory activity can be provided. Such novel compounds are useful as therapeutic agents for diseases associated with GSK3 function, such as anticancer agents.

In the present invention, GSK3 refers to a protein encoded by the GSK3 gene. If not specifically distinguished, it includes the isomer GSKα And both GSKβ. The GSK3 protein includes a GSK3 protein encoded by the full-length GSK3 gene or a GSK3 protein encoded by a GSK3 gene variant (including a variant variant, a substitution variant or an addition variant). In the present invention, GSK3 also includes homologs from various animal species.

In the present invention, a GSK3 inhibitor refers to an inhibitor that acts as a kinase of GSK3.

In the present invention, the terms "tumor" and "cancer" are used interchangeably. Further, in the present invention, tumors, malignant tumors, cancer, malignant neoplasms, cancer tumors, sarcomas, and the like are collectively referred to as "tumor" or "cancer".

In the present invention, the "C ₁ -C ₆ alkyl group" means an alkyl group having a linear or branched chain having 1 to 6 carbon atoms. Examples of the "C ₁ -C ₆ alkyl group" include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a third butyl group.

Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The respective substituents in the formula (1) are explained below.

In the following general formula (1),

R ₁ represents a carboxyl group, an amine carbenyl group or a cyano group.

R ₂ represents a methyl group or a hydrogen atom.

R ₃ represents a halogen atom, and a fluorine atom or a chlorine atom is preferred, and a fluorine atom is particularly preferred.

R ₄ represents a piperidinyl group which may have a substituent selected from the above group A, a pyridyl group which may have a substituent selected from the above group A, or a substituent selected from the above group A. a cyclohexyl group or a hydrogen atom.

Here, the bonding position of the piperidinyl group and the pyridyl group is not particularly limited, but is preferably bonded at a position of 3 or 4 positions.

The substituent substituted with a piperidinyl group, a pyridyl group and a cyclohexyl group is not particularly limited. In the case of a piperidinyl group and a pyridyl group, it is preferably substituted on a nitrogen atom, and as the substituent, an ethylidene group and a methyl group are particularly preferable. As the substituent of the cyclohexyl group, a hydroxyl group is preferred.

X ₁ represents CH, CF or N.

X ₂ represents CH ₂ , NH or S.

Further, the compound of the present invention is more preferably any one of the following compounds.

When the compound represented by the formula (1) of the present invention has a basic group such as an amine group, a pharmaceutically acceptable salt can be prepared as desired. Examples of such a salt include a hydrogen halide such as a hydrochloride or a hydroiodide; a mineral acid salt such as a nitrate, a perchlorate, a sulfate or a phosphate; a methanesulfonate and a trifluoromethanesulfonic acid; Lower alkane sulfonate such as salt or ethanesulfonate; aryl sulfonate such as besylate or p-toluenesulfonate; formic acid, acetic acid, malic acid, fumarate, succinate, citrate , an acid salt such as tartrate, oxalate or maleate; and an amine salt such as ornidamine, glutamate or aspartate; preferably a hydrohalide and an organic acid salt.

When the compound represented by the formula (1) of the present invention has an acidic group such as a carboxyl group, a base addition salt can be generally formed. Examples of the pharmaceutically acceptable salt include an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an inorganic salt such as an ammonium salt; a dibenzylamine salt and a sulphate salt; Alkyl phenylglycine, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N,N'-di Benzyl ethylenediamine salt, diethanolamine salt, N-benzyl-N-(2-phenylethoxy)amine salt, piperazine An organic amine salt such as a salt, a tetramethylammonium salt or a hydroxymethylaminomethane salt.

The compound represented by the formula (1) or a salt thereof of the present invention may be present as a free form or a solvate. It also exists as a hydrate due to absorption of moisture in the air. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate or an ethanolate is preferable. Further, in the case where a nitrogen atom is present in the compound of the present invention represented by the formula (1), it may be an N-oxide, and such solvates and N-oxides are also included in the scope of the present invention.

The compound represented by the formula (1) of the present invention may have an optical isomer such as a cis isomer or a trans isomer, a tautomer or a d body, or a l body depending on the kind or combination of the substituent. Various isomers such as isomers, but the compounds of the present invention include all such isomers, stereoisomers, and any isomers and stereoisomers in any ratio, unless otherwise specified. mixture.

The compound represented by the formula (1) of the present invention may also contain an atomic isomer of a non-natural ratio in one or a majority of the constituent atoms. Examples of the atomic isomers include hydrazine ( ² H), hydrazine ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). These compounds are useful as therapeutic or prophylactic agents, research reagents, such as analytical reagents, and diagnostic agents, such as in vivo imaging diagnostics. All isomorphic variants of the compounds represented by the general formula (1), whether or not they are radioactive, are included in the scope of the present invention.

Furthermore, the present invention also encompasses a compound (1) which is converted into an active ingredient of the pharmaceutical composition of the present invention by a reaction of an enzyme, a gastric acid or the like under physiological conditions in vivo, that is, the compound The compound which is changed to the compound (1) by enzyme oxidation, reduction, hydrolysis, or the like, or the like, which is hydrolyzed by gastric acid or the like, is a "pharmaceutically acceptable pre-drug compound" of the compound (1).

As the precursor drug, when the compound (1) has an amine group, a compound in which the amine group is thiolated, alkylated, or phosphorylated is exemplified (for example, the amine group is thiolated, alanine-methylated, Pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinylmethylation , a trimethyl ethoxymethylated methyl group, a third butylated compound, etc.), etc., when the compound (1) has a hydroxyl group, the hydroxy group is thiolated, alkylated, phosphorylated, or borated. a compound (for example, the hydroxy group is ethoxylated, palmitoylated, propylated, trimethylacetylated, amber thiolated, fumaryl, propylamine, dimethylaminomethyl Carbonylated compounds, etc.). Further, when the compound (I) has a carboxyl group, a compound in which the carboxyl group is esterified or amide-amined (for example, the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylamino group) a compound such as a esterification, a trimethylacetoxymethyl esterification, an ethoxycarbonyloxyethyl esterification, a guanidation or a methyl amidation, etc.).

The compound of the present invention can be produced from the compound (1) by a known method. Further, the compound of the present invention is also pre-medicated In the case of the Hirokawa Bookstore's 1990 publication "Development of Pharmaceutical Products", Volume 7 of the Molecular Design, pages 163 to 198, the physiological conditions changed to the compound (1).

Next, a representative production method of the compound represented by the general formula (1) will be described. The compound of the present invention can be produced by various production methods, and the production method shown below is an example, and the present invention should not be construed as being limited to the examples. Further, at the time of the reaction, the substituent may be protected by an appropriate protecting group, and the type of the protecting group is not particularly limited. The starting materials used herein may be purchased in the form of a commercial product, or a compound known in the literature, or may be synthesized by referring to the examples or reference examples.

[Manufacturing Method 1]

When benzoic acid 2 having a nitro group can be obtained or synthesized, it can be synthesized as follows. The manufacturing procedure of the latter half of the latter half, the preferred order, varies depending on the compound. Further, the substituent R in the enamine 4 is an alkyl group such as a methyl group, an ethyl group, an isopropyl group or a t-butyl group, and COOR represents an ester group. This ester group can be synthesized in the same manner even if it is replaced with a cyano group.

The respective steps of the above schematic diagram are shown below (in the schematic diagram, R ₂ , R ₃ , R ₄ , X ₁ , and X ₂ are synonymous with the above).

step 1

The nitration reaction from compound 1 to 2 is carried out under the conditions generally known to be nitration (Albright, L.F.; Carr.R.V.C.; Schmitt, R.J. Eds. Nitration; ACS Symposium Series 623, 1996). Specifically, the substrate which is easily nitrated can be used as a solvent using acetic acid, concentrated sulfuric acid or the like as a solvent, and is used at room temperature using 1 mol to an excess of potassium nitrate. In the case of a substrate which is difficult to carry out by nitration, concentrated sulfuric acid or acetic anhydride or trifluoroacetic anhydride can be used as a solvent by using a large amount of excess nitric acid or fuming nitric acid under heating conditions. There are also cases where the solvent is not used and the nitration is carried out only with fuming nitric acid. Further, as the nitro source, a salt such as cerium (IV) nitrate or an ester such as butyl nitrite may be used. The situation. Further, there has been reported a method of coexisting nitrogen dioxide with ozone gas (Suzuki, H.; Murashima, T.; Shimizu, K.; Tsukamoto, K. Chem. Lett. 1991, 817-818).

Step 2

The conversion from the compound to 23 is carried out in the presence of a catalyst amount of N,N-dimethylformamide in a suitable solvent (dichloromethane, tetrahydrofuran, etc.) which does not adversely affect the reaction. The excess of the grass is carried out by the action of chlorine. The reaction time is from 30 minutes to 24 hours, and the reaction temperature is from 0 ° C to 80 ° C, preferably from 0 ° C to room temperature. Thionyl chloride can also be used as a reagent. In general, the residue of the reagent and the solvent is directly used in the next step.

Step 3

The conversion from compound 3 to 5 can be made to 1 mol to several moles of the corresponding enamine 1 molar in a suitable solvent (toluene, tetrahydrofuran, acetonitrile, etc.) which does not adversely affect the reaction. Implemented by chlorine action. If necessary, a base such as triethylamine or diisopropylethylamine may be present in a molar amount of several moles. The reaction temperature is in the range of 0 ° C to 100 ° C, preferably 0 ° C to room temperature. When it is desired to carry out the cyclization reaction, it may be heated to 50 ° C to 100 ° C in the presence of a base. The reaction time is preferably from 30 minutes to 10 hours, more preferably from about 30 minutes to 3 hours.

Step 4

The cyclization reaction from compound 5 to 6 is carried out in a suitable solvent (tetrahydrofuran, acetone, acetonitrile, etc.) which does not adversely affect the reaction, using a suitable base such as sodium hydride or potassium carbonate. . It can be carried out at a reaction temperature of from 0 ° C to 100 ° C. Use sodium hydride Preferably, it is 0 ° C to 40 ° C, and when potassium carbonate is used, it is preferably 60 ° C to 100 ° C. The reaction time is preferably from about 30 minutes to 10 hours, more preferably from about 30 minutes to 3 hours.

Step 5

The reduction reaction from compound 6 to 7 is carried out in a suitable solvent (N,N-dimethylformamide, dichloroethane, etc.) which does not adversely affect the reaction, and is used for a substrate under a hydrogen atmosphere. 100 wt% of palladium carbon catalyst was used. The reaction time varies depending on the matrix and ranges from several hours to several days. The reaction temperature is preferably from about 0 ° C to 40 ° C. The reduction reaction from compound 9 to 10, 12 to 13 was also carried out in the same manner.

Other catalysts such as palladium hydroxide and platinum carbon catalyst may be used, and it may be reduced under acidic conditions using a metal such as iron or zinc. Further, a salt such as sodium dithionite may also be used.

Step 6

The substitution reaction from compound 7 to 8 is carried out in an appropriate solvent (N,N-dimethylhydrazine, N-methylpyrrolidone or the like) which does not adversely affect the reaction, and amine 1 is used for the mother nucleus 1 mole. Moer ~ a few moles to implement. Depending on the case, a base such as triethylamine is allowed to coexist. In the case of the quinolinone core, the reaction temperature is preferably from 40 ° C to 150 ° C, more preferably from 60 ° C to 100 ° C. The reaction time is carried out in a few hours to several days. when In the case of a ruthenium core (X1 is an N atom), the reactivity of the mother nucleus is low, and the reaction temperature is 80 ° C to 120 ° C, and the reaction time is 12 hours to several days, but it is preferably in a microwave reaction apparatus. The method of heating at 160 ° C for 1 hour. Further, it can also be synthesized by performing a coupling reaction using a metal catalyst such as palladium. In this case, the reaction site is preferably a fluorine atom or a chlorine atom instead of a fluorine atom. As a solvent, it is especially preferred as 1,4-two Alkane and toluene are 1 molar to the mother nucleus, 1 mole to several moles of amine or aromatic amine, 1 mole to several moles of sodium citrate, sodium butoxide, etc. Medium ginseng (dibenzylideneacetone) dipalladium, etc. 0.01~0.1 mol, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or 2 as a catalytic ligand. 0.01-0.2 mol of 2'-bis(diphenylphosphino)-1,1'-binaphthyl, etc., is carried out at a reaction temperature of 70 ° C to 120 ° C and a reaction time of 6 hours to several days. The same applies to the case of the compound 10 to 11, and the 13 to 14.

Step 7

Deesterification from compound 6 to 9, in the case of methyl ester, ethyl ester or isopropyl ester, is carried out under ordinary basic conditions. It is used in an appropriate solvent such as an alcohol which is easily mixed with water, and is used in an amount of 1 mol to a large excess of aqueous sodium hydroxide solution, preferably about 3 to 10 m. The reaction temperature is from room temperature to 100 ° C, preferably from 50 ° C to 80 ° C. The reaction time is carried out in about several hours to one day. In addition to sodium hydroxide, potassium hydroxide, lithium hydroxide or the like can be used. Further, depending on the case, a reaction such as concentrated hydrochloric acid-acetic acid under acidic conditions may be selected. On the other hand, in the case of the third butyl ester, a few moles of a large excess of trifluoroacetic acid are allowed to act in a suitable solvent (dichloromethane or the like) which does not adversely affect the reaction. The reaction temperature is preferably from 0 ° C to room temperature, and the reaction time is preferably from 1 hour to 1 day. The same applies to the case of the compound 7 to 10 and the compound 8 to 11.

Step 8

The amidation step from compound 9 to 12 may also be carried out in a suitable solvent (dichloromethane or the like) which does not adversely affect the reaction, for 1-ethyl-3-(3-dimethylaminopropyl). A condensing agent such as carbodiimide is added to an acidic additive such as HOBt (1-hydroxybenzotriazole), but it is preferred to use (benzotriazol-1-yloxy)tripyrrolidinium hexafluorophosphate ( (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) 1 moles to several moles, triethylamine and other base number of moles ~ a large excess of moles, ammonium chloride and other nitrogen sources a few moles ~ a large excess of Moer to implement. The reaction temperature is about 0 ° C to 40 ° C, and the reaction time is about several hours to several days. Further, depending on the substrate, for example, after preparing ruthenium chloride using grass chloroform or the like, a simple method of adding ammonia water to the reaction system can also be synthesized. The solvent system is preferably one which does not adversely affect the reaction, and is easily mixed with water (tetrahydrofuran, acetonitrile, two Alkane, etc.). The reaction temperature is carried out at about 0 ° C to 60 ° C. The reaction time is from 30 minutes to several days, preferably from 30 minutes to several hours. On the other hand, it is also possible to synthesize without heating the ester and heating it with an ammonia/methanol solution or ammonia water in a sealed tube. The reaction temperature is 60 ° C to 100 ° C, and the reaction time is half a day to several days. The steps from compound 10 to 13 and from compound 11 to 14 are also carried out in the same manner.

Step 9

The cyanation step of the compounds 14 to 15 can also be carried out by using a dehydrating agent such as triphosgene or phosphorus pentachloride, but it is preferably used in Tetrahedron Letter, No. 21, pp1813-1816, 1977. The method of acetic anhydride. In a solvent (dichloroethane, etc.) which does not adversely affect the reaction, trifluoroacetic anhydride 1 mol to excess molar, triethylamine or the like is used. 1 mole ~ excess mole. Alternatively, the reaction can be carried out in pyridine as a solvent and a base. The reaction temperature is preferably from 0 ° C to 40 ° C, and the reaction time is preferably from 30 minutes to several days.

[Manufacturing Method 2]

It can be synthesized from benzoic acid without nitro group as follows. The timing of carrying out the cyclization reaction varies depending on the compound. As the nitrogen source, benzylamine, allylamine, azide, ammonia or the like can be used (in the schematic view, R, R ₂ , R ₃ , R ₄ , X ₁ and X ₂ are synonymous with the above).

Step 10

From the introduction of the compound 18 to the N atom of 20, the p-methoxybenzylamine can be made in a solvent (N,N-dimethylformamide, etc.) which does not adversely affect the reaction. The ear acts to proceed. Preferably, an amine which is easily deprotected such as p-methoxybenzylamine or allylamine is selected. The reaction temperature is from 60 ° C to 200 ° C, preferably from 80 ° C to 100 ° C. The reaction time is carried out in a few hours to several days. As other nitrogen sources, sodium azide can also be selected. The procedure from compound 19 to 21 was also carried out in the same manner.

Step 11

The deprotection step from compound 21 to 11-p-methoxybenzylamine can be as PROTECTIVE GROUPS in Organic Synthesis It is described that contact reduction using a palladium carbon catalyst or the like in a hydrogen atmosphere or an oxidative removal method using DDQ or the like is used. Preferably, in a suitable solvent (dichloromethane, dichloroethane, etc.) which does not adversely affect the reaction, a trifluoroacetic acid number of moles is used, and a large excess is used, and if necessary, a catalyst amount is added to a few moles of benzoic acid. The method of ether. The reaction temperature is from room temperature to 60 ° C, and the reaction time is from several hours to about half a day. Subsequent conversion to a carboxylic acid and a substitution reaction were carried out in the same manner as in Steps 6 and 7.

When allylamine is used, it can be carried out by a method using isomerization of an allyl group as described in PROTECTIVE GROUPS in Organic Synthesis. Preferably, in the alcohol solution, a palladium carbon catalyst is used in an amount of 10 to 100% by weight, and methanesulfonic acid or trifluoroacetic acid is 1 mol to a large amount of excess molar coexistence. The reaction temperature is from room temperature to 100 ° C, preferably from 60 to 80 ° C. The reaction time is carried out in a few hours to one day. The subsequent conversion to a carboxylic acid and a substitution reaction are carried out in the same manner as in the steps 6 and 7.

[Manufacturing Method 3]

The compound in which the 9-position of the quinoline ring is a hydrogen atom may be a benzoic acid equivalent, but may be easily synthesized by a method in which a halogen atom is reductively removed as follows (in the schematic view, R represents an ester group, a carboxyl group, Aminomethyl hydrazino, nitrile, R ₂ , R ₃ , R ₄ , X ₁ , X ₂ are synonymous with the above).

Step 12

The reduction reaction from the compound 22 to 23 is carried out using a suitable solvent (dichloroethane, methanol, ethanol, tetrahydrofuran containing an antioxidant such as BHT, etc.) which does not adversely influence the reaction. It is preferred to use a mixed solvent of an aprotic solvent and an alcohol. It is carried out under a hydrogen atmosphere using a catalyst such as palladium carbon in an amount of 10 to 100% by weight, preferably about 30 to 50% by weight. The reaction temperature is 0 to 40 ° C, but is preferably room temperature. The reaction time is carried out in a few hours to several days.

[Manufacturing Method 4]

The pyridine type compound can be synthesized from the following brominated intermediate 25 in the same manner as in the above "Production Method 2".

Step 13

The bromination reaction from the compound 24 to 25 is carried out in a suitable solvent (tetrahydrofuran, diethyl ether or the like) which does not adversely affect the reaction, and a suitable alkali such as methyl lithium or n-butyllithium of 2 mol or more is used. Thereafter, a bromine source (1,2-dibromotetrachloroethane or phenyltrimethylammonium bromide or the like) is used in an amount of 1 mole to a large excess of moules, preferably about several moles. The reaction temperature is about -100 ° C to room temperature, and the reaction time is 30 minutes to 6 hours.

[Manufacturing Method 5]

The above enamine 4 can be synthesized by a known method as described in the literature (Synthesis, (7), 1162-1170, 2006 (Method A) or Europian Journal Organic Chemistry (3) 505-511, 2005 (Method B).

The compound of the present invention inhibits GSK3 and thus acts as a GSK3 inhibitor. It is known that GSK3 is involved in diabetes and Alzheimer's disease, and thus the compounds of the present invention are also useful for the treatment of such diseases, but are preferably used for cancer treatment.

The type of cancer to be treated is not particularly limited as long as it is a cancer that is sensitive to the GSK3 inhibitor, but includes blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, and esophagus. Cancer, stomach cancer, appendix cancer, colon cancer, anal cancer, biliary tract cancer, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor , melanoma, breast cancer, uterine body cancer, cervical cancer, ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, kidney cancer, bladder cancer or testicular cancer.

It is preferably a blood cancer such as leukemia or acute leukemia in which a MLL (mixed-lineage leukemia) gene is transposed, pancreatic cancer, colorectal cancer, glioma cells, melanoma, or the like in which activation of GSK3 can be observed.

The proliferation inhibitory activity of the cells can be examined using a proliferation inhibition test method generally used by those skilled in the art. The proliferation inhibitory activity of the cells can be carried out, for example, by comparing the degree of proliferation of cells (for example, tumor cells) in the presence or absence of a test compound as described in Test Example 2 below. The degree of proliferation can be tested using, for example, a test line for measuring living cells. Examples of the method for measuring living cells include an incorporation test of [ ³ H]-thymidine, a BrdU method, an MTT assay, and the like.

Further, the anti-tumor activity in vivo can be examined using an anti-tumor test method commonly used by those having ordinary knowledge in the art. For example, by transplanting various tumor cells to mice, rats, etc., and confirming the survival of the transplanted cells, the compound of the present invention can be administered orally, intravenously, etc., after several days to several weeks, compared with The anti-tumor activity of the present invention in vivo was confirmed by the tumor-free proliferation of the drug in the group and the tumor growth in the compound administration group.

The pharmaceutical composition of the present invention comprises a compound of the present invention and a pharmaceutically acceptable carrier, and can be administered as various injections such as intravenous injection, intramuscular injection, subcutaneous injection, or oral administration or transdermal administration. And other methods are given. A pharmaceutically acceptable carrier means a pharmaceutically acceptable material relating to the delivery of a compound of the invention or a composition comprising a compound of the invention from an organ or organ to other organs or organs (eg, shaping) Agents, diluents, additives, solvents, etc.).

As a preparation method of the preparation, an appropriate preparation (for example, an oral preparation or an injection) can be selected according to the administration method, and it can be prepared by the preparation of various preparations which are usually used. As the oral preparation, for example, a tablet, Powders, granules, capsules, pills, tablets, solutions, syrups, elixirs, emulsions, or oily or aqueous suspensions, and the like. In the case of oral administration, the state of the free body or the state of the salt can be maintained. The aqueous preparation can be prepared by forming an acid addition product with a pharmaceutically acceptable acid or by forming an alkali metal salt such as sodium. In the case of an injection, a stabilizer, a preservative or a dissolution aid or the like can be used in the preparation. It may also be used as a preparation prepared at the time of use, and a solution containing such an auxiliary agent or the like may be contained in a container, and then freeze-dried or the like to prepare a solid preparation. Further, the one-time administration component may be accommodated in one container, or the multiple administration component may be accommodated in one container.

As the solid preparation, for example, a tablet, a powder, a granule, a capsule, a pill, or a tablet can be mentioned. These solid preparations may contain both the compound of the present invention and a pharmaceutically acceptable additive. Examples of the additives include fillers, extenders, binders, disintegrators, dissolution promoters, wetting agents, and lubricants, and these may be selected and mixed as needed.

As the liquid preparation, for example, a solution, a syrup, an elixir, an emulsion, or a suspending agent can be mentioned. These liquid preparations may contain both the compound of the present invention and a pharmaceutically acceptable additive. As the additive, for example, a suspending agent or an emulsifier may be mentioned, and these may be selected and mixed as needed, and formulated.

The compound of the present invention can be used for the treatment of mammals, especially human cancers. The dosage and the interval of administration depend on the location of the disease, the height, weight, sex or medical history of the patient, and may be appropriately selected according to the judgment of the physician. In the case where a human is administered a compound of the present invention, the administration amount ranges from about 0.01 mg/kg body weight to about 500 mg/kg body weight per day. It is preferably from about 0.1 mg/kg body weight to about 100 mg/kg body weight. In the case of administration to a human, it is preferably administered once every day, or from 2 to 4 times, preferably at appropriate intervals. Further, the amount of one day may be more than the above amount as needed according to the judgment of the physician.

The compounds of the invention may also be used in combination with other anti-tumor agents. Examples thereof include antitumor antibiotics, antitumor plant components, BRM (biological responsive control substances), hormones, vitamins, antitumor antibodies, molecular target drugs, alkylating agents, metabolic antagonists, and other antitumor agents. Agents, etc.

More specifically, examples of the alkylating agent include alkylating agents such as nitrogen mustard, nitrogen mustard N-oxide or chlorambucil, carboquone or thiotepa An aziridine-based alkylating agent such as thiotepa, an epoxide-based alkylating agent such as dibromomannitol or dibromodulcitol, carmustine, and lomo Lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin or ramustine (ranimustine) and other nitrosourea alkylating agents, busulfan, improsulfan tosilate or dacarbazine.

Examples of the various metabolic antagonists include an anthraquinone metabolic antagonist such as 6-mercaptopurine, 6-thioguanine or sulphoinosine, fluorouracil, tegafur, tegafur uracil, and carmofur ( Carbofur, dextrofluridine, broxuridine, cytarabine or enocitabine Agent, f-aminopterin or trimetrexate (trimetrexate) and other folate metabolism antagonists.

As the antitumor antibiotic, for example, mitomycin C, bleomycin, pilomycin, daunorubicin, arubicin, doxorubicin, pirarubicin, THP-doxorubicin can be cited. (adriamycin), 4'-Epi-doxorubicin or anthracycline is an antibiotic agent, chromomycin A3 or actinomycin D.

Examples of the antitumor plant component include vinca alkaloids such as vindesine, vincristine or vinblastine, paclitaxel, and docetaxel. Cedar, or etoposide or teniposide, such as epipodophyllotoxin.

Examples of the BRM include tumor necrosis factor or indomethacin.

Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasinone, betamethasone, triamcinolone, oxymetholone, Nandrolone, methenolone, fosfestrol, ethinylstilbestrol, chlormadinone or medroxyprogesterone.

Examples of the vitamin include vitamin C or vitamin A.

Examples of the antitumor antibody and the molecular target drug include trastuzumab, rituximab, cetuximab, nimotuzumab, and tibezumab. Nodumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib , sunitinib (sunitinib), lapatinib (lapatinib), sorafenib (sorafenib) and the like.

As other antitumor agents, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, and ifosfamide may be mentioned. Ifosfamide), cyclophosphamide, melphalan (melphalan), L-aspartate glutamate, aceglatone, sizofiran, picibanil, procarbazine Procarbazine), pipoburoman, neocarzinostatin, hydroxyurea, ubenimex or krestin.

Also included in the present invention are methods and/or methods of preventing cancer which are characterized by administration of a compound of the present invention or a salt thereof.

Further, the present invention also encompasses the use of the compound of the present invention, a salt thereof or a solvate thereof for producing the above-mentioned medicine.

[Examples]

The present invention will be specifically described by the following examples, but the present invention is not limited thereto, and is not limited by any meanings. Further, in the present specification, the reagents, solvents, and starting materials not specifically described may be obtained from commercially available sources, or may be synthesized according to a method known in the literature.

Reference examples and examples (synthesis) related to the present invention are shown below.

Example 1

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-{[3-(pyridin-2-yl)propyl]amino}-1,2 -dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(step 1)

Ethyl [(4R)-4-methyl-1,3-tetrahydrothiazole-2-ylidene]

To a solution of (2R)-2-aminopropane-1-thiol (5 g, 39.17 mmol) in ethanol (50 mL), EtOAc (EtOAc) (4.52 g, 39.17 mmol). The reaction solution was warmed to 80 ° C and stirred for 3 days. The reaction solution was returned to room temperature, diluted with chloroform, and washed with saturated aqueous sodium hydrogen carbonate and brine. After drying over anhydrous sodium sulfate, the title compound (m.

¹ H-NMR (DMSO-D ₆ ) δ: 1.12-1.28 (6H, m), 2.84 (1H, dd, J = 11.4, 6.5 Hz), 3.33 (1H, dd, J = 9.9, 5.7 Hz), 3.93 -4.03 (2H, m), 4.08-4.18 (1H, d, J = 40.0 Hz), 4.51 (1H, s), 8.16 (1H, brs)

ESI m/z188(M+H) ⁺

(Step 2)

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-oxo-1,2-dihydro-5H-[1,3]thiazolo[3,2- a] ethyl quinoline-4-carboxylate

2,3,4,5-Tetrafluoro-6-nitro-benzoic acid (20.80 g, 86.99 mmol) was suspended in dichloromethane (200 mL), and dichloromethane (17.51 mL, 200.74 mmol) was added dropwise at room temperature. And 1 drop of N,N-dimethylformamide was stirred for 18 hours. To a solution of the residue obtained by concentrating the residue in vacuo <RTI ID=0.0> (12.53 g, 66.91 mmol), diisopropylethylamine (34.97 mL, 200.74 mmol). After heating to 90 ° C and stirring for 4 hours, the reaction liquid was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aq. After drying over anhydrous sodium sulfate, the title compound (10.1 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, t, J = 7.1 Hz), 1.51 (3H, d, J = 6.6 Hz), 3.05 (1H, d, J = 11.5 Hz), 3.63 (1H, Dd, J = 11.5, 7.6 Hz), 4.41 (2H, q, J = 7.1 Hz), 5.74 - 5.81 (1H, m)

(Step 3)

(1R)-6-amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1,3]thiazolo[3,2- a] ethyl quinoline-4-carboxylate

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-o-oxy-1,2-dihydro-5H-[1,3]thiazolo[3,2 -a]ethyl quinoline-4-carboxylate (3.91 g, 10.07 mmol) was dissolved in N,N-dimethylformamide (50 mL), and 10% Pd-C (AD, wet weight 3 g) was added to The mixture was stirred at room temperature for 30 hours under a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was poured into water, and the precipitated solid was filtered to give the title compound (2.79 g).

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1 Hz), 1.44 (3H, d, J = 6.6 Hz), 2.95 (1H, d, J = 11.5 Hz), 3.55 (1H, Dd, J=11.5, 7.7 Hz), 4.39-4.49 (2H, m), 5.68-5.75 (1H, m), 7.00 (2H, s)

(Step 4)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-{[3-(pyridin-2-yl)propyl]amino}-1,2 -Dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1,3]thiazolo[3,2 -a]ethyl quinoline-4-carboxylate (2.79 g, 7.79 mmol) dissolved in dimethyl hydrazine (50 mL), 3-(2-pyridyl)propylamine (4.88 g, 23.36 mmol), triethyl Amine (7.60mL, 54.50 mmol), stirred at 120 ° C for 8 hours and at 90 ° C for 15 hours. The reaction solution was diluted with chloroform, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 1.39 (3H, d, J = 6.1 Hz), 1.42 (3H, t, J = 7.1 Hz), 2.04-2.12 (2H, m), 2.87-2.93 (3H, m ), 3.45-3.56 (3H, m), 4.39-4.47 (2H, m), 4.53 (1H, br s), 5.64-5.74 (1H, m), 6.74 (2H, br s), 7.11-7.18 (2H , m), 7.61 (1H, td, J = 7.6, 1.9 Hz), 8.51 - 8.57 (1H, m)

(Step 5)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-{[3-(pyridin-2-yl)propyl]amino}-1,2 -dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,9-difluoro-1-methyl-5-oxo-8-{[3-(pyridin-2-yl)propyl]amino}-1, Ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate (3.80 g, 8.01 mmol) was dissolved in ethanol (50 mL) and 1M sodium hydroxide was added dropwise. Aqueous solution (48.05 mL, 48.05 mmol). The reaction solution was heated to 60 ° C and stirred for 2.5 hours. After a large portion of the ethanol was evaporated under reduced pressure, 1M aqueous hydrochloric acid (50 mL) and a saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the mixture was extracted with 10% methanol / chloroform. After concentrating under reduced pressure, the title compound was evaporated.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, d, J = 6.7 Hz), 2.08-2.15 (2H, m), 2.88-3.00 (3H, m), 3.52-3.63 (3H, m), 5.01 (1H, br s), 5.72-5.78 (1H, m), 6.49 (2H, br s), 7.13-7.18 (2H, m), 7.62 (1H, td, J = 7.6, 1.8 Hz), 8.55 (1H ,d,J=4.3Hz)

HRESIMS calculated for C ₂₁ H ₂₀ F ₂ N ₄ O ₃ S+H 447.13024, found 447.12693

Example 2

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-(methylamino)-1,2-dihydro-5H-[1,3]thiazole And [3,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-(methylamino)-1,2-dihydro-5H-[1,3]thiazole And [3,2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[[sub. 1,3]Ethylthiazolo[3,2-a]quinoline-4-carboxylate (300 mg, 0.84 mmol) was dissolved in dimethylhydrazine (20 mL), and methylamine hydrochloride (452 mg, 6.70 mmol) was added. Triethylamine (254 mg, 2.51 mmol) was stirred at 100 ° C for 19 hours. The reaction mixture was diluted with EtOAc. The solvent was evaporated.

¹ H-NMR (CDCl ₃ ) δ: 1.36-1.45 (6H, m), 2.88 (1H, d, J = 11.5 Hz), 3.12-3.18 (3H, m), 3.49 (1H, dd, J = 11.5, 7.7 Hz), 4.06 (1H, br s), 4.36-4.51 (2H, m), 5.66-5.72 (1H, m), 6.76 (2H, br s)

(Step 2)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-(methylamino)-1,2-dihydro-5H-[1,3]thiazole And [3,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,9-difluoro-1-methyl-5-oxooxy-8-(methylamino)-1,2-dihydro-5H-[1,3] Ethyl thiazolo[3,2-a]quinoline-4-carboxylate (288 mg, 0.78 mmol) was dissolved in dimethyl hydrazide (5 mL), and 1M aqueous sodium hydroxide (4.0 mL, 4.0 mmol). The reaction solution was heated to 60 ° C and stirred for 2 hours. After distilling off most of the ethanol under reduced pressure, 1N aqueous hydrochloric acid (4 mL) was added and then extracted with 10% methanol / chloroform. After concentrating under reduced pressure, the title compound was crystalljjjjjjjjjj

¹ H-NMR (DMSO-D ₆ ) δ: 1.30 (3H, d, J = 6.1 Hz), 3.00 - 3.11 (3H, m), 3.14 (1H, d, J = 11.7 Hz), 3.58 (1H, dd , J=11.7, 7.7 Hz), 5.67-5.81 (1H, m), 6.38 (1H, br s), 7.18 (2H, br s)

HRESIMS calculated: C ₁₄ H ₁₃ F ₂ N ₃ O ₃ S+H 342.07239, found 342.006854

Example 3

(1R)-6-amino-8-{[(2S)-1,4-di Alkan-2-ylmethyl]amino]-7,9-difluoro-1-methyl-5-o-oxy-1,2-dihydro-5H-[1,3]thiazolo[3,2 -a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1, obtained in Step 3 of Example 1. 3] Ethyl thiazolo[3,2-a]quinoline-4-carboxylate (50 mg, 0.14 mmol) in dimethyl sulfonium solution (1 ml), 1-[(2S)-1,4- two Alkan-2-yl]methylamine (49 mg, 0.42 mmol) and triethylamine (58 μl, 0.42 mmol) were stirred at 100 ° C overnight. After diluting with ethyl acetate, it was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (ethyl acetate-hexane) to give a solid. A 1 M aqueous sodium hydroxide solution (780 μl, 0.78 mmol) was added to the obtained solid (55 mg). The mixture was neutralized with aq. EtOAc. The title compound (38 mg, 69%) was obtained eluted elute

¹ H-NMR (DMSO-D ₆ ) δ: 1.30 (3H, d, J = 5.7 Hz), 3.15 (1H, d, J = 11.5 Hz), 3.25 (1H, dd, J = 11.5, 9.7 Hz), 3.33-3.77(9H,m),5.71-5.78(1H,m),6.26(1H,br s),7.23(2H,br s)

MS (ESI) m/z: 428 [M+H] ⁺

Example 4

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1-methyl-5-sideoxy-1,2 -dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-6-amino-8-{[(1-tert-butoxycarbonyl)piperidin-4-yl]amino}-7,9-difluoro-1-methyl-5-side oxygen Ethyl-1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[[sub. 1,3]ethyl thiazolo[3,2-a]quinoline-4-carboxylate (100 mg, 0.28 mmol), 4-amino-1-t-butoxycarbonylpiperidine (190 mg, 0.95 mmol) A mixture of N-methylpyrrolidone (1 ml) was stirred at 100 ° C for 11 hours. The reaction mixture was partitioned between EtOAc (EtOAc m. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.38-1.44 (10H, m), 1.47 (9H, s), 2.83-2.96 (3H, m), 3.50 (1H, dd, J = 11.2, 7.6 Hz), 3.76 -3.85 (2H, m), 4.03-4.10 (2H, m), 4.39-4.47 (2H, m), 5.65-5.72 (1H, m), 6.79 (1H, br s)

(Step 2)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-(piperidin-4-ylamino)-1,2-dihydro-5H-[ 1,3]ethyl thiazolo[3,2-a]quinoline-4-carboxylate

(1R)-6-Amino-8-{[(1-tert-butoxycarbonyl)piperidin-4-yl]amino}-7,9-difluoro-1-methyl-5-side Ethyloxy-1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate (140 mg) was dissolved in dichloromethane (1 mL) Trifluoroacetic acid (2 ml) was added and stirred at room temperature for 30 min. The solvent was evaporated to dryness crystals crystals crystals

¹ H-NMR (DMSO-D6) δ: 1.26 (3H, t, J = 7.0 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.65-1.75 (2H, m), 2.00-2.06 (2H, m), 2.93-3.03 (2H, m), 3.11 (1H, d, J = 11.4 Hz), 3.29-3.36 (2H, m), 3.55 (1H, dd, J = 11.4, 7.3 Hz), 3.77-3.86 (1H,m), 4.20 (2H,q,J=7.0Hz), 5.56-5.77(3H,m), 8.21-8.31(1H,m),8.52-8.59(1H,m)

(Step 3)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1-methyl-5-sideoxy-1,2 -dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,9-difluoro-1-methyl-5-oxo-8-(piperidin-4-ylamino)-1,2-dihydro-5H- [1,3]Ethyl thiazolo[3,2-a]quinoline-4-carboxylate (56 mg, 0.13 mmol) was dissolved in dichloromethane (1 ml), triethylamine (27 μl) Chlorochloride (12 μl) was stirred at the same temperature for 0.5 hours. The reaction mixture was partitioned between EtOAc (EtOAc m. The residue was purified by silica gel chromatography (chloroform:methanol = 19:1) to afford solid.

The solid (40 mg, 0.08 mmol) obtained above was dissolved in tetrahydrofuran (0.5 ml)-ethanol (0.5 ml), and 1M aqueous sodium hydroxide (0.29 ml) was added, and the mixture was stirred at 60 ° C for 8 hours. After the reaction mixture was allowed to cool, 1M hydrochloric acid (0.3 ml) was added under ice-cooling, and the mixture was partitioned to ethyl acetate-saturated brine. The organic layer was dried (MgSO4).

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.44 (2H, m), 1.41 (3H, d, J = 6.3 Hz), 2.12-2.20 (2H, m), 2.13 (3H, s), 2.74-2.83 (1H,m), 2.98 (1H,d,J=11.5Hz), 3.16-3.25(1H,m), 3.58(1H,dd,J=11.5,7.8Hz),3.83-4.09(3H,m), 4.60 (1H, d, J = 12.9 Hz), 5.71-5.79 (1H, m), 6.54 (2H, br s)

Example 5

(1R)-8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7,9-difluoro-1-methyl-5-sideoxy -1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-6-amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1,3]thiazolo[3,2- a] quinoline-4-carboxylic acid

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1] obtained in Step 3 of Example 1. , 3] a suspension of ethyl thiazolo[3,2-a]quinoline-4-carboxylate (11.27g) in ethanol (50ml), heated at 65 ° C, adding 1M aqueous sodium hydroxide solution for 10 minutes (33.5ml). After stirring at the same temperature for 50 minutes, it was cooled to room temperature. Acetic acid (1.92 ml) was added to the reaction mixture, and the mixture was stirred at room temperature, and the precipitated solid was filtered and washed with water. The mixture was dried while being heated by vacuum pumping to 40 ° C to obtain a mixture (3.75 g) of a mixture of the desired carboxylic acid having a molar purity of about 70%. This intermediate was used in the next reaction without further purification.

ESI-MS m/z: 331 (M+H) ⁺

(Step 2)

(1R)-8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7,9-difluoro-1-methyl-5-sideoxy -1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

The solid obtained in the previous step (200 mg), 1-[(3S)-3-amino-1-piperidyl]ethanone (175 mg, 1.23 mmol) and diiso Propylethylamine (200 μl, 1.15 mmol) was dissolved in dimethyl hydrazine (3.0 ml) and stirred at 100 ° C for 2 days. The reaction mixture was diluted with EtOAc. After the solvent was distilled off, the title compound (yield: 93 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.43 (3H, m), 1.53-1.86 (3H, m), 2.00-2.20 (4H, m), 2.96 (1H, t, J = 11.4 Hz), 3.18 -3.66 (3.7H, m), 3.79-4.07 (2.3H, m), 4.14-4.36 (1H, m), 5.66-5.82 (1H, m), 6.31-6.76 (2H, br)

MS (ESI) m/z: 453 (M+H) ⁺

Example 6

(1R)-8-{[(3R)-1-Ethylpiperidin-3-yl]amino}-6-amino-7,9-difluoro-1-methyl-5-sideoxy -1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

Using the solid obtained in Step 1 of Example 5 and 1-[(3R)-3-amino-1-piperidinyl]ethanone, the title of the solid was obtained in the same manner as in Step 2 of Example 5. Compound.

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 6.0 Hz), 1.51-1.71 (2H, m), 1.71-1.89 (1H, m), 2.05-2.19 (4H, m), 2.97 (1H, t, J = 11.2 Hz), 3.13-3.40 (2H, m), 3.48-3.66 (1.5H, m), 3.78-4.01 (2H, m), 4.08-4.32 (1.5H, m), 5.65 -5.84(1H,m),6.32-6.78(2H,m)

MS (ESI) m/z: 453 (M+H) ⁺

Example 7

(1R)-6-Amino-7,9-difluoro-1-methyl-8-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}-5 -Sideoxy-1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

Using the solid obtained in Step 1 of Example 5 and (3R)-1-(methylsulfonyl)piperidin-3-ylamine, the title of the solid was obtained in the same manner as in Step 2 of Example 5. Compound.

¹ H-NMR (CDCl ₃ ) δ: -4.45 (1H, s), 1.40 (3H, d, J = 6.3 Hz), 1.66-1.81 (2H, m), 1.82-2.00 (2H, m), 2.82 ( 3H, s), 2.96 (1H, d, J = 11.2 Hz), 3.15-3.27 (2H, m), 3.28-3.38 (1H, m), 3.46-3.65 (2H, m), 4.04-4.16 (1H, m), 4.43-4.54 (1H, m), 5.70-5.81 (1H, m), 6.36-6.68 (2H, br)

MS (ESI) m / z: 489 (M + H) ⁺

Example 8

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, 2-Dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-9-chloro-7,8-difluoro-1-methyl-6-nitro-5-oxo-1,2-dihydro-5H-[1,3]thiazolo[3, 2-a]quinoline-4-carboxylic acid ethyl ester

3-Chloro-2,4,5-trifluoro-6-nitro-benzoic acid (6.24 g, 24.4 mmol) was suspended in dichloromethane (80 ml), and 2 drops of N,N-dimethylformamidine were added dropwise. The amine was added dropwise with chloroform (4.26 ml, 48.8 mmol) at room temperature over 20 minutes. After stirring at room temperature for 2 hours, it was concentrated under reduced pressure, and toluene was evaporated to give an oily residue. A part of the above residue (4.76 g) was dissolved in tetrahydrofuran (60 ml), and [(4R)-4-methyl-1,3-tetrahydrothiazole obtained in the step 1 of Example 1 was added dropwise under ice cooling. Ethyl 2-acetate (2.50 g, 13.4 mmol) in tetrahydrofuran (10 mL). After stirring at room temperature for 1 hour, aq. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness crystals crystals crystals crystals crystals The oil was dissolved in tetrahydrofuran (50 mL). EtOAc (EtOAc) After stirring at room temperature for 45 minutes, a 10% aqueous citric acid solution was added to the mixture and the mixture was evaporated. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and purified by silica gel column chromatography (hexane: ethyl acetate = 1:1). The obtained solid was washed with EtOAc (EtOAc)

¹ H-NMR (CDCl ₃ ) δ: 1.24-1.45 (6H, m), 3.01 (1H, d, J = 11.4 Hz), 3.59 (1H, dd, J = 10.5, 7.3 Hz), 4.38-4.44 (2H , m), 6.72-6.78 (1H, m)

(Step 2)

(1R)-6-amino-9-chloro-7,8-difluoro-1-methyl-5-oxo-1,2-dihydro-5H-[1,3]thiazolo[3, 2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-amino-7,8-difluoro-1-methyl-5-oxooxy-1,2-dihydro-5H-[1,3]thiazolo[3,2-a] Ethyl quinoline-4-carboxylate

(1R)-9-Chloro-7,8-difluoro-1-methyl-6-nitro-5-o-oxy-1,2-dihydro-5H-[1,3]thiazolo[3 , a mixture of ethyl 2-a]quinoline-4-carboxylate (1.74 g, 4.30 mmol) in tetrahydrofuran (30 ml) and N,N-dimethylformamide (15 ml), 5% palladium carbon (AD, wet weight 870 mg), and stirred at room temperature for 6 hours under a hydrogen atmosphere. The catalyst was filtered while washing with ethyl acetate, and the obtained filtrate was washed twice with water, once with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated, and purified by silica gel column chromatography (hexane: ethyl acetate = 1:1 - ethyl acetate) to give the title of the title 9-chloro (1.15g) 9-Hydrogen (174 mg) solid.

9-chlorine

¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 6.0 Hz), 1.42 (3H, t, J = 6.9 Hz), 2.90 (1H, d, J = 11.0 Hz), 3.53 (1H, Dd, J=11.0, 6.9 Hz), 4.40-4.47 (2H, m), 6.66-6.72 (1H, m)

9-H body

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.3 Hz), 1.50 (3H, d, J = 6.4 Hz), 2.94 (1H, d, J = 10.1 Hz), 3.56 (1H, Dd, J=10.5, 7.8 Hz), 4.45 (2H, q, J=7.0 Hz), 5.02-5.09 (1H, m), 6.19 (1H, dd, J=11.7, 6.6 Hz)

(Step 3)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, Ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate

(1R)-6-Amino-9-chloro-7,8-difluoro-1-methyl-5-oxo-1,2-dihydro-5H-[1,3]thiazolo[3 , a solution of ethyl 2-a]quinoline-4-carboxylate (251 mg) in dimethyl hydrazine (2.0 mL), 1-ethyl-l-propyl-4-aminopiperidine (300 mg) at 65 ° C Stir for 2 days. After the solvent was distilled off under reduced pressure, dichloromethane and a saturated aqueous solution of sodium chloride were added to the residue. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified (jjjjjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, d, J = 6.4 Hz), 1.31-1.53 (5H, m), 1.97-2.23 (5H, m), 2.74-2.91 (2H, m), 3.12 - 3.27 (1H, m), 3.49 (1H, dd, J = 11.4, 6.9 Hz), 3.75-3.89 (1H, m), 3.89-4.02 (1H, m), 4.28-4.36 (1H, m), 4.38 -4.48(2H,m),4.48-4.58(1H,m),6.37-6.47(1H,m),6.70-7.20(2H,br)

(Step 4)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, Ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5-oxirane-1 , a solution of ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate (327 mg) in tetrahydrofuran (5.0 mL), 10% palladium carbon catalyst (AD, wet weight 118 mg), and stirred under a hydrogen atmosphere for 4 hours. Ethanol (2.5 mL) was added, and after stirring for 5 hours under a hydrogen atmosphere, a vermiculite filter was used. The filtrate was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.07-1.65 (8H, m), 1.92-2.60 (5H, m), 2.63-2.80 (1H, m), 2.86-3.06 (1H, m), 3.06-4.01 ( 4H, m), 4.26-4.72 (4H, m), 6.14-6.88 (4H, m)

(Step 5)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, 2-Dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5-oxirane-1 , a solution of ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate (246 mg) in ethanol (50 mL), 1M aqueous sodium hydroxide (1595 μL) ), stirring at 70 ° C for 3 hours. After neutralizing 1 M hydrochloric acid (1600 μL) to the reaction mixture, dichloromethane and a saturated aqueous solution of sodium chloride were added. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.39-1.71 (5H, m), 2.01-2.26 (5H, m), 2.88-3.05 (2H, m), 3.22-3.36 (1H, m), 3.55-3.74 ( 2H, m), 3.80-3.93 (1H, m), 4.36-4.55 (2H, m), 5.09-5.28 (1H, m), 5.69-5.82 (1H, m), 6.30-6.57 (2H, br)

MS (ESI) m/z: 435 (M+H) ⁺

Example 9

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-oxo-1,2-dihydro- 5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-6-Amino-9-chloro-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2 -Dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-Amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2-dihydro-5H- obtained in Step 2 of Example 8. [1,3] thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (257 mg) in dimethyl hydrazine (2 mL), 4-amino-1-methylpiperidine (261 μL), stirred at 65 ° C for 28 hours. After the solvent was evaporated under reduced pressure, the residue was purified mjjjjjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, d, J = 6.4 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.45-1.67 (2H, m), 1.92-2.05 (1H, m ), 2.05-2.22 (3H, m), 2.30 (3H, s), 2.70-2.89 (3H, m), 3.48 (1H, dd, J = 11.00, 6.9 Hz), 3.67-3.82 (1H, m), 4.29-4.50(3H,m), 6.38-6.48(1H,m),6.67-7.16(2H,br)

(Step 2)

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-oxo-1,2-dihydro- 5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester

(1R)-6-Amino-9-chloro-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1, A solution of ethyl 2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylate (322 mg) in THF (5.0 mL) 113 mg), stirred under a hydrogen atmosphere for 4 hours. After adding ethanol (2.5 mL) and stirring under a hydrogen atmosphere for 4.5 hours, acetic acid (200 μL) was added, and the mixture was stirred under a hydrogen atmosphere for 6 hours. Using meteorite The filter was filtered and the filtrate was concentrated under reduced pressure. The residue was purified with a EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.1 Hz), 1.49 (3H, d, J = 6.6 Hz), 1.55-1.69 (2H, m), 2.00-2.12 (2H, m ), 2.13 - 2.25 (2H, m), 2.32 (3H, s), 2.74 - 2.86 (2H, m), 2.89 (1H, d, J = 11.2 Hz), 3.27 - 3.41 (1H, m), 3.54 ( 1H, dd, J = 11.4, 7.7 Hz), 4.18-4.28 (1H, m), 4.37-4.50 (2H, m), 5.02-5.14 (1H, m), 5.63 (1H, d, J = 6.6 Hz) , 6.62-6.98 (2H, br)

(Step 3)

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-oxo-1,2-dihydro- 5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-oxooxy-1,2-dihydro -5H-[1,3]A solution of ethyl thiazolo[3,2-a]quinoline-4-carboxylate (280 mg) in ethanol (50 mL), 1M aqueous sodium hydroxide (1933 μL) at 70 ° C Stir for 3 hours. 1 M hydrochloric acid (1933 μL) was added to the reaction mixture, and after neutralizing, dichloromethane and a saturated aqueous sodium chloride solution were added. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. EtOAc m.

¹ H-NMR (CD ₃ OD) δ: 1.42 (3H, d, J = 6.4 Hz), 1.56-1.76 (2H, m), 1.99-2.12 (2H, m), 2.23 - 2.38 (5H, m), 2.86-2.98(2H,m), 3.11(1H,d,J=11.4Hz), 3.46-3.80(2H,m),5.35-5.51(1H,m),5.98(1H,d,J=6.4Hz)

MS (ESI) m / z: 407 (M + H) ⁺

Example 10

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, 2-Dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxydecylamine

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl obtained in Step 5 of Example 8. a solution of benzyl-5-o-oxy-1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid (106 mg) in dichloromethane (4.0 mL) Among them, ammonium chloride (123 mg), (benzotriazol-1-yloxy)tripyrrolidinium hexafluorophosphate (183 mg), and triethylamine (367 μL) were added, and the mixture was stirred at room temperature for 5 days. Methylene chloride and a saturated aqueous solution of sodium chloride were added to the reaction mixture. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified on a silica gel column (dichloromethane:methanol=50:1→15:1) and a silica gel column (ethyl acetate:methanol=50:1→15:1). The title compound (74 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.41-1.63 (5H, m), 2.06-2.18 (5H, m), 2.87 (1H, d, J = 11.2 Hz), 2.91-3.02 (1H, m), 3.19 -3.33 (1H, m), 3.45-3.65 (2H, m), 3.80-3.91 (1H, m), 4.23-4.31 (1H, m), 4.42-4.52 (1H, m), 5.03-5.14 (1H, m), 5.52-5.61 (1H, m), 5.72 (1H, d, J = 6.6 Hz), 6.54 - 6.95 (2H, m), 10.02 (1H, d, J = 5.1 Hz)

MS (ESI) m/z: 434 (M+H) ⁺

Example 11

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-oxo-1,2-dihydro- 5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxydecylamine

(1R)-6-Amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5- side obtained in Step 3 of Example 9. Addition of chloro-1,2-dihydro-5H-[1,3]thiazolo[3,2-a]quinoline-4-carboxylic acid (123 mg) in dichloromethane (5.0 mL) Ammonium (165 mg), (benzotriazol-1-yloxy)tripyrrolidinium hexafluorophosphate (236 mg), and triethylamine (485 μL) were stirred at room temperature for 3 days. Methylene chloride and a saturated aqueous solution of sodium chloride were added to the reaction mixture. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and purified by a NH(R) gel column (dichloromethane:methanol=100:1→50:1) and an NH(R) rubber column (ethyl acetate:methanol=20:1→15:1). The residue obtained the title compound (m.

¹ H-NMR (CDCl ₃ ) δ: 1.48 (3H, d, J = 6.3 Hz), 1.56-1.76 (2H, m), 2.00-2.12 (4H, m), 2.14 - 2.26 (2H, m), 2.32 (3H, s), 2.76-2.86 (2H, m), 2.86 (1H, d, J = 11.2 Hz), 3.30-3.42 (1H, m), 3.48 (1H, dd, J = 11.2, 7.8 Hz), 4.25-4.33 (1H, m), 5.03-5.13 (1H, m), 5.52-5.60 (1H, m), 5.70 (1H, d, J = 6.6 Hz), 10.04 (1H, d, J = 4.6 Hz)

MS (ESI) m/z: 406 (M+H) ⁺

Example 12

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-{[2-(pyridin-2-ylamino)ethyl]amino}-1 ,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(step 1)

(4R)-4-methyl-1,2,3-oxatetrahydrothiazole-3-carboxylic acid tert-butyl ester 2,2-dioxide

In a solution of imidazole (10.7 g, 56.8 mmol), triethylamine (12.5 ml, 89.6 mmol) in dichloromethane (200 ml), at 50 ° C, thiosyl chloride (3.3 ml, 44.8 mmol) and [(R) A solution of tert-butyl 2-hydroxy-1-methylethyl]aminecarboxylate (7.0 g, 40 mmol) in dichloromethane (100 ml), and the mixture was stirred at -5 to 0 °C for 24 hours. After adding water (300 ml) to the reaction mixture, the layers were separated into two layers. The organic layer was washed with brine (300 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in acetonitrile (200 ml). Into this solution, sodium periodate (9.4 g, 44 mmol), cesium chloride (83 mg, 0.4 mmol) and water (200 ml) were added under ice cooling, and the mixture was stirred at -5 to 0 ° C for 4 hours and a half. After adding water (300 ml) to the reaction mixture, it was extracted twice with diethyl ether (300 ml). Will extract The solution was washed with brine (300 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (3H, d, J = 6.3 Hz), 1.56 (9H, s), 4.20 (1H, dd, J = 9.2, 2.8 Hz), 4.37-4.46 (1H) , m), 4.67 (1H, dd, J = 9.0, 6.1 Hz)

(Step 2)

(5R)-2-(1-ethoxycarbonylmethylene)-5-methylpyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of ethyl acetate (5.5 g, 42.1 mmol) in EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH . n-Butyllithium (1.67 M in n-hexane, 25.7 ml, 42.1 mmol) was added to the mixture, and the mixture was stirred at the same temperature for 15 minutes. (4R)-4-methyl-1,2,3-oxatetrahydrothiazole-3-carboxylic acid tert-butyl ester 2,2-dioxide (5.0 g, 21.1 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 17 hours. 6M Hydrochloric acid (17.5 ml) was added to the reaction mixture, and stirred at room temperature for 1 hour. After a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, ethyl acetate (200 ml × 3) was evaporated. The extract was washed with brine (200 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was applied to a column chromatography (200 g), and hexane: ethyl acetate = 10:1. Compound (3.3 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.19-1.27 (6H, m), 1.53 (9H, s), 1.54-1.67 (1H, m), 1.91-2.06 (1H, m), 2.87-3.01 ( 1H, m), 3.41-3.52 (1H, m), 4.07-4.16 (2H, m), 4.23-4.33 (1H, m), 6.47 (1H, s)

(Step 3)

Ethyl 2-[(5R)-5-methylpyrrolidin-2-ylidene]

a solution of (5R)-2-(1-ethoxycarbonylmethylene)-5-methylpyrrolidin-1-carboxylic acid tert-butyl ester (3.3 g, 12.3 mmol) in dichloroethane (60 ml) Trifluoroacetic acid (6 ml) was added and the mixture was stirred at room temperature for 27 hr. Ice water was added to the reaction mixture, and the mixture was neutralized with an aqueous sodium hydrogencarbonate solution, and then separated into two layers. The aqueous layer was extracted with chloroform (50 ml × 2). The solvent was distilled off under reduced pressure, and the obtained residue was applied to hexane column chromatography (50 g), and the solvent was evaporated. The title compound (1.8 g).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.23 (3H, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.3 Hz), 1.45-1.56 (1H, m), 2.07-2.16 (1H , m), 2.52-2.68 (2H, m), 3.84-3.95 (1H, m), 4.10 (2H, q, J = 7.1 Hz), 4.48 (1H, s), 7.90 (1H, br s)

(Step 4)

2-[(5R)-5-methylpyrrolidin-2-ylidene]-3-oxo-3-(2,3,4,5-tetrafluoro-6-nitrophenyl)propionate Ethyl ester

Add N,N-dimethylformamide (5 drops) to a solution of 2,3,4,5-tetrafluoro-6-nitrobenzoic acid (3.1 g, 12.8 mmol) in dichloromethane (50 ml) Chlorophyll chloride (3.3 ml, 38.3 mmol) was stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure and evaporated tolu. A solution of ethyl 2-[(5R)-5-methylpyrrolidin-2-ylidene]acetate (1.8 g, 10.7 mmol) in toluene (10 ml) was added to this suspension, and the mixture was stirred at room temperature for 30 min. . After a saturated aqueous solution of sodium hydrogencarbonate (50 ml) was added, and ethyl acetate (50 ml × 3) was evaporated. The extract was washed with saturated brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was applied to a column chromatography (60 g), and hexane:ethyl acetate = 3:1 was dissolved and concentrated under reduced pressure to obtain an oil. The title compound (3.8 g) was used directly in the next reaction.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.10 (3H, t, J = 7.1 Hz), 1.39 (3H, d, J = 6.6 Hz), 1.63-1.74 (1H, m), 2.26-2.38 (1H , m), 3.24 (1H, br s), 3.44 (1H, br s), 3.95-4.08 (2H, m), 4.09-4.22 (1H, m), 11.52 (1H, br s)

(Step 5)

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline Ethyl 4-carboxylate

2-[(5R)-5-Methylpyrrolidine-2-ylidene]-3-oxo-3-(2,3,4,5-tetrafluoro-6-nitrophenyl)propanoic acid Ethyl ester (3.8g) of 1,4-two Sodium hydride (55% in oil, 0.53 g, 12.2 mmol) was added and the mixture was stirred at room temperature for 15 hr. After 10% aqueous citric acid solution was added to the reaction mixture under ice-cooling, ethyl acetate (30 ml × 3). The extract was washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to chromatography on silica gel column chromatography. 1.1g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (3H, t, J = 6.8 Hz), 1.44 (3H, d, J = 6.8 Hz), 2.05-2.12 (1H, m), 2.39-2.51 (1H , m), 3.36-3.57 (2H, m), 4.37 (2H, q, J = 7.1 Hz), 5.28-5.38 (1H, m)

(Step 6)

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline 4-carboxylic acid

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina Acetic acid (8 ml) and hydrochloric acid (8 ml) were added to ethyl phthalate-4-carboxylate (1.1 g, 3.0 mmol), and the mixture was stirred at 80 ° C for one hour and half. After cooling, ice water was added to the reaction mixture, and the precipitate was filtered to give the title compound (0.9 g).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50 (3H, d, J = 6.6 Hz), 2.20 (1H, dd, J = 12.8, 8.7 Hz), 2.44-2.58 (1H, m), 3.54-3.67 (1H,m), 4.17 (1H, dd, J=20.4, 9.2 Hz), 5.41-5.52 (1H, m), 14.15 (1H, br s)

(Step 7)

(1R)-6-amino-7,8,9-trifluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline 4-carboxylic acid

(1R)-7,8,9-trifluoro-1-methyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina A solution of porphyrin-4-carboxylic acid (0.9 g, 26 mmol) in N,N-dimethylformamide (30 ml) was added to a 10% palladium carbon catalyst (AD, wet weight 0.2 g), and the mixture was placed under a hydrogen atmosphere. Stir at room temperature for 3 days. The reaction mixture was filtered over EtOAc (EtOAc) (EtOAc) The solvent was distilled off under reduced pressure, and the obtained residue was washed with ethyl ether and diethyl ether to afford the title compound (0.35 g).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.41 (3H, d, J = 6.3 Hz), 2.04-2.13 (1H, m), 2.35-2.48 (1H, m), 3.45-3.58 (1H, m) , 4.08 (1H, dd, J = 20.0, 9.5 Hz), 5.31-5.41 (1H, m), 6.81 (2H, br s)

(Step 8)

(1R)-6-amino-7,9-difluoro-1-methyl-5-oxo-8-{[2-(pyridin-2-ylamino)ethyl]amino}-1 ,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,8,9-trifluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina 2-(2-Pyridylamino)ethylamine 2 hydrochloride (0.2 g, 0.96 mmol) and triethyl phenyl phthalate (100 mg, 0.32 mmol) in dimethyl hydrazide (3 ml) Amine (0.27 mL, 1.9 mmol) was added and the mixture was stirred at 100 ° C for 15 hours under nitrogen. Ice water was added to the reaction mixture, and ethyl acetate (40 ml × 3) was evaporated. The extract was washed with water (40 ml × 3) and brine (40 ml), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by fractional silica gel chromatography (chloroform: methanol = 20:1). The obtained residue was solidified by a solvent mixture of ethyl acetate and n-hexane to give the title compound (25 mg).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34 (3H, d, J = 6.3 Hz), 2.00 (1H, dd, J = 12.7, 9.0 Hz), 2.27-2.40 (1H, m), 3.38-3.50 (1H, m), 3.70 (2H, br s), 3.77 (2H, br s), 4.02 (1H, dd, J = 19.7, 9.6 Hz), 4.69 (1H, s), 5.28 (1H, br s) , 6.06 (1H, s), 6.44 (1H, d, J = 8.5 Hz), 6.48 (2H, br s), 6.63 (1H, dd, J = 6.8, 5.1 Hz), 7.41 (1H, td, J = 7.3, 2.2 Hz), 8.12 (1H, d, J = 3.9 Hz)

MS (FAB): 430 (M + H) ⁺

Example 13

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(step 1)

(1R)-9-chloro-7,8-difluoro-1-methyl-6-nitro-5-o-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a] Ethyl quinoline-4-carboxylate

3-Chloro-2,4,5-trifluoro-6-nitro-benzoic acid (39 g, 153 mmol) was suspended in dichloromethane (300 ml), then added with dichloromethane (40 ml), N,N-dimethyl After the methotrexate (2 drops), stir for 17 hours. The reaction mixture was concentrated under reduced vacuo. Toluene was added again, and the solvent was distilled off under reduced pressure.

The residue was dissolved in toluene (400 ml), and ethyl 2-[(5R)-5-methylpyrrolidine-2-ylidene) obtained in Step 3 of Example 12 was added dropwise under ice cooling (26 g, A solution of 154 mmol) in toluene (40 ml). After the reaction mixture was stirred at room temperature for 1 hour, it was poured into a saturated aqueous The aqueous layer was extracted with EtOAc. The residue was dissolved in acetone (300 ml), potassium carbonate (26 g) was added, and the mixture was heated to reflux for 12 hours. The mixture was diluted with MgSO.sub.2, and evaporated. The residue was purified by EtOAc EtOAcjjjj(

¹ H-NMR (CDCl ₃ ) δ: 1.35-1.39 (6H, m), 2.01-2.08 (1H, m), 2.41-2.51 (1H, m), 3.37-3.53 (2H, m), 4.34-4.39 ( 2H, m), 6.17-6.25 (1H, m)

(Step 2)

(1R)-6-amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a] Ethyl quinoline-4-carboxylate

(1R)-6-amino-7,8-difluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4 -carboxylic acid ethyl ester

(1R)-9-Chloro-7,8-difluoro-1-methyl-6-nitro-5-o-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a ] Quinoline-4-carboxylic acid ethyl ester (34.6 g, 89.54 mmol) was dissolved in a mixed solvent of dichloroethane (200 ml)-ethanol (200 ml), and 10% palladium carbon catalyst (AD, wet weight 7.6 g) was added. It was stirred under a hydrogen atmosphere for 16 hours. After the solvent was filtered off, the solvent was evaporated, evaporated, evaporated, evaporated

Further, a chlorine-reduced compound (1.15 g) of a solid (mixture with impurities) was also obtained. This compound was used in the next step without further purification.

9-Cl body

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, d, J = 6.4 Hz), 1.39 (3H, t, J = 7.1 Hz), 1.90-1.97 (1H, m), 2.33 - 2.43 (1H, m ), 3.31-3.37 (2H, m), 4.39 (2H, q, J = 7.2 Hz), 6.14 - 6.22 (1H, m)

9-H body

No equipment information

(Step 3)

(1R)-6-amino-7,8-difluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4 -carboxylic acid

(1R)-6-Amino-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- The ethyl 4-carboxylate (1.15 g) was dissolved in tetrahydrofuran (10 ml)-ethanol (5 ml). Acetic acid (0.82 ml) was added, and the title compound (1.05 g) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 1.32 (3H, d, J = 6.4 Hz), 2.00 (1H, dd, J = 12.4, 8.7 Hz), 2.30-2.42 (1H, m), 3.47-3.57 (1H, m), 3.83 (1H, dd, J = 19.3, 8.7 Hz), 5.01-5.10 (1H, m), 6.97 (1H, dd, J = 12.4, 6.4 Hz), 7.81 (1H, br s)

(Step 4)

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- Dimethylhydrazine (4 ml) was added to 4-carboxylic acid (300 mg, 0.88 mmol) and 1-methyl-piperidin-4-ylamine (350 mg), and stirred at 100 ° C for 3 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was purified with EtOAc EtOAcjjjjj(

¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 6.4 Hz), 1.59-1.83 (2H, m), 2.02-2.11 (3H, m), 2.17-2.24 (2H, m), 2.33 (3H, s), 2.36-2.45 (1H, m), 2.77-2.87 (2H, m), 3.33-3.43 (1H, m), 3.46-3.58 (1H, m), 4.06 (1H, dd, J= 19.5, 9.4 Hz), 4.40-4.46 (1H, m), 4.76-4.84 (1H, m), 5.75 (1H, d, J = 6.4 Hz), 6.51 (2H, br s)

Example 14

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1-methyl-5- oxo-1,2,3, 5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(1R)-6-Amino-7,8-difluoro-1-methyl-5-oxirane-1,2,3,5-tetrahydropyrrolo[1] obtained in Step 3 of Example 13. 1,2-a]quinoline-4-carboxylic acid (300 mg, 0.88 mmol), 1-ethenyl-piperidin-4-ylamine (440 mg) was added with dimethyl hydrazine (4 ml) at 100 ° C Stir for 3 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. Residue The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 6.9 Hz), 1.48-1.55 (2H, m), 2.05-2.17 (6H, m), 2.36-2.46 (1H, m), 2.92 -2.99 (1H, m), 3.24 - 3.32 (1H, m), 3.48-3.65 (2H, m), 3.82-3.90 (1H, m), 4.03-4.11 (1H, m), 4.39-4.42 (1H, m), 4.45-4.52 (1H, m), 4.78-4.85 (1H, m), 5.77 (1H, d, J = 6.4 Hz), 6.54 (2H, br s)

Example 15

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(step 1)

(1R)-6-amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a] Quinoline-4-carboxylic acid

(1R)-6-Amino-9-chloro-7,8-difluoro-1-methyl-5-sideoxy-1,2,3,5-tetra which was obtained in Step 2 of Example 13. Ethyl pyrrolo[1,2-a]quinoline-4-carboxylic acid ethyl ester (4.9 g, 13.7 mmol) was added to ethanol (50 ml), and the mixture was heated to 60 ° C to obtain a homogeneous solution. Add 1M aqueous sodium hydroxide solution (41 ml) at the same temperature, stir for 1.5 hours, and add acetic acid. (3.2 ml), cooled to room temperature. The precipitate was filtered, washed with water, evaporated, evaporated

¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, d, J = 6.9 Hz), 1.99-2.07 (1H, m), 2.38-2.49 (1H, m), 3.50-3.61 (1H, m), 4.01 -4.10(1H,m), 6.30-6.38(1H,m)

(Step 2)

(1R)-6-amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a] Quinoline-4-carboxyguanamine

(1R)-6-Amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a To the quinoline-4-carboxylic acid (7.3 g, 22.2 mmol), ammonium chloride (23.8 g, 444 mmol), dichloromethane (200 ml) was added, and (benzotriazol-1-yloxy)tripyrrolidine was added. Hexafluorophosphate (12.1 g, 23.3 mmol) and triethylamine (93 ml) were stirred for 18 hours. The reaction mixture was diluted with methylene chloride, washed with 1M aqueous sodium sulfate and dried over magnesium sulfate. Methanol was added to the residue, and the title compound (3.54 g).

¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, d, J = 6.6 Hz), 1.91-1.97 (1H, m), 2.32-2.43 (1H, m), 3.51-3.61 (1H, m), 4.00 (1H, ddd, J = 19.6, 9.8, 2.6 Hz), 5.59 (1H, br s), 6.19-6.23 (1H, m), 9.72 (1H, s)

(Step 3)

(1R)-6-Amino-9-chloro-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2 ,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(1R)-6-Amino-9-chloro-7,8-difluoro-1-methyl-5-oxooxy-1,2,3,5-tetrahydropyrrolo[1,2-a To the quinoline-4-carboxydecylamine (500 mg, 1.53 mmol) and 1-methyl-piperidin-4-ylamine (765 μl), dimethylhydrazine (5 ml) was added, and the mixture was stirred at 110 ° C for 2.5 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was partitioned between methylene chloride and saturated aqueous sodium hydrogen sulfate. The residue was purified by EtOAc EtOAcjjjj(

¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, d, J = 6.0 Hz), 1.48-1.65 (2H, m), 1.80-1.88 (2H, m), 1.98-2.03 (1H, m), 2.07 -2.20(3H,m), 2.30(3H,s),2.34-2.44(1H,m),2.75-2.84(2H,m),3.14-3.19(1H,m),3.58(1H,dt,J= 19.3, 8.7 Hz), 3.73-3.80 (1H, m), 3.86 (1H, dq, J = 19.0, 4.8 Hz), 4.50 (1H, d, J = 7.8 Hz), 5.51-5.55 (1H, m), 6.04-6.12(1H,m), 6.72-7.20(1H,m),9.85-9.94(1H,m)

(Step 4)

(1R)-6-amino-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(1R)-6-Amino-9-chloro-7-fluoro-1-methyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1, 2,3,5-Tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine (200 mg, 0.47 mmol) dissolved in methanol (5 ml)-tetrahydrofuran (5 ml), 10% palladium carbon catalyst (AD, wet weight 200 mg), stirred under a hydrogen atmosphere for 20 hours. The solvent was filtered, and the solvent was evaporated to dryness.

¹ H-NMR (CDCl ₃ ) δ: 1.40 (4H, d, J = 6.4 Hz), 2.00 (1H, dd, J = 12.6, 8.5 Hz), 2.04-2.11 (2H, m), 2.16-2.24 (2H) , m), 2.27-2.37 (5H, m), 2.78-2.85 (2H, m), 3.32-3.41 (1H, m), 3.48-3.58 (1H, m), 4.05 (1H, dd, J = 19.2, 9.2 Hz), 4.26-4.32 (1H, m), 4.68-4.75 (1H, m), 5.47-5.54 (1H, m), 5.71 (1H, d, J = 6.9 Hz), 6.71 (2H, br s) , 10.09-10.17 (1H, m)

Example 16

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1-methyl-5- oxo-1,2,3, 5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(step 1)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5- oxirane-1, 2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

To the compound obtained in the step 2 of Example 15 (250 mg, 0.76 mmol), 1-ethyl-n-yl-piperidin-4-ylamine (430 mg), dimethyl hydrazide (1.5 ml) was added at 110 ° C Stir for 4 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, d, J = 6.4 Hz), 1.35-1.50 (2H, m), 1.80-1.87 (2H, m), 2.03-2.20 (4H, m), 2.35 -2.44(1H,m), 2.79-2.90(1H,m),3.14-3.25(2H,m),3.53-3.63(1H,m),3.77-3.91(2H,m),3.93-4.02(1H, m), 4.44 - 4.55 (2H, m), 5.50 - 5.55 (1H, m), 6.02 - 6.11 (1H, m), 6.80 - 7.18 (1H, m), 9.81 - 9.90 (1H, m)

(Step 2)

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1-methyl-5- oxo-1,2,3, 5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(1R)-8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1-methyl-5-sideoxy-1 , 2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine (230 mg, 0.51 mmol) dissolved in methanol (5 ml)-tetrahydrogen Furan (5 ml) was added with a 10% palladium carbon catalyst (AD, wet weight: 272 mg), and stirred under a hydrogen atmosphere for 6 hours. The catalyst was filtered off, and the solvent was evaporated to dryness crystals crystals crystals crystals crystals .

¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 6.4 Hz), 1.45-1.56 (2H, m), 1.98-2.04 (1H, m), 2.08-2.17 (5H, m), 2.27 -2.36 (1H, m), 2.92-3.01 (1H, m), 3.24-3.31 (1H, m), 3.49-3.62 (2H, m), 3.82-3.88 (1H, m), 4.01-4.10 (1H, m), 4.26-4.30 (1H, m), 4.42-4.51 (1H, m), 4.68-4.78 (1H, m), 5.49-5.56 (1H, m), 5.72 (1H, d, J = 6.9 Hz) , 6.75 (2H, br s), 10.08-10.12 (1H, m)

Example 17

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1,1-dimethyl-5-oxirane-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(step 1)

(1-hydroxy-5,5-dimethylpyrrolidin-2-yl)acetic acid isopropyl ester

Add 1.14M lithium diisopropylamide/n-hexane-tetrahydrofuran solution (95 ml) in tetrahydrofuran (300 ml) under argon. It was cooled to -78 °C. Isopropyl acetate (11.5 ml) was added dropwise at the same temperature, and the mixture was stirred for 20 minutes after the completion of the dropwise addition. A solution of 5,5-dimethyl-1-pyrroline N-oxide (9.0 g, 78 mmol) in tetrahydrofuran (50 ml) was added dropwise at the same temperature, and the mixture was stirred for 1.5 hours. After the reaction was quenched with aq. EtOAc (EtOAc) The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.17 (3H, s), 1.23 (6H, d, J = 6.4 Hz), 1.36-1.46 (1H, m), 1.51-1.64 (1H) , m), 1.93-2.01 (1H, m), 2.38 (1H, dd, J = 14.7, 7.8 Hz), 2.68 (1H, dd, J = 14.7, 5.0 Hz), 3.29-3.37 (1H, m), 4.82 (1H, br s), 4.97-5.07 (1H, m)

(Step 2)

(5,5-Dimethylpyrrolidine-2-ylidene) isopropyl acetate

(1-Hydroxy-5,5-dimethylpyrrolidin-2-yl)acetic acid isopropyl ester (14,3 g, 66 mmol) was dissolved in dichloromethane (200 ml), and triphenylphosphine (26 g, 100 mmol) was added. Carbon tetrachloride (9.6 ml, 100 mmol) and triethylamine (14 ml) were heated under reflux for 3 hours. After the reaction mixture was allowed to cool, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. : 2) The title compound (11.5 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.3 Hz), 1.28 (6H, s), 1.78 (2H, t, J = 7.7 Hz), 2.63 - 2.67 (2H, m), 4.41 (1H, s), 4.95-5.04 (1H, m), 7.84 (1H, br s)

(Step 3)

7,8,9-trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- Isopropyl 4-carboxylate

2,3,4,5-Tetrafluoro-6-nitro-benzoic acid (10 g, 42 mmol) was suspended in dichloromethane (150 ml), and then added with chlorobenzene (11 ml) and N,N-dimethylformamide. After the amine (2 drops), it was stirred for 24 hours. The reaction mixture was concentrated under reduced vacuo.

The residue was dissolved in toluene (100 ml), and a solution of &lt;RTIgt;(5,5- </RTI> </RTI> <RTIgt; </RTI> <RTIgt; After the reaction mixture was stirred at room temperature for 2 hr. The aqueous layer was extracted with EtOAc. The residue was dissolved in acetone (100 ml), and potassium carbonate (6.6 g) was added, and the mixture was refluxed for 18 hours. Under ice cooling, it was made weakly acidic with 1M hydrochloric acid and extracted with ethyl acetate. The aqueous layer containing the insoluble material was extracted with dichloromethane, and the organic layer was combined and dried over magnesium sulfate. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 1.35 (6H, d, J = 6.0 Hz), 1.77 (6H, d, J = 4.1 Hz), 2.27 (2H, t, J = 7.6 Hz), 3.30 (2H, t, J = 7.6 Hz), 5.15-5.25 (1H, m)

(Step 4)

7,8,9-trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- 4-carboxylic acid

7,8,9-Trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline Acetic acid (15 ml) and concentrated hydrochloric acid (15 ml) were added to isopropyl 4-carboxylate (1.9 g, 4.8 mmol), and stirred at 80 ° C for 1.5 hours. Ice water was added to the reaction mixture, and the crystals crystals crystals crystals

¹ H-NMR (CDCl ₃ ) δ: 1.84 (6H, d, J = 3.7 Hz), 2.34 (2H, t, J = 7.8 Hz), 3.87 (2H, t, J = 7.6 Hz)

(Step 5)

6-Amino-7,8,9-trifluoro-1,1-dimethyl-5-o-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- 4-carboxylic acid

7,8,9-Trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline 4-carboxylic acid (6.9 g, 19.4 mmol) was dissolved in N,N-dimethylformamide (250 ml), and a 5% palladium carbon catalyst (M, wet weight 820 mg) was added, and the reaction was carried out under a hydrogen atmosphere for 20 hours. Stir. The catalyst was filtered off with vermiculite, and the filtrate was concentrated under reduced pressure. Suspending the residue in dichloro The title compound (3.6 g) was obtained. Further, the mother liquid was purified by a silica gel column chromatography (chloroform:methanol = 19:1) to give the title compound (762 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 1.67 (7H, d, J = 3.7 Hz), 2.20 (2H, t, J = 7.6 Hz), 3.61 (2H, t, J = 7.6 Hz), 7.80 ( 2H, br s)

(Step 6)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1,1-dimethyl-5-oxirane-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

6-Amino-7,8,9-trifluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline 4-carboxylic acid (1.6 g, 4.9 mmol), 1-(4-amino-piperidin-1-yl)ethanone (1.53 g, 10.8 mmol) was added with dimethyl hydrazine (20 ml) at 100 The mixture was stirred at ° C for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (dichloromethane:methanol = 10:0 - 9:1). Methanol and dimethyl ether were added to the residue.

¹ H-NMR (CDCl ₃ ) δ: 1.35 - 1.46 (2H, m), 1.70 (3H, s), 1.71 (3H, s), 2.07-2.12 (1H, m), 2.12 (3H, s), 2.18 (2H, t, J = 7.8 Hz), 2.74-2.84 (1H, m), 3.16-3.26 (1H, m), 3.71 (2H, t, J = 7.6 Hz), 3.81-4.06 (3H, m), 4.60 (1H, d, J = 13.7 Hz), 6.62 (2H, br s)

Example 18

6-Amino-7,9-difluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3 ,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

1-methyl-piperidin-4-ylamine (1.4 ml) and dimethyl hydrazine (15 ml) were added to the compound obtained in the step 5 of Example 17 (925 mg, 2.84 mmol). Stir. After the reaction mixture was cooled, the solvent was evaporated. mjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.61 (2H, m), 1.70 (3H, s), 1.71 (3H, s), 2.05-2.19 (6H, m), 2.31 (3H, s), 2.77 -2.88(2H,m), 3.67-3.78(3H,m),4.03-4.10(0H,m),6.59(2H,s)

Example 19

8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7,9-difluoro-1,1-dimethyl-5-sideoxy- 1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

To a solution of the compound (135 mg) obtained in Step 5 of Example 17 and 1-ethyl-mercapto-3-aminopiperidine (180 mg) in dimethyl hydrazine (2.0 ml) was added diisopropylethylamine ( 211 μL), stirred at 100 ° C for 4 hours. A saturated aqueous solution of sodium chloride and water were added to the mixture, and ethyl acetate and dichloromethane were evaporated. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. After the residue was purified by EtOAc EtOAc (EtOAc:EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 1.56-1.88 (9H, m), 2.05-2.23 (6H, m), 3.19-3.40 (2H, m), 3.50-3.59 (0.5H, m), 3.64-3.76 (2H,m),3.81-3.98(2H,m),4.09-4.27(1.5H,m),6.48-6.78(2H,br)

Example 20

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1,1-dimethyl-5-oxirane-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

To the compound obtained in the step 6 of Example 17 (1.98 g, 4.42 mmol), ammonium chloride (4.72 g, 88.3 mmol), dichloromethane (80 ml) was added, and (benzotriazol-1-yloxy) was added. ) Tripyrrolidinium hexafluorophosphate (2.8 g, 5.3 mmol), triethylamine (18.5 ml) and stirred for 7 hours Time. The reaction mixture was diluted with chloroform, washed with 1M aqueous sodium sulfate and water, and dried over magnesium sulfate. Ethyl acetate was added to the residue.

¹ H-NMR (CDCl ₃ ) δ: 1.33-1.45 (2H, m), 1.66 (3H, s), 1.67 (3H, s), 2.07-2.17 (6H, m), 2.75-2.83 (1H, m) , 3.15-3.23 (1H, m), 3.62 (2H, t, J = 7.3 Hz), 3.81-3.93 (3H, m), 4.54-4.62 (1H, m), 5.49-5.56 (1H, m), 6.73 (2H, br s), 9.81 (1H, s)

Example 21

6-Amino-7,9-difluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3 ,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

The compound obtained in Example 18 (1.19 g, 2.8 mmol) was dissolved in dichloromethane (50 ml), ammonium chloride (3.0 g, 57 mmol), triethylamine (12 ml), (benzotriazol-1-yl) Oxy)tripyrrolidinium hexafluorophosphate (1.6 g) was stirred for 2 hours. The reaction mixture was diluted with methylene chloride, washed with 1M aqueous sodium sulfate and dried over magnesium sulfate. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc:

¹ H-NMR (CDCl ₃ ) δ: 1.67 (3H, s), 1.67 (3H, s), 2.04-2.13 (4H, m), 2.18-2.27 (2H, m), 2.36 (3H, s), 2.85 - 2.94 (2H, m), 3.62 (2H, t, J = 7.6 Hz), 3.67-3.76 (1H, m), 3.88-3.95 (1H, m), 5.48-5.54 (1H, m), 6.62-6.80 (2H,m), 9.81-9.85 (1H, m)

Example 22

8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7,9-difluoro-1,1-dimethyl-5-sideoxy- 1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

To a solution of the compound obtained in Example 19 (70 mg) in dichloromethane (1.5 ml), 1-hydroxybenzotriazole (22 mg), 2M ammonia methanol (350 μL), 1-(3-dimethylamine) Propyl)-3-ethylcarbodiimide hydrochloride (39 mg) was stirred at room temperature for 3 days. Methylene chloride (3.0 ml), 2M ammonia methanol solution (300 μl), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg) were added to the reaction mixture. Stir at room temperature for 4 hours. After the reaction solution was diluted with dichloromethane, 10% citric acid water was added. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, ethyl acetate was added to the residue and washed and filtered. The title compound (20 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.53-1.72 (9.5H, m), 2.00-2.20 (5.5H, m), 3.15-3.38 (2H, m), 3.49-3.68 (2H, m), 3.77- 3.95 (2.25H, m), 3.98-4.25 (1.25H, m), 5.50-5.65 (1H, m), 6.57-6.94 (2H, br), 9.70-9.93 (1H, m)

Example 23

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1,1-dimethyl-5-oxirane-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carbonitrile

(step 1)

(1-hydroxy-5,5-dimethylpyrrolidin-2-yl)acetonitrile

A solution of 1.14 M lithium diisopropylamide/n-hexane-tetrahydrofuran (37.2 ml, 42.4 mmol) was added dropwise to a solution of acetonitrile (2.2 ml, 42.4 mmol) in tetrahydrofuran (20 ml). . A solution of 5,5-dimethyl-1-pyrroline N-oxide (4.0 g, 35.3 mmol) in tetrahydrofuran (5 ml) was added at -78 °C. The reaction mixture was stirred at -78 °C for 45 minutes, water was added and the mixture was warmed to room temperature. Water was added to the reaction mixture solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified with EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.18 (3H, s), 1.47-1.68 (3H, m), 1.96-2.08 (1H, m), 2.59 (2H, d, J = 5.5Hz), 3.17-3.26(1H,m), 4.50(1H,br s)

(Step 2)

(5,5-dimethylpyrrolidine-2-ylidene)acetonitrile

In a solution of (1-hydroxy-5,5-dimethylpyrrolidin-2-yl)acetonitrile (3.48 g, 22.6 mmol), triethylamine (12.6 ml, 902 mmol) in dichloromethane (40 ml) Methane sulfonium chloride (2.1 ml, 27.1 mmol) was added. The reaction mixture was heated to reflux for 1 hour and warmed to room temperature. The reaction mixture was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, and ethyl acetate was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified with EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.22-1.32 (6H, m), 1.82-1.89 (2H, m), 2.61-2.67 (1H, m), 2.83-2.89 (1H, m), 3.61-3.63 ( 0.5H, m), 3.87-3.90 (0.5H, m), 4.83 (0.5H, brs), 5.18 (0.5H, br s)

(Step 3)

2-(5,5-Dimethylpyrrolidin-2-yl)-3-oxo-3-(2,3,4,5-tetrafluoro-6-nitrophenyl)propanenitrile

To a suspension of 2,3,4,5-tetrafluoro-6-nitrobenzoic acid (1.5 g, 6.34 mmol) in dichloromethane (30 ml) was added chlorohydrin (1.1 ml, 12.7 mmol), N, N M-dimethylformamide (2 drops) was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. Residue Toluene (30 ml) was added thereto, and the mixture was cooled with ice, and triethylamine (1.3 ml, 9.52 mmol), (5,5-dimethylpyrrolidine-2-ylidene) acetonitrile (864 mg, 6.34 mmol) was added. The reaction mixture was stirred for 1 hour under ice cooling, and then stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was evaporated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAcjjjjjjj

¹ H-NMR (CDCl ₃ ) δ: 1.56 (6H, s), 2.06 (2H, t, J = 7.7 Hz), 3.14 (2H, t, J = 7.7 Hz), 10.24 (1H, br s)

(Step 4)

7,8,9-trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- 4-carbonitrile

2-(5,5-Dimethylpyrrolidin-2-yl)-3-oxo-3-(2,3,4,5-tetrafluoro-6-nitrophenyl)propanenitrile ( Acetone (40 ml) and potassium carbonate (1.06 g, 7.68 mmol) were added to 2.11 g and 5.91 mmol. The reaction mixture was stirred at room temperature overnight and concentrated. Water was added to the residue and extracted with chloroform. The organic layer was concentrated under reduced pressure to give a solid. The title compound (1.91 g) was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.83 (3H, s), 1.84 (3H, s), 2.44 (2H, t, J = 7.8 Hz), 3.42 (2H, t, J = 7.8 Hz)

(Step 5)

6-Amino-7,8,9-trifluoro-1,1-dimethyl-5-o-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline- 4-carbonitrile

7,8,9-Trifluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline To the -4-carbonitrile (302 mg, 0.90 mmol), N,N-dimethylformamide (5 ml), methanol (5 ml), water (5 ml), sodium dithionite (623 mg, 2.69 mmol), at 70- Stir at 75 ° C for 3 hours. The reaction mixture was warmed to room temperature, water was added and filtered to give a solid. The filtrate was extracted with chloroform, dried over anhydrous sodium sulfate and filtered. The obtained solid was combined and purified with EtOAcjjjjjjj

¹ H-NMR (DMSO-D ₆ ) δ: 1.65 (3H, s), 1.66 (3H, s), 2.25 (2H, t, J = 7.3 Hz), 3.28 (2H, t, J = 7.3 Hz), 7.89 (2H, br s)

(Step 6)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7,9-difluoro-1,1-dimethyl-5-oxirane-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carbonitrile

6-Amino-7,8,9-trifluoro-1,1-dimethyl-5-o-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline A solution of -4-carbonitrile (50 mg, 0.16 mmol), 1-(4-aminopiperidin-1-yl)ethanone (69 mg, 0.49 mmol) in dimethylhydrazine (2 ml) was stirred at 80 ° C for 4.5 hours. . The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (35% ethyl acetate / EtOAc /EtOAc Ethanol was added to the obtained solid, which was filtered to give the title compound (yel.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.45 (2H, m), 1.69 (3H, s), 1.70 (3H, s), 2.06-2.18 (5H, m), 2.23 (2H, t, J = 7.6 Hz), 2.73-2.83 (1H, m), 3.15-3.27 (3H, m), 3.80-3.96 (3H, m), 4.54-4.62 (1H, m), 6.76 (2H, br s)

MS (m/z): 430 (M+H)

Example 24

6-Amino-7,9-difluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3 ,5-tetrahydropyrrolo[1,2-a]quinoline-4-carbonitrile

A solution of the compound obtained in the step 5 of Example 23 (59 mg, 0.19 mmol), 4-amino-1-methylpiperidine (66 mg, 0.58 mmol) in dimethylhydrazine (2 ml) was stirred at 80 ° C 3 hours. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (15% methanol / chloroform) to afford a solid. The solid obtained It was purified by flash chromatography on EtOAc (EtOAc:EtOAc) Ethanol was added to the obtained solid, and the obtained title compound (yield: 57 mg, 74%).

¹ H-NMR (CDCl ₃ ) δ: 1.47-1.58 (2H, m), 1.69 (3H, s), 1.70 (3H, s), 2.00-2.18 (4H, m), 2.22 (2H, t, J = 7.6 Hz), 2.31 (3H, s), 2.77-2.86 (2H, m), 3.23 (2H, t, J = 7.6 Hz), 3.63 - 3.75 (1H, m), 3.90-3.99 (1H, m), 6.73 (2H, br s)

MS (m/z): 402 (M+H)

Example 25

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

(step 1)

(1-hydroxy-5,5-dimethylpyrrolidin-2-yl)acetic acid tert-butyl ester

To a solution of tetrahydrofuran (400 ml), 1.1 M lithium diisopropylamide (n-hexane-tetrahydrofuran solution, 200 ml) was added and the mixture was cooled to -78 °C. Tributyl acetate (29 ml) was added dropwise at the same temperature, and the mixture was stirred for 30 minutes after the completion of the dropwise addition. Thereto, a solution of 5,5-dimethyl-1-pyrroline N-oxide (22.3 g, 194 mmol) in tetrahydrofuran (50 ml) was added dropwise, and the mixture was stirred for 2 hours. Add saturated ammonium chloride water solution After the reaction was quenched, the mixture was partitioned with ethyl acetate-br. The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.17 (3H, s), 1.36-1.43 (1H, m), 1.45 (9H, s), 1.52-1.60 (2H, m), 1.92 -2.02 (1H, m), 2.32 (1H, dd, J = 14.4, 8.0 Hz), 2.63 (1H, dd, J = 14.7, 5.0 Hz), 3.26-3.35 (1H, m), 4.77 (1H, br s)

(Step 2)

(5,5-dimethylpyrrolidine-2-ylidene)acetic acid tert-butyl ester

(1-Hydroxy-5,5-dimethylpyrrolidin-2-yl)acetic acid tert-butyl ester (45.9 g, 200 mmol) was dissolved in dichloromethane (500 ml), and triphenylphosphine (75 g, 286 mmol) was added. Carbon tetrachloride (229 ml, 300 mmol) and triethylamine (42 ml) were heated and refluxed for 4 hours. After the reaction mixture was allowed to cool, the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The title compound (30 g) was obtained as a solid.

¹ H-NMR (CDCl _{3 )} δ: 1.28 (6H, s), 1.47 (9H, s), 1.76 (2H, t, J = 7.8 Hz), 2.61-2.65 (2H, m), 4.37 (1H, s ), 7.74 (1H, br s)

(Step 3)

9-Chloro-7,8-difluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina Tert-butyl phthalate-4-carboxylate

3-Chloro-2,4,5-trifluoro-6-nitro-benzoic acid (10 g, 39.1 mmol) was dissolved in dichloromethane (150 mL), and N,N-dimethylformamide 5 drops were added dropwise The grass chloroform (3.58 mL, 41.1 mmol) was added dropwise at room temperature. After stirring for 2.5 hours, it was concentrated under reduced pressure, and toluene was azeotroped to give an oily residue.

To a solution of the enamine (6.89 g, 32.6 mmol) in tetrahydrofuran (150 mL). After stirring at room temperature for 30 minutes, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was evaporated. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and then purified by silica gel column chromatography (10% ethyl acetate/hexanes: 30%) to give an oil.

Sodium hydride (55% in oil, 1.43 g, 35.8 mmol) was added in EtOAc. After stirring at room temperature for 1.5 hours, a 10% aqueous citric acid solution was added to the reaction mixture under ice cooling, and ethyl acetate was evaporated. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The obtained solid was washed with EtOAc (EtOAc m.) In addition, the filtrate is concentrated under reduced pressure and put into silicone Column chromatography (20% ethyl acetate / hexanes: 50%)

¹ H-NMR (CDCl ₃ ) δ: 1.56 (9H, s), 1.97 (6H, s), 2.19 (2H, t, J = 7.1 Hz), 3.27 (2H, t, J = 7.3 Hz)

(Step 4)

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina Porphyrin-4-carboxylic acid

9-Chloro-7,8-difluoro-1,1-dimethyl-6-nitro-5-oxy-1,2,3,5-tetrahydropyrrolo[1,2-a] The quinoline-4-carboxylic acid tert-butyl ester (4.53g, 10.6mmol) was dissolved in 1,2-dichloroethane (150mL), and 10% palladium carbon (AD, wet weight 906mg) was added to the hydrogen atmosphere. Stir at room temperature for 9 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give a toluene to afford oil.

Trifluoroacetic acid (15 mL) was added to a dichloromethane solution (60 mL). After concentrating under reduced pressure, the title compound (3.24 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.98 (6H, s), 2.15 (2H, t, J = 7.0 Hz), 3.73 (2H, t, J = 7.0 Hz)

(Step 5)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxirane-1,2,3,5-tetrahydropyrrolo[1,2-a] N-methylpyrrolidone (1.5 mL) was added to quinoline-4-carboxylic acid (201 mg, 0.586 mmol) and 1-(4-aminopiperidin-1-yl)ethanone (250 mg, 1.76 mmol). Stir at °C for 2 hours and a half. The reaction solution was partitioned between water and ethyl acetate, and a 10% aqueous citric acid solution was added. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and then purified to silica gel column (10% methanol / chloroform) to afford solid 9-Cl intermediate (181 mg).

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.49 (2H, m), 1.88 (3H, s), 1.92 (3H, s), 2.08-2.13 (7H, m), 2.85 (1H, t, J = 12.8 Hz), 3.21 (1H, t, J = 11.9 Hz), 3.67 (2H, t, J = 6.6 Hz), 3.78-3.85 (1H, m), 3.94-4.05 (1H, m), 4.49-4.62 ( 2H, m), 6.70-6.99 (2H, brs)

A part of the above intermediate (140 mg, 0.301 mmol) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and isopropyl alcohol (4 mL). 10% palladium on carbon (AD, wet weight 100 mg) was added, and the mixture was stirred at room temperature for 15 hours under a hydrogen atmosphere. After the catalyst was filtered, the filtrate was evaporated to dryness crystals crystals crystals

¹ H-NMR (CDCl ₃ ) δ: 1.47-1.55 (2H, m), 1.77 (6H, s), 2.08-2.18 (3H, m), 2.13 (3H, s), 2.99 (1H, t, J = 13.8 Hz), 3.29 (1H, t, J = 13.9 Hz), 3.51-3.59 (1H, m), 3.72 (2H, t, J = 7.8 Hz), 3.86-3.89 (1H, m), 4.12 (1H, Dd, J = 14.0, 7.0 Hz), 4.37-4.40 (1H, m), 4.45-4.49 (1H, m), 6.14 (1H, d, J = 6.6 Hz), 6.50-6.69 (2H, brs)

Example 26

6-Amino-7-fluoro-8-[(trans-4-hydroxycyclohexyl)amino]-1,1-dimethyl-5-oxirane-1,2,3,5-tetrahydro Pyrrolo[1,2-a]quinoline-4-carboxydecylamine

The title compound was obtained as a solid, m. m.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.58 (5H, m), 1.74 (6H, s), 1.99-2.23 (6H, m), 3.22-3.35 (1H, m), 3.67 (2H, t, J=7.8Hz), 3.69-3.81(1H,m),4.13-4.24(1H,m),5.44-5.57(1H,m),6.06(1H,d,J=6.8Hz),6.53-6.90(2H ,br),10.03-10.15(1H,m)

MS (ESI) m / z: 403 (M + H) ⁺

Example 27

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-aminopiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid hydrochloride

N-methylpyrrolidone (8 mL) was added to the compound obtained in Step 4 of Example 25 (1.03 g, 3.01 mmol) and 4-amino-1-methylpiperidine (1.13 mL, 9.03 mmol). Stir at °C for 4 and a half hours. The reaction solution was concentrated under reduced pressure and the solvent was evaporated. The residue was subjected to a column chromatography (5% methanol/chloroform→10%→chloroform:methanol:water=7:3:1) to obtain an amorphous 9-Cl.

The amorphous material was dissolved in a mixed solvent of 1,2-dichloroethane (15 mL) and ethanol (15 mL), and 10% palladium carbon (AD, wet weight: 550 mg) was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere. hour. After adding ammonia water to the reaction liquid, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Ethanol (10 mL) was added to the obtained residue, and the mixture was heated to 95 ° C, and aqueous ammonia was added until the insoluble matter was dissolved. Heating in this state slowly vaporizes ammonia to precipitate a solid. It was returned to room temperature and filtered to give the title compound (646 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, s), 1.85 (2H, m), 2.05 (2H, m), 2.20 (2H, t, J = 7.9 Hz), 2.60 (3H, brs ), 2.88-3.00 (2H, m), 3.22-3.31 (2H, m), 3.51-3.67 (3H, m), 6.15-6.24 (2H, m), 7.01-7.10 (2H, brs)

Example 28

6-Amino-7-fluoro-8-{[(2R)-1-hydroxypropan-2-yl]amino}-1,1-dimethyl-5-sideoxy-1,2,3, 5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

The title compound was obtained as a solid, m. m.

¹ H-NMR (CDCl ₃ ) δ: -3.73 (1H, s), 1.33 (3H, d, J = 6.1 Hz), 1.77 (6H, d, J = 9.8 Hz), 2.15-2.21 (1H, br) , 2.21 (2H, t, J = 7.9 Hz), 3.59-3.76 (4H, m), 3.78-3.88 (1H, m), 4.49-4.58 (1H, m), 6.28 (1H, d, J = 6.8 Hz ), 6.40-6.59 (2H, br)

MS (ESI) m/z: 364 (M+H) ⁺

Example 29

8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7-fluoro-1,1-dimethyl-5-oxirane-1,2 ,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

Using the compound obtained in the above step 4 of Example 25 and 1-[(3S)-3-amino-1-piperidinyl]ethanone, in the same manner as in Step 5 of Example 25, solid was obtained. Title compound.

¹ H-NMR (CDCl ₃ ) δ: -3.93 (0.2H, s), -3.77 (0.8H, s), 1.55-1.97 (8H, m), 2.02-2.28 (6H, m), 2.63 (1H, Dd, J = 12.9, 9.8 Hz), 3.11-3.24 (1H, m), 3.26-3.86 (5H, m), 4.34 - 4.48 (1H, m), 4.70 - 4.81 (1H, m), 6.14 (0.2H , d, J = 6.6 Hz), 6.33 (0.8H, d, J = 7.1 Hz), 6.42-6.70 (2H, m)

Example 30

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(step 1)

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quina Porphyrin-4-carboxyguanamine

9-Chloro-7,8-difluoro-1,1-dimethyl-6-nitro-5-oxo-1,2,3,5-tetrahydropyrrole obtained in Step 3 of Example 25. And a solution of [1,2-a] quinoline-4-carboxylic acid tert-butyl ester (7.5 g, 17.5 mmol) in dichloromethane (200 ml) was added trifluoroacetic acid (2.6 ml) and stirred at room temperature for 2 hr. . Toluene was added, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane, dichloromethane (3.88 ml, 45.2 mmol) was added dropwise and 1 drop of N,N-dimethylformamide was added dropwise. After stirring for 2 hours at room temperature, the solvent was distilled off under reduced pressure. Soluble in two The alkane (25 ml) was added dropwise to aqueous ammonia (50 ml) under ice cold. After stirring at room temperature for 1 hour, water was added, and a solid (5.6 g) was collected by filtration. The obtained crude product was dissolved in N,N-formamide: 1,2-dichloroethane:acetic acid = 1:1:0.2 (150 ml), and 10% palladium carbon (AD, wet weight 1.0 g) was added. Stir at room temperature for one night under a hydrogen atmosphere. After filtration, the mother liquid was concentrated, and the residue was purified eluting eluted eluted eluted

¹ H-NMR (DMSO-D ₆ ) δ: 1.86 (6H, s), 2.06 (2H, t, J = 7.2 Hz), 3.43 (2H, t, J = 6.9 Hz), 7.34 (1H, d, J =3.4Hz), 8.91 (1H, d, J = 4.0Hz)

MS (ESI) m/z: 342[M+H] ⁺

(Step 2)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1,1-dimethyl-5-oxirane-1,2 ,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxirane-1,2,3,5-tetrahydropyrrolo[1,2-a] Add 1-(4-Aminopiperidin-1-yl)ethanone (250 mg, 1.76 mmol) to a solution of quinoline-4-carboxydecylamine (200 mg, 0.59 mmol) in dimethyl sulfoxide (5 ml). Stir at 100 ° C for one night. Water was added, and the mixture was extracted with chloroform (10% methanol). The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.34-1.44 (1H, m), 1.47-1.55 (1H, m), 1.79 (3H, s), 1.80 (3H, s), 1.84-1.93 (2H, m), 2.66-2.73 (1H, m), 3.08-3.15 (1H, m), 3.38 (2H, t, J = 6.9 Hz), 3.76-3.83 (2H, m), 4.23-4.29 (1H, m) , 5.08-5.12 (1H, m)

MS (ESI) m/z: 464 [M+H] ⁺

(Step 3)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-9-chloro-7-fluoro-1,1-dimethyl-5-oxirane-1, Add 10% to 2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine (110 mg, 0.24 mmol) in dichloromethane-methanol (4:1, 2.5 ml) Palladium on carbon (AD, wet weight 30 mg) was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the mother liquid was concentrated, and the residue was purified eluted eluted eluted eluted

¹ H-NMR (DMSO-D ₆ ) δ: 1.34-1.51 (2H, m), 1.68 (6H, s), 1.85-1.98 (2H, m), 2.01 (3H, s), 2.10 (2H, t, J=7.7Hz), 2.73-2.81(1H,m), 3.16-3.24(1H,m), 3.49(2H,t,J=7.7Hz), 3.56-3.64(1H,br m),3.84(1H, d, J = 14.3 Hz), 4.32 (1H, d, J = 13.2 Hz), 5.98 (1H, d, J = 6.9 Hz), 6.06 (1H, d, J = 6.9 Hz), 7.00 (1H, d, J=4.6Hz), 9.53 (1H, d, J=4.6Hz)

MS (ESI) m/z: 430 [M+H] ⁺

Example 31

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

(step 1)

6-Amino-9-chloro-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2, 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxirane-1,2,3,5-tetrahydrol obtained in Step 1 of Example 30 Add 4-amino-1-methylpiperidine (0.162 ml) to a solution of pyrrolo[1,2-a]quinoline-4-carboxydecylamine (200 mg, 0.59 mmol) in N-methylpyrrolidone (5 ml). , 1.29 mmol), stirred at 80 ° C overnight. Water was added to extract with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.53-1.63 (2H, m), 1.79 (6H, s), 1.82-1.88 (2H, m), 1.96-2.05 (4H, m), 2.18 (3H, s), 2.68-2.78 (2H, br m), 3.38 (2H, t, J = 7.2 Hz), 3.55-3.62 (1H, br m), 5.02 (1H, d, J = 7.4 Hz), 7.18 (1H) , d, J = 5.2 Hz), 9.17 (1H, d, J = 4.0 Hz)

MS (ESI) m/z: 436[M+H] ⁺

(Step 2)

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

6-Amino-9-chloro-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2 Add 3% palladium carbon to a solution of 3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine (130 mg, 0.30 mmol) in dichloromethane-methanol (4:1, 4 ml) (AD, wet weight 30 mg), and stirred at room temperature overnight under a hydrogen atmosphere. After filtration, the mother liquid was concentrated.

¹ H-NMR (DMSO-D ₆ ) δ: 1.68 (6H, s), 1.79-1.90 (2H, m), 2.04-2.13 (4H, m), 2.74 (4H, br s), 3.50 (2H, t , J=7.4Hz), 3.58-3.65(1H,m), 6.03(1H,d,J=6.9Hz), 6.24(1H,d,J=8.6Hz),7.00-7.03(1H,m),9.50 -9.53 (1H, m), 10.17-10.27 (1H, br m)

MS (ESI) m/z: 402 [M+H] ⁺

Example 32

8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7-fluoro-1,1-dimethyl-5-oxirane-1,2 ,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxydecylamine

Using the compound obtained in the first step of Example 30 and 1-[(3S)-3-amino-1-piperidyl]ethanone, the same procedure as in Step 2 and Step 3 of Example 30 was used. The title compound is solid.

¹ H-NMR (CDCl ₃ ) δ: 1.52-1.97 (9H, m), 2.00-2.25 (6.25H, m), 2.64 (0.75H, dd, J = 12.9, 9.5 Hz), 3.09-3.24 (0.75H , m), 3.24 - 3.87 (4.5H, m), 4.20-4.34 (1H, m), 4.68-4.80 (0.75H, m), 5.43-5.58 (1H, m), 6.07 (0.25H, d, J =7.1 Hz), 6.25 (0.75H, d, J = 6.8 Hz), 6.55-6.93 (2H, br), 9.96-10.17 (1H, m)

MS (ESI) m / z: 430 (M + H) ⁺

Example 33

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydropyrrolo[1,2-a]quinoline-4-carbonitrile

The compound (223 mg, 0.519 mmol) obtained in the step 3 of Example 30 and methylene chloride (20 mL) of triethylamine (0.579 mL, 4.15 mmol) were added to trifluoroacetic anhydride (0.145) under ice bath. mL, 1.04 mmol) and stirred. After 30 minutes, trifluoroacetic anhydride (0.145 mL, 1.04 mmol) and triethylamine (0.290 mL, 2.07 mmol) were then added and stirred for 30 min. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the mixture was stirred for 18 hr, then extracted with chloroform and dried over anhydrous sodium sulfate. The obtained residue was dissolved in ethanol (10 mL), and 1N aqueous sodium hydroxide (2 mL) was added, and the mixture was stirred at 40 ° C for 20 hours. The reaction solution was concentrated under reduced pressure, diluted with water and evaporated. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated evaporated evaporated. The obtained solid was washed with diethyl ether toield

¹ H-NMR (CDCl ₃ ) δ: 1.49-1.56 (2H, m), 1.75 (6H, s), 2.08-2.13 (2H, m), 2.13 (3H, s), 2.26 (2H, t, J = 7.3 Hz), 2.98 (1H, t, J = 12.6 Hz), 3.22 (2H, t, J = 8.2 Hz), 3.29 (1H, m), 3.47-3.57 (1H, m), 3.86 (1H, d, J=14.7Hz), 4.28 (1H, dd, J=8.0, 3.4Hz), 4.45 (1H, br d, J=14.7Hz), 6.02 (1H, d, J=7.8Hz), 6.63-6.83 (2H , m)

Example 34

8-{[(3S)-1-Ethylpiperidin-3-yl]amino}-6-amino-7-fluoro-1,1-dimethyl-5-oxirane-1,2 ,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carbonitrile

The title compound was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.50-1.97 (8H, m), 1.99-2.33 (6H, m), 2.48-2.65 (1H, m), 3.08-3.55 (4.65H, m), 3.69-3.89 (1.35H, m), 4.22-4.39 (1H, m), 4.71-4.84 (1H, m), 6.03 (0.2H, d, J = 6.6 Hz), 6.22 (0.8H, d, J = 6.6 Hz) , 6.53 - 6.93 (2H, m)

Example 35

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

(step 1)

4-bromo-2,6-dichloro-5-fluoropyridine-3-carboxylic acid

To a solution of 2,6-dichloro-5-fluoropyridine-3-carboxylic acid (50 g, 0.24 mol) in tetrahydrofuran (1000 ml), methyl lithium (1 M diethyl ether solution, 500 ml) was added dropwise at -78 ° C for 1 hour. , 0.50 mol). The reaction solution was stirred for 2 hours while raising the temperature until reaching -20 ° C, and then cooled again to -78 ° C. After adding 1,2-dibromotetrachloroethane (85 g, 0.26 mol) to the reaction mixture, the mixture was stirred at 0 ° C for 1 hour and 30 minutes. After the reaction solution was diluted with ice water, it was washed with chloroform. To the obtained aqueous layer, 1M aqueous hydrochloric acid was added and the mixture was evaporated. This compound was used in the next step without further purification.

MS (ESI) m/z: 244 (M+H) ⁺

(Step 2)

3-(4-Bromo-2,6-dichloro-5-fluoropyridin-3-yl)-2-(5,5-dimethylpyrrolidin-2-ylidene)-3-oxopropionic acid Propane-2-ester

For 4-bromo-2,6-dichloro-5-fluoropyridine-3-carboxylic acid (8.1 g, 28 mmol), add sulfoxide (20 ml, 0.27 mol) and dimethylformamide (catalytic amount) Stir at 100 ° C for 1 hour. The reaction solution was evaporated under reduced pressure, and the obtained residue was dissolved in THF (100 ml). Adding examples at room temperature A solution of the compound (6.0 g, 28 mmol) obtained from m. The solvent was evaporated under reduced pressure, and the mixture was evaporated. The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 0.95-0.98 (6H, m), 1.45 (6H, s), 1.96-1.99 (2H, m), 3.40-3.45 (2H, m), 4.87-4.92 (1H, m), 11.62 (1H, br s)

MS (ESI) m/z: 469 (M+H) ⁺

(Step 3)

3-[2,6-Dichloro-5-fluoro-4-(prop-2-en-1-ylamino)pyridin-3-yl]-2-(5,5-dimethylpyrrolidine-2 -subunit)-3-oxopropionate propan-2-ester

3-(4-Bromo-2,6-dichloro-5-fluoropyridin-3-yl)-2-(5,5-dimethylpyrrolidin-2-ylidene)-3-oxo-propyl To a solution of the acid propyl-2-carboxylate (5.0 g, 10.1 mmol) in acetonitrile (20 ml) was added EtOAc (EtOAc, EtOAc) After the solvent was evaporated under reduced pressure, the residue was diluted with ethyl acetate. The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 1.43 86H, d, J = 10.3 Hz), 1.56 (6H, s), 1.92-2.00 (2H, m), 3.19-3.28 (1H, m), 3.45-3.54 ( 1H,m),3.94-3.97(2H,m),4.57-4.60(1H,m),4.88-4.9,3.45-3.54(1H,m),3.94-3.97(2H,m),4.57-4.60(1H , m), 4.88-4.95 (1H, m), 5.18 (1H, dd, J = 10.3, 1.2 Hz), 5.25 (1H, dd, J = 17.1, 1.2 Hz), 5.84-5.93 (1H, m), 11.56 (1H, br s)

MS (ESI) m / z: 444 (M + H) ⁺

(Step 4)

2-Chloro-3-fluoro-9,9-dimethyl-5-oxo-4-(prop-2-en-1-ylamino)-5,7,8,9-tetrahydropyrrole [1,2-a][1,8] Pyridin-6-carboxylic acid propane-2-ester

3-[2,6-Dichloro-5-fluoro-4-(prop-2-en-1-ylamino)pyridin-3-yl]-2-(5,5-dimethylpyrrolidine- To a solution of 2-ylidene-3-oxopropionic acid propane-2-ester (2.37 g, 5.1 mmol) in tetrahydrofuran (50 ml), 55% aqueous sodium hydride (0.46 g, 10.6 mmol) Stir at 0 ° C for 1 hour and 30 minutes. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the organic layer was extracted with ethyl acetate. The obtained organic layer was washed with water, saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure.

¹ H-NMR (CDCl ₃ ) δ: 1.38 (6H, d, J = 5.7 Hz), 1.78 (6H, s), 2.12 (2H, t, J = 7.7 Hz), 3.24 (2H, t, J = 7.7 Hz), 4.15-4.19(2H,m), 5.15-5.18(1H,m),5.24-5.29(2H,m),5.92-5.98(1H,m),11.18-11.21(1H,m)

MS (ESI) m/z: 408 [M+H] ⁺

(Step 5)

4-amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-a][1,8 ] Pyridine-6-carboxylic acid

2-Chloro-3-fluoro-9,9-dimethyl-5-oxo-oxy-4-(prop-2-en-1-ylamino)-5,7,8,9-tetrahydropyrrole And [1,2-a][1,8] Add 10% palladium on carbon (350 mg) and methanesulfonic acid (210 mg, 2.2 mmol) to a solution of pyridine-6-carboxylic acid prop-2- ester (700 mg, 1.7 mmol) in isopropanol (20 ml), and stir at 80 °C. hour. After the insoluble material was filtered off, the solvent was evaporated to dryness, and the obtained residue was dissolved in ethanol (10 ml) and tetrahydrofuran (10 ml), and 1 M sodium hydroxide aqueous solution (10 ml) was added and stirred at 50 ° C for 19 hours. After the reaction mixture was cooled to room temperature, acetic acid was added and the mixture was added, and water was added, and the precipitated solid was filtered to give the title compound (370 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, s), 2.16 (2H, t, J = 7.7 Hz), 3.63 (2H, t, J = 7.7 Hz), 8.17 (1H, s), 9.06 (1H, s)

MS (ESI) m/z: 326 [M+H] ⁺

(Step 6)

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-a][1, 8] To a solution of pyridine-6-carboxylic acid (60 mg, 0.18 mmol) in N-methylpyrrolidone (1 ml), 1-(4-aminopiperidin-1-yl)ethanone (52 mg, 0.37 mmol) and triethyl The amine (51 μl, 0.37 mmol) was stirred at 100 ° C overnight. The reaction solution was diluted with ethyl acetate and washed with water and brine. The aqueous layer was further extracted with chloroform (10% methanol). After the solvent was evaporated under reduced pressure, the residue was purified mjjjjjjjjjj 40mg).

¹ H-NMR (DMSO-D ₆ ) δ: 1.40-1.57 (2H, m), 1.76 (6H, s), 1.84-1.93 (2H, m), 2.02 (3H, s), 2.13 (2H, t, J=8.0Hz), 2.60-2.64(1H,m), 3.06-3.11(1H,m), 3.58(2H,t,J=8.0Hz),3.87-3.91(1H,m),4.01-4.09(1H , m), 4.38-4.43 (1H, m), 7.09-8.26 (4H, m)

ESI-MS m/z: 432 (M+H) ⁺

Example 36

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

1-methylpiperidin-4-amine (525 mg, 4.61 mmol) was added to a solution of the compound (300 mg, 0.92 mmol) obtained from Stir at 160 ° C for 1 hour. After the solvent was evaporated under reduced pressure, the residue was purified (jjjjjjjjjj 220mg).

¹ H-NMR (CDCl ₃ ) δ: 1.58-1.67 (2H, m), 1.81 (6H, s), 2.04-2.08 (2H, m), 2.13-2.19 (4H, m), 2.33 (3H, s) , 2.84-2.89 (2H, m), 3.72 (2H, t, J = 8.0 Hz), 3.89-3.95 (1H, m), 4.81-4.84 (1H, m)

ESI-MS m/z: 404 (M+H) ⁺

Example 37

4-amino-3-fluoro-9,9-dimethyl-2-[{1-(2-methoxyethyl)piperidin-4-yl}amino]-5-sideoxy-5 ,7,8,9-tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

The title compound was obtained as a solid, m. m.

¹ H-NMR (D ₂ O+NaOD) δ: 1.50-1.58 (2H, m), 1.70 (6H, s), 1.93-1.97 (2H, m), 2.13 (2H, t, J = 7.8 Hz), 2.21-2.26(2H,m), 2.60(2H,t,J=5.8Hz), 2.93-2.97(2H,m), 3.10(2H,t,J=7.8Hz),3.37(3H,s),3.61 (2H, t, J = 5.8 Hz), 3.89-3.93 (1H, m)

ESI-MS m/z: 448 (M+H) ⁺

Example 38

4-amino-3-fluoro-2-[{1-(2-hydroxy-2-methylpropyl)piperidin-4-yl}amino]-9,9-dimethyl-5-side oxygen Base-5,7,8,9-tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

Using the compound obtained in Step 5 of Example 35 and 1-(4-aminopiperidin-1-yl)-2-methylpropan-2-ol, the title of solid was obtained in the same manner as in Example 36. Compound.

¹ H-NMR (D ₂ O+NaOD) δ: 1.55-1.63 (2H, m), 1.71 (6H, s), 1.89-1.92 (2H, m), 2.14 (2H, t, J = 7.9 Hz), 2.31-2.36(2H,m), 2.44(2H,s), 2.99-3.03(2H,m), 3.10(2H,t,J=7.8Hz),3.88-3.94(1H,m)

ESI-MS m/z: 462 (M+H) ⁺

Example 39

4-amino-3-fluoro-9,9-dimethyl-5-oxo-2-[{1-(2,2,2-trifluoroethyl)piperidin-4-yl}amino ]-5,7,8,9-tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid

The title compound was obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.61-1.69 (2H, m), 1.80 (6H, s), 2.03-2.07 (2H, m), 2.17 (2H, t, J = 8.0 Hz), 2.53-2.58 (2H, m), 3.00-3.06 (4H, m), 3.72 (2H, t, J = 8.0 Hz), 3.90-3.94 (1H, m), 4.81 (1H, d, J = 6.3 Hz)

ESI-MS m/z: 472 (M+H) ⁺

Example 40

4-amino-3-fluoro-9,9-dimethyl-5-oxo-2-(pyridin-3-ylamino)-5,7,8,9-tetrahydropyrrolo[1, 2-a][1,8] Pyridine-6-carboxylic acid

(step 1)

2-Chloro-3-fluoro-4-(4-methoxybenzylamino)-9,9-dimethyl-5-oxirane-5,7,8,9-tetrahydropyrrolo[1, 2-a][1,8] Pyridin-6-carboxylic acid tert-butyl ester

Using the compound obtained in Step 1 of Example 35, and the compound obtained in Step 2 of Example 25, in the same manner as in Steps 2, 3, and 4 of Example 35, and changing the allylamine of Step 3 This was carried out as p-methoxybenzylamine (5 eq.) to give the title compound as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.58 (9H, s), 1.76 (6H, s), 2.10 (2H, t, J = 7.9 Hz), 3.20 (2H, t, J = 7.9 Hz), 3.79 ( 3H, s), 4.67-4.69 (2H, m), 6.84-6.87 (2H, m), 7.25-7.27 (2H, m), 11.41-11.44 (1H, m)

MS (ESI) m/z: 502 [M+H] ⁺

(Step 2)

4-amino-3-fluoro-9,9-dimethyl-5-oxo-2-(pyridin-3-ylamino)-5,7,8,9-tetrahydropyrrolo[1, 2-a][1,8] Pyridine-6-carboxylic acid

2-Chloro-3-fluoro-4-(4-methoxybenzylamino)-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1 ,2-a][1,8] Pyridin-6-carboxylic acid tert-butyl ester (1.0 g, 1.99 mmol), 3-aminopyridine (375 mg, 9.98 mmol), BINAP (62 mg, 0.1 mmol) dissolved in two Alkane (20 ml) was added with cesium carbonate (1.3 g) for nitrogen substitution. Bis-palladium benzylideneacetone (90 mg) was added, and the mixture was stirred at 80 ° C for 15 hours, and heated under reflux for 4 hours. 3-Aminopyridine (200 mg), BINAP (65 mg), and palladium benzylideneacetone (95 mg) were added, and the mixture was heated under reflux for 15 hours. The reaction mixture was partitioned between EtOAc and EtOAc. The residue was roughly purified by column chromatography (dichloromethane:methanol = 10:0 to 9:1) to afford intermediate.

To a solution of the above intermediate in dichloromethane (3 ml), trifluoroacetic acid (3 ml) was added and stirred for 7 hr. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the solvent was evaporated again. Add 4M hydrochloric acid / two to the residue Alkane, after distilling off the solvent again, use two The title compound (554 mg) was obtained as a solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.58 (6H, s), 2.08 (2H, t, J = 7.8 Hz), 3.60 (2H, t, J = 7.8 Hz), 7.80-7.86 (1H, m ), 8.31-8.36 (1H, m), 8.50-8.53 (1H, m), 8.91-8.94 (1H, m), 9.87-9.93 (1H, m)

Example 41

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxy guanamine

(step 1)

4-amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-a][1,8 ] Pyridine-6-carboxy guanamine

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxirane-5,7,8,9-tetrahydropyrrole obtained in Step 5 of Example 35 [ 1,2-a][1,8] To a solution of the pyridine-6-carboxylic acid (1.2 g, 3.7 mmol) in dichloromethane (30 ml), EtOAc (3. <RTI ID=0.0></RTI></RTI><RTIgt; 1-Hydroxy)tripyrrolidinium hexafluorophosphate (2.1 g, 4.1 mmol) was stirred at room temperature for 5 hours. The reaction solution was diluted with chloroform, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated.

¹ H-NMR (CDCl ₃ ) δ: 1.80 (6H, s), 2.13 (2H, t, J = 8.0 Hz), 3.75 (2H, t, J = 8.0 Hz), 5.31-5.56 (2H, m), 9.70 (2H, br s)

MS (ESI) m/z: 325 [M+H] ⁺

(Step 2)

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxy guanamine

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2- a ][1, 8] Add 1-(4-Aminopiperidin-1-yl)ethanone (330 mg, 2.3 mmol) to a solution of pyridine-6-carboxy decylamine (250 mg, 0.77 mmol) in dimethyl hydrazide (5 ml). The mixture was stirred at 150 ° C for 3.5 hours under irradiation. After the solvent was distilled off under reduced pressure, the residue was washed with ethyl acetate and methanol to afford the crude purified product A of the title compound, and the object of the filtrate was purified by column chromatography (chloroform: methanol = 99) :1-9:1) Purification, obtaining crude purified body B. After the combination of A and B, the title compound (230 mg) was obtained.

¹ H-NMR (CD ₃ OD) δ: 1.46-1.61 (2H, m), 1.80-1.82 (6H, m), 1.92-2.14 (7H, m), 2.77-3.16 (2H, m), 3.59-3.62 (2H,m), 3.90-4.29 (3H,m)

ESI-MS m/z: 431 (M+H) ⁺

Example 42

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxy guanamine

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxirane-5,7,8,9-tetrahydropyrrole obtained in Step 1 of Example 41 [ 1,2-a][1,8] To a solution of pyridine-6-carboxy decylamine (250 mg, 0.77 mmol) in dimethyl hydrazine (3 ml), 1-methylpiperidin-4-amine (390 μl, 3.1 mmol) was added under microwave irradiation at 150 ° C Stir for 3 hours. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (NH) (chloroform:methanol=99:1-9:1) and chromatographic column chromatography (chloroform:methanol=99:1) 9:1) The title compound (160 mg) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 1.59-1.66 (2H, m), 1.72 (6H, s), 1.78-1.83 (2H, m), 1.90-1.95 (2H, m), 2.04 (2H, t, J=8.0 Hz), 2.18 (3H, s), 2.80-2.84 (2H, m), 3.53 (2H, t, J = 8.0 Hz), 3.76-3.83 (1H, m), 6.86-9.50 (5H , m)

ESI-MS m/z: 403 (M+H) ⁺

Example 43

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydropyrrolo[1,2-a]-1,8- Pyridine-6-carbonitrile

(step 1)

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-a]-1,8 - Pyridine-6-carbonitrile

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1] obtained in Step 1 of Example 41 ,2-a][1,8] A suspension of pyridine-6-carboxy decylamine (1.01 g, 3.11 mmol) and triethylamine (1.3 m, 9.33 mmol) in dichloromethane (20 ml) was added trifluoroacetic anhydride (0.66 μl, 4.67 mmol) under ice cooling. ). The reaction mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by column chromatography (20% ethyl acetate / EtOAc) Ethanol was added to the obtained solid.

¹ H-NMR (DMSO-D ₆ ) δ: 1.72 (6H, s), 2.18 (2H, t, J = 7.8 Hz), 3.30 (2H, t, J = 7.8 Hz), 8.00 (1H, s), 9.36 (1H, s)

(Step 2)

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydropyrrolo[1,2-a]-1,8- Pyridine-6-carbonitrile

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-a]-1, 8- A solution of pyridine-6-carbonitrile (144 mg, 0.44 mmol), 1-methylpiperidin-4-ylamine (153 mg, 1.33 mmol) in N-methylpyrrolidone (2 ml) was stirred at 120 ° C for 15 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on EtOAc (EtOAc) The residue was purified by flash chromatography on EtOAc EtOAc (EtOAc) The residue was purified by preparative PLC (20% methanol / chloroform) to afford a solid. To the obtained solid was added n-hexane / ethyl acetate = 1:1.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.68 (2H, m), 1.79 (6H, s), 2.00-2.23 (6H, m), 2.32 (3H, s), 2.80-2.90 (2H, m) , 3.24 (2H, t, J = 7.8 Hz), 3.81-3.94 (1H, m), 4.68-4.75 (1H, m)

Example 44

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydropyrrolo[1,2-a]-1,8- Pyridine-6-carbonitrile

The title compound was obtained as a solid, m. m.

¹ H-NMR (DMSO-D ₆ ) δ: 1.34-1.58 (2H, m), 1.72 (6H, s), 1.80-1.94 (2H, m), 2.01 (3H, s), 2.14 (2H, t, J = 7.8 Hz), 2.56-2.66 (1H, m), 3.02-3.13 (1H, m), 3.22 (2H, t, J = 7.8 Hz), 3.83-4.06 (2H, m), 4.33-4.44 (1H ,m),7.03 (1H,d,J=7.8Hz)

ESI-MS (m/z): 413 (M+H) ⁺

Example 45

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydroimidazo[1,2-a]quinoline-4-carboxylic acid

(step 1)

2-(2-ethoxy-2-oxooxyethylidene)-4,4-dimethylimidazolidin-1-carboxylic acid benzyl ester

Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (10.0 g, 51.1 mmol) to a solution of 1,2-diamino-2-methylpropane (4.96 g, 56.2 mmol) in ethanol. ), stirred at room temperature for 1 hour. After the solvent was distilled off, a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and tetrahydrofuran (150 ml) was added dropwise, and N-(benzyloxycarbonyloxy)-succinimide (5.95 g, 23.9 mmol) in tetrahydrofuran (50 ml) was added dropwise. ), stirred at room temperature for 2 hours. After extracting with ethyl acetate, the residue was dried over anhydrous sodium sulfate. This compound was used in the next reaction without further purification.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.28 (3H, s), 1.33 (3H, s), 3.59-3.61 (2H, m), 4.10 (2H, q , J = 7.2 Hz), 5.22 (1H, s), 7.34 - 7.39 (5H, m)

MS (ESI) m/z: 319 [M+H] ⁺

(Step 2)

4-ethyl 9-chloro-7,8-difluoro-1,1-dimethyl-6-nitro-5-oxo-1,2-dihydroimidazo[1,2-a]quina 3-benzyl ester of porphyrin-3,4(5H)-dicarboxylate

To a solution of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid (2.0 g, 7.83 mmol) in dichloromethane, dichloromethane (0.75 ml) and N,N-dimethyl Formamidine (1 drop), stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness crystals crystalsssssssssssssssssssssssss A solution of benzyl pyridine-1-carboxylate (4.41 g, 13.9 mmol) in tetrahydrofuran (70 ml) was stirred at room temperature for 1 hour. Water was added, and the mixture was extracted with EtOAc. The residue was purified by silica gel chromatography (chloroform-methanol) to afford solid (4.63 g). Diisopropylethylamine (14.4 ml, 82.8 mmol) was added to the obtained solid (4.60 g, 8.28 mmol) in tetrahydrofuran (200 ml), and heated under reflux for 2 days. After cooling to room temperature, water was added and extracted with ethyl acetate. The solvent was evaporated under reduced pressure. ethyl acetate was evaporated.

¹ H-NMR (DMSO-D ₆ ) δ: 1.14 (3H, t, J = 7.2 Hz), 1.89 (6H, s), 4.03-4.07 (4H, m), 5.25 (2H, s), 7.35-7.44 (5H,m)

MS (ESI) m/z: 536[M+H] ⁺

(Step 3)

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]quina Ethyl phthalate-4-carboxylate

9-Chloro-7,8-difluoro-1,1-dimethyl-6-nitro-5-oxo-1,2-dihydroimidazo[1,2-a]quinoline-3 , a solution of 4,5(5H)-dicarboxylic acid 3-benzyl 4-ethyl ester (500 mg) in N,N-dimethylformamide (10 ml) was added 5% palladium on carbon (AD, wet weight: 150 mg). Stir at room temperature overnight under a hydrogen atmosphere. After filtration, the mother liquid was concentrated.

¹ H-NMR (DMSO-D ₆ ) δ: 1.25 (3H, t, J = 7.2 Hz), 1.82 (6H, s), 3.54 (2H, s), 4.19 (2H, q, J = 7.3 Hz), 8.62 (1H, s)

MS (ESI) m/z: 372 [M+H] ⁺

(Step 4)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 - tetrahydroimidazo[1,2-a]quinoline-4-carboxylic acid ethyl ester

6-Amino-9-chloro-7,8-difluoro-1,1-dimethyl-5-oxirane-1,2,3,5-tetrahydroimidazo[1,2-a] Add 1-(4-Aminopiperidin-1-yl)ethanone (528 mg, 3.71 mmol) to a solution of quinolin-4-carboxylic acid ethyl ester (230 mg) in dimethyl sulfoxide (3 ml) at 130 ° Stir for one night. Water was added, and the mixture was extracted with chloroform (10% methanol) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.23 (3H, t, J = 7.2 Hz), 1.31-1.49 (2H, m), 1.66-1.68 (6H, m), 1.83-1.96 (2H, m) , 2.01 (3H, s), 2.76 (1H, t, J = 11.2 Hz), 3.18 (1H, t, J = 11.5 Hz), 3.56 (3H, s), 3.83 (1H, d, J = 14.9 Hz) , 4.15 (2H, q, J = 7.1 Hz), 4.30 (1H, d, J = 14.9 Hz), 5.69-5.72 (1H, m), 5.86 (1H, d, J = 6.9 Hz), 8.41 (1H, s)

MS (ESI) m/z: 460 [M+H] ⁺

(Step 5)

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydroimidazo[1,2-a]quinoline-4-carboxylic acid

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3, Ethyl 5-tetrahydroimidazo[1,2-a]quinoline-4-carboxylate (70 mg, 0.15 mmol) To a mixed solution of alkane-water-methanol (15:7:10, 3.2 ml), lithium hydroxide monohydrate (13 mg, 0.3 mmol) was added and stirred at room temperature overnight. Acetic acid (26 μl, 0.46 mmol) was added, and the mixture was extracted with chloroform (10% methanol) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.33-1.50 (2H, m), 1.84-1.96 (2H, m), 2.01 (3H, s), 2.73-2.79 (1H, m), 3.16-3.23 ( 1H, m), 3.64-3.66 (3H, m), 3.81-3.86 (1H, m), 4.29-4.34 (1H, m), 5.95 (1H, d, J = 6.9 Hz), 6.09 (1H, d, J=6.9Hz), 7.03 (1H, br s), 8.75 (1H, s)

MS (ESI) m/z: 432 [M+H] ⁺

Example 46

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydroimidazo[1,2-a]quinoline-4-carboxylic acid

(step 1)

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Ethyl tetrahydroimidazo[1,2-a]quinoline-4-carboxylate

The title compound was obtained in the same manner as in Step 4 of Example 45.

¹ H-NMR (DMSO-D ₆ ) δ: 1.23 (3H, t, J = 7.2 Hz), 1.49-1.58 (2H, m), 1.65 (6H, s), 1.85 (2H, d, J = 12.0 Hz) ), 1.96-2.02 (2H, m), 2.17 (3H, s), 2.74-2.79 (2H, m), 3.55 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 5.64-5.67 ( 1H,m), 5.82 (1H,d,J=6.9Hz), 8.40(1H,s)

MS (ESI) m/z: 432 [M+H] ⁺

(Step 2)

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydroimidazo[1,2-a]quinoline-4-carboxylic acid

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-1,2,3,5 - Ethyl tetrahydroimidazo[1,2-a]quinoline-4-carboxylate (159 mg, 0.37 mmol) To a mixed solution of alkane-water-methanol (3:1:1, 5 ml), lithium hydroxide monohydrate (93 mg, 2.21 mmol) was added and stirred at room temperature overnight. After adding acetic acid (148 μl, 2.58 mmol) to adjust to acidity, it was adjusted to be alkaline by adding aqueous ammonia, and extracted with chloroform containing 10% methanol, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.52-1.61 (2H, m), 1.69 (6H, s), 1.82-1.88 (2H, m), 1.96-2.03 (3H, m), 2.17 (3H, s), 2.73-2.80 (2H, m), 3.23 - 3.31 (1H, m), 3.64 (2H, s), 5.91 (1H, d, J = 6.9 Hz), 6.05 (1H, d, J = 6.3 Hz) ), 7.01 (1H, br s), 8.73 (1H, s)

MS (ESI) m/z: 404 [M+H] ⁺

Example 47

8-[(1-Ethylpiperidin-4-yl)amino]-6-amino-7-fluoro-1,1-dimethyl-5-sideoxy-1,2,3,5 -tetrahydroimidazo[1,2-a]quinoline-4-carboxydecylamine

An ammonia-methanol solution (8N, 1 ml) and aqueous ammonia (1 ml) were added to the compound obtained in the step 4 of Example 45 (80 mg, 0.17 mmol), and the mixture was stirred at 100 ° C overnight. After concentrating, it was purified by EtOAc (EtOAc:EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.32-1.50 (2H, m), 1.68 (6H, s), 1.85-1.97 (2H, m), 2.01 (3H, s), 2.75-2.80 (1H, m), 3.16-3.22 (1H, m), 3.54-3.61 (9H, m), 3.83 (1H, d, J = 12.0 Hz), 4.30 (1H, d, J = 12.0 Hz), 5.70-5.74 (1H , m), 5.89 (1H, d, J = 6.9 Hz), 6.85 (1H, d, J = 5.2 Hz)

MS (ESI) m/z: 431 [M+H] ⁺

Example 48

6-Amino-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5- oxo-1,2,3,5- Tetrahydroimidazo[1,2-a]quinoline-4-carboxydecylamine

An ammonia-methanol solution (8 M, 1 ml) and aqueous ammonia (50 ml) were added to the compound obtained in the step 1 of Example 46 (200 mg, 0.46 mmol), and the mixture was stirred at 80 ° C overnight. After concentration, the title compound (45 mg) was obtained.

¹ H-NMR (DMSO-D ₆ ) δ: 1.53-1.63 (2H, m), 1.66 (6H, s), 1.88 (2H, d, J = 11.5 Hz), 2.13 (2H, t, J = 11.5 Hz) ), 2.24 (3H, s), 2.84 (2H, d, J = 11.5 Hz), 3.22-3.32 (1H, m), 3.59 (2H, s), 5.77 (1H, d, J = 6.9 Hz), 5.84 (1H, d, J = 6.9 Hz), 6.91 (1H, d, J = 5.2 Hz), 8.19 (1H, s), 9.39 (1H, s), 9.73 (1H, d, J = 5.2 Hz)

MS (ESI) m/z: 403[M+H] ⁺

Example 49

6-Amino-9-chloro-4-cyano-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy -1,2-dihydroimidazo[1,2-a]quinoline-3(5H)-carboxylic acid

(step 1)

2-(cyanomethyl)-4,4-dimethyl-4,5-dihydro-1H-imidazole-1-carboxylic acid tert-butyl ester

To a solution of ethyl 2-cyanoethane phthalimidate hydrochloride (5.12 g, 34.5 mmol) in ethanol (130 ml), 1,2-diamino-2-methylpropane (3.93 ml, 37.9) Methyl), stirred at room temperature for 2 hours. After the solvent was distilled off, tetrahydrofuran (300 ml) and a saturated aqueous solution of sodium hydrogen carbonate (150 ml) and dibutyl tricarbonate (8.27 g, 37.9 mmol) were added, and the mixture was stirred at room temperature for 1 hour. It was extracted with ethyl acetate and washed with brine. The solvent was evaporated to dryness.

¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, s), 1.34 (3H, s), 1.52 (9H, s), 3.45 (1H, s), 3.53 (1H, s), 3.59 (2H, s )

MS (ESI) m/z: 436[M+H] ⁺

(Step 2)

6-Amino-9-chloro-4-cyano-7,8-difluoro-1,1-dimethyl-5-oxooxy-1,2-dihydroimidazo[1,2-a] Quinoline-3(5H)-carboxylic acid tert-butyl ester

To a solution of 3-chloro-2,4,5-trifluoro-6-nitrobenzoic acid (858 mg, 3.36 mmol) in dichloromethane, dichloromethane (0.32 ml) and N,N-dimethylmethyl Indoleamine (1 drop), stirred for 3 hours. The reaction solution was concentrated under reduced pressure to give a toluene solution (30 ml), which was added dropwise to 2-(cyanomethyl)-4,4-dimethyl-4,5-dihydro-1H-imidazole-1 A toluene solution (10 ml) of a carboxylic acid tert-butyl ester (817 mg, 3.44 mmol) was stirred at room temperature for 2 hr. Triethylamine (436 μl, 3.13 mmol) was added and stirred for one night. After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. Potassium carbonate (520 mg, 3.76 mmol) was added to a solution of the residue (1. Water was added, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate. Ethyl acetate was added, and the precipitated solid was collected by filtration. A solution of the obtained solid (620 mg) in N,N-dimethylformamide (10 ml) was added 10% palladium carbon (AD, wet weight: 120 mg), and stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the mother liquid was concentrated, and the residue was purified eluted eluted elut elut elut elut elut

MS (ESI) m/z: 425 [M+H] ⁺

(Step 3)

6-Amino-9-chloro-4-cyano-7-fluoro-1,1-dimethyl-8-[(1-methylpiperidin-4-yl)amino]-5-sideoxy -1,2-dihydroimidazo[1,2-a]quinoline-3(5H)-carbonitrile

6-Amino-9-chloro-4-cyano-7,8-difluoro-1,1-dimethyl-5-oxooxy-1,2-dihydroimidazo[1,2-a To a solution of quinoline-3(5H)-carboxylic acid tert-butyl ester (150 mg) in N-methylpyrrolidone (5 ml), 4-amino-1-methylpiperidine (266 μl, 2.12 mmol) was added Stir at 130 degrees for one night. The solvent was distilled off, and the title compound (20 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.58-1.67 (2H, m), 1.76 (6H, s), 2.02-2.09 (2H, m), 2.19 (2H, t, J = 10.6 Hz), 2.32 (3H) , s), 2.78-2.87 (2H, m), 3.22-3.31 (1H, br m), 3.66 (2H, s), 4.17-4.22 (1H, m), 5.85 (1H, d, J = 6.9 Hz) , 6.37 (1H, s), 6.64 (1H, br s)

MS (ESI) m/z: 385 [M+H] ⁺

Example 50

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydroimidazo[1,2-a][1,8] Pyridine-6-carboxy guanamine

(step 1)

2-chloro-3-fluoro-4-[(4-methoxybenzyl)amino]-9,9-dimethyl-5-oxo-8,9-dihydro-5H-imidazo[ 1,2-a][1,8] 7-benzyl 6-ethyl pyridine-6,7-dicarboxylate

To the compound obtained in the step 1 of Example 35 (5 g, 17.3 mmol), sulfinium chloride (8 ml) and N,N-dimethylformamide (3 drops) were added dropwise, and the mixture was stirred at 70 ° C for 2 hours. The solvent was evaporated under reduced pressure. Toluene was added to the residue. After a solution of the compound (6.1 g, 19 mmol. The reaction mixture was partitioned between EtOAc EtOAc m. The solvent was evaporated under reduced pressure. EtOAcjjjjjjjj

Acetonitrile (30 ml) and p-methoxybenzylamine (4.7 ml) were added to the above oil (6.85 g), and stirred at 50 ° C for 2 hours. Further, p-methoxybenzylamine (1 ml) was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was partitioned between EtOAc and EtOAc. The residue was purified by EtOAc (EtOAc:EtOAc:EtOAc

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.68 (3H, s), 1.69 (3H, s), 3.79 (3H, s), 3.98 (2H, s), 4.22 (2H, q, J = 7.2 Hz), 4.59 (2H, d, J = 5.5 Hz), 5.24 (2H, s), 6.82-6.85 (2H, m), 7.27-7.30 (2H, m), 7.35 -7.38(5H,m), 10.62(1H,t,J=5.5Hz)

(Step 2)

2-Chloro-3-fluoro-4-[(4-methoxybenzyl)amino]-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydroimidazolium [1,2-a][1,8] Pyridine-6-carboxylic acid

2-Chloro-3-fluoro-4-[(4-methoxybenzyl)amino]-9,9-dimethyl-5-oxo-8,9-dihydro-5H-imidazole [1,2-a][1,8] 7-Benzyl pyridine-6,7-dicarboxylate (299 mg, 0.33 mmol) was dissolved in tetrahydrofuran (3 ml)-methanol (3 ml), lithium hydroxide monohydrate (56 mg, 1.32 mmol), water (1 ml), stir for 3 days. 1M Hydrochloric acid (1.35 ml) was added to the reaction mixture, and the mixture was applied to ethyl acetate The organic layer was dried (MgSO4), evaporated, evaporated, evaporated

¹ H-NMR (CDCl ₃ ) δ: 1.79 (3H, s), 1.80 (3H, s), 3.78-3.81 (5H, m), 4.63 (2H, d, J = 5.5 Hz), 6.86-6.90 (2H , m), 7.29-7.33 (2H, m), 9.20 (1H, s), 10.04-10.09 (1H, m)

(Step 3)

4-amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydroimidazo[1,2-a][1,8 ] Pyridine-6-carboxy guanamine

2-Chloro-3-fluoro-4-[(4-methoxybenzyl)amino]-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydroimidazole And [1,2-a][1,8] Ammonium chloride (208 mg, 3.89 mmol), (benzotriazol-1-yloxy)tripyrrolidine was added to a suspension of dihydroethane (2 ml) of pyridine-6-carboxylic acid (87 mg, 0.19 mmol). Hexafluorophosphate (122 mg, 0.23 mmol), triethylamine (814 μl, 5.84 mmol) was stirred at room temperature overnight. It was diluted with chloroform containing 10% methanol and washed with a 1M aqueous sodium hydroxide solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, ethyl acetate was added, and the precipitated solid was collected by filtration. Trifluoroacetic acid (149 μl, 2.02 mmol) was added to a suspension (2 ml) of m. After the solvent was distilled off, aqueous ammonia was added to make a basicity, and the precipitate was filtered to give the title compound (45 mg).

¹ H-NMR (DMSO-D ₆ ) δ: 1.90 (6H, s), 3.63-3.65 (2H, br m), 9.21. (1H, br s)

MS (ESI) m/z: 326 [M+H] ⁺

(Step 4)

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydroimidazo[1,2-a][1,8] Pyridine-6-carboxy guanamine

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydroimidazo[1,2-a][1, 8] 4-Amino-1-methylpiperidine (1.39 ml, 11.1 mmol) was added to a solution of pyridine-6-carboxy decylamine (360 mg, 1.11 mmol) in dimethyl sulfonium (18 ml). The mixture was stirred for 15 minutes. After adding ammonia water, it was extracted with chloroform containing 10% methanol, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.54-1.64 (8H, m), 1.74-1.80 (2H, m), 1.95 (2H, br s), 2.18 (3H, s), 2.75-2.83 (2H , m), 3.63 (2H, s), 3.85-3.92 (1H, m), 6.47 (1H, br s), 6.65 (1H, d, J = 6.9 Hz), 6.97 (1H, d, J = 5.2 Hz) ), 9.47 (1H, br s), 9.68 (1H, d, J = 5.2 Hz), 9.90 (1H, s)

MS (ESI) m/z: 404 [M+H] ⁺

Example 51

2-[(1-Ethylpiperidin-4-yl)amino]-4-amino-3-fluoro-9,9-dimethyl-5-sideoxy-5,7,8,9 -tetrahydroimidazo[1,2-a][1,8] Pyridine-6-carboxy guanamine

4-Amino-2-chloro-3-fluoro-9,9-dimethyl-5-oxo-5,7,8,9-tetrahydroimidazolium obtained in Step 3 of Example 50 [ 1,2-a][1,8] 1-(4-Aminopiperidin-1-yl)ethanone (1.12 g, 7.88 mmol) was added to a solution of pyridine-6-carboxydecylamine (300 mg) in dimethyl sulfonium (10 ml) under microwave irradiation Stir at 150 degrees for 15 minutes. After adding ammonia water, it was extracted with chloroform containing 10% methanol, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.32-1.52 (2H, m), 1.62 (6H, s), 1.78-1.91 (2H, m), 2.01 (3H, s), 2.60 (1H, t, J = 12.6 Hz), 3.08 (1H, t, J = 12.6 Hz), 3.63 (2H, s), 3.84 (1H, d, J = 13.7 Hz), 4.09 - 4.18 (1H, m), 4.37 (1H, d, J = 12.6 Hz), 6.49 (1H, br s), 6.72 (1H, d, J = 8.0 Hz), 6.99 (1H, d, J = 4.9 Hz), 9.50 (1H, br s), 9.68 ( 1H,d,J=4.9Hz), 9.90 (1H, s)

MS (ESI) m/z: 464 [M+H] ⁺

Example 52

4-amino-3-fluoro-9,9-dimethyl-2-[(1-methylpiperidin-4-yl)amino]-5-sideoxy-5,7,8,9- Tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid formate

To a solution of the compound (70 mg, 0.21 mmol) obtained in Step 5 of Example 35 and 1-methylpiperidin-4-amine (49 mg, 0.43 mmol) in N-methylpyrrolidone (1 ml), 60 μl, 0.43 mmol), stirred at 100 ° C for 3 days. The reaction mixture was purified by EtOAc (EtOAc:EtOAc)

¹ H-NMR (DMSO-D ₆ ) δ: 1.61-1.71 (2H, m), 1.75 (6H, s), 1.80-1.86 (2H, m), 2.00-2.07 (2H, m), 2.13 (2H, t, J = 7.8 Hz), 2.23 (3H, s), 2.86-2.91 (2H, m), 3.57 (2H, t, J = 7.8 Hz), 3.79-3.88 (1H, m), 6.58-8.61 (2H , m), 7.23 (1H, d, J = 7.8 Hz), 8.17 (1H, s)

MS (ESI) m/z: 404 [M+H] ⁺

Example 53

4-amino-3-fluoro-2-[{1-(2-hydroxy-2-methylpropyl)piperidin-4-yl}amino]-9,9-dimethyl-5-side oxygen Base-5,7,8,9-tetrahydropyrrolo[1,2-a][1,8] Pyridine-6-carboxylic acid hydrochloride

The compound obtained in the step 5 of Example 35 (500 mg, 1.5 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylpropan-2-ol (397 mg, 2.3 mmol) Triethylamine (1.1 ml, 7.7 mmol) was added to a solution of hydrazide (10 ml), and the mixture was stirred at 150 ° C for 6 hours under microwave irradiation. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [chloroform:methanol=99:1→9:1 (v/v). After the residue obtained is diluted with methanol, 4N hydrochloric acid-two is added. The alkane solution was stirred. After the solvent was distilled off under reduced pressure, the obtained residue was added ethyl acetate and ethyl acetate, and solidified to obtain a solid object (150 mg).

¹ H-NMR (D2O + NaOD) δ: 1.55-1.63 (2H, m), 1.71 (6H, s), 1.89-1.92 (2H, m), 2.14 (2H, t, J = 7.9 Hz), 2.31 2.36(2H,m), 2.44(2H,s), 2.99-3.03(2H,m), 3.10(2H,t,J=7.8Hz),3.88-3.94(1H,m)

ESI-MS m/z: 462[M+H] ⁺

Example 54

6-Amino-7,9-difluoro-1,1-dimethyl-8-[{1-(2-hydroxy-2-methylpropyl)piperidin-4-yl}amino]-5 -Sideoxy-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acid

Using the compound obtained in the step 5 of Example 17 and 1-(4-aminopiperidin-1-yl)-2-methylpropan-2-ol, the title of solid was obtained in the same manner as in Example 17. Compound.

¹ H-NMR (D2O + NaOD) δ: 1.21 (6H, s), 1.52-1.59 (2H, m), 1.65 (3H, s), 1.66 (3H, s), 1.87-1.93 (2H, m), 2.17-2.27(4H,m), 2.37(2H,s),2.92-2.95(2H,m),3.11(2H,t,J=7.5Hz),3.53-3.677(1H,m)

ESI-MS m/z: 479 (M+H) ⁺

(Test Example 1 GSK-3 inhibitory activity)

The kinase activity of GSK3 in the presence or absence of the test compound is determined. The matrix peptide is phosphorylated by the kinase activity of GSK3. Since the change in the charge of the phosphate group is negative (negative) compared to the unphosphorylated substrate, the change is electrophoretically separated (Mobility Shift Assay method). The degree of phosphorylation.

(1) Sample preparation and enzyme reaction

The GST-GSK3 protein (GSK3β, carnabioscience) which is introduced into the N-terminal side of the full length (1-420 amino acid) of human GSK3β and which is expressed in an insect cell virus.

Then, a GSK3β enzyme solution containing the above GST-GSK3 protein and 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT, 10 mM MgCl ₂ was prepared and dispensed into a 384-well plate (Corning). .

The test compound was dissolved in DMSO and a dilution series was prepared using DMSO. This compound solution was added to the dispensed GSK3 enzyme solution, mixed, and pre-incubated for 30 minutes at room temperature.

In the well containing the above-mentioned test compound, a matrix solution (100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT, 10 mM MgCl ₂ , ATP (final concentration 20 μM), FL- was added. Peptide 15 (Caliper Lifesciences) was mixed and allowed to stand at 28 ° C for 1.5 hours, and the enzyme reaction was allowed to proceed.

As a positive control for confirming the progress of the enzyme reaction, DMSO was used instead of the compound solution, and as a negative control in which the enzyme reaction was not carried out, the substrate solution was replaced by removing the ATP from the substrate solution, and the same operation was performed. .

(2) Detection of enzyme reaction

After the enzyme reaction, a reaction stop solution (100 mM HEPES (pH 7.4), 0.015% Brij-35, 40 mM EDTA, 0.1% Coating Reagent 3 (Caliper life science) was added to each well, and Caliper life science EZ Reader II was used. , separating the phosphorylated substrate from the unphosphorylated substrate, and determining the ratio of the phosphorylation of the matrix peptide to the inhibition and inhibition activity. By fitting the measured value in the Sigmoid curve, The concentration at which the compound showed 50% inhibition was calculated as the IC ₅₀ value of the GSK3β enzyme inhibitory activity.

Each of the compounds of the examples had an IC ₅₀ value of 20 nM or less.

(Test Example 2 Anti-cell test)

Cell line A375 cells (ATCC) from human malignant melanoma were inoculated into a 96-well plate (2000/well), and added to each well after preparing a dilution series of the sample containing the compound to be tested. After incubation at 4, the ^{CellTiter-Glo TM Luminescent Cell Viability Assay} (Promega) was added to each well and measuring the change of the amount of ATP. The 50% cell proliferation inhibitory activity (GI ₅₀ ) was calculated by the following formula.

100×[(TT ₀ )/(CT ₀ )]=50

(Here, the measured value of the added hole of the compound to be tested in the T system for 4 days, the measured value of the non-added hole of the test compound in the C system for 4 days, and the initial measured value when the T ₀ is added to the test compound).

Among the compounds of the examples which have been tested, the compounds of Examples 1 to 16, 18 to 36, 39 to _{50, 52,} and 53 have a GI ₅₀ value of 50 nM or less.

(Test Example 3) In vivo antitumor effect

A375 cells from human malignant melanoma cells were formulated to 4×10 ⁷ cells/mL, and 0.1 mL of tumor cell suspension was transplanted into the skin of BALB/c nude mice (female, 5-6 weeks old). 7~10 days. After confirming that the average tumor volume exceeded 100 mm ³ , the tumor volume value was subjected to grouping (n=5), and the test compound was suspended in 0.5% methylcellulose, and orally administered to mice. The administration amount was set as a preliminary test for oral administration of a mouse for each compound, and 1/2 of the lowest single administration dose of the death case was taken as the maximum tolerance (MTD). The MTD was set as the maximum dose, and the dose of a plurality of doses was evaluated to evaluate the efficacy of a single administration. The drug effect is measured by the electronic digital caliper over time to measure the long diameter (mm) and short diameter (mm) of the tumor, and according to the formula below, the tumor growth inhibition rate (GI%) on the judgment day (after 1 week of administration) ) to conduct an evaluation.

GI(%)=(1-A/B)×100

A: average tumor volume of the compound administration group on the judgment day (*)

B: mean tumor volume of the untreated control group on the judgment day (*)

*: The tumor volume was calculated as 1/2×[tumor long diameter]×[tumor short diameter]×[tumor short diameter].

Among the example compounds which were tested, Examples 1, 2, 11, 13, 18, 20, 21, 22, 25, 27, 30, 32, 36-44, 47, 50, 53, 54 were below the MTD. The concentration showed inhibition of tumor proliferation with GI (%) > 30.

Claims (10)

a compound or a salt thereof, represented by the formula (1); Wherein R ₁ represents a carboxyl group, an amine carbenyl group or a cyano group, R ₂ represents a methyl group or a hydrogen atom, R ₃ represents a halogen atom, and R ₄ represents a piperidine which may also have a substituent selected from the following Group A; The group may also have a pyridyl group selected from the substituents of the following Group A, a cyclohexyl group which may have a substituent selected from the following Group A, or a hydrogen atom, and X ₁ represents CH, CF or N, and X ₂ represents CH ₂ , NH or S]A group: C ₁ -C ₆ alkyl group, ethyl sulfonyl group, methyl sulfonyl group or hydroxy group which may be substituted by 1 to 3 halogen atoms, a hydroxyl group or a methoxy group. The compound of claim 1 or a salt thereof, wherein R ₁ is a carboxyl group or a cyano group. a compound or a salt thereof, which is selected from one of the group consisting of; A glyco-synthetase kinase 3 (GSK3) inhibitor comprising the compound of any one of claims 1 to 3, or a salt thereof. A pharmaceutical composition according to any one of claims 1 to 3, or a salt thereof, as an active ingredient. An anticancer agent, which is a compound of any one of claims 1 to 3, or a salt thereof, as an active ingredient. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a salt thereof, and a pharmaceutically acceptable carrier. A method of treating cancer, which comprises administering a compound of any one of claims 1 to 3 or a salt thereof. Such as the anticancer agent of claim 6, wherein the cancerous blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, Gastric cancer, appendix cancer, colon cancer, anal cancer, biliary cancer, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanin Tumor, breast cancer, uterine body cancer, cervical cancer, ovarian cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, kidney cancer, bladder cancer or testicular cancer. Such as the treatment method of the cancer of claim 8, wherein the cancerous blood cancer (leukemia, lymphoma, multiple myeloma), brain tumor, head and neck cancer, esophageal cancer, stomach cancer, appendic cancer, colon cancer, anal cancer, timid Cancer, cholangiocarcinoma, pancreatic cancer, gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma, thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor, melanoma, breast cancer, endometrial cancer, cervical cancer, ovary Cancer, osteosarcoma, soft sarcoma, Kaposi's sarcoma, muscle tumor, kidney cancer, bladder cancer or testicular cancer.