JP2005053903A - Quinolone derivative or its salt - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new quinolone derivative or the pharmaceutically acceptable salt thereof having excellent platelet aggregation-inhibiting action and useful as a medicine, particularly a platelet aggregation inhibitor or a P2Y12 inhibitor. <P>SOLUTION: The quinolone derivative or its salt is represented by formula (I) (wherein X is C-R<SP>7</SP>, N or the like; Y is C-R<SP>6</SP>, N or the like; R<SP>11</SP>is H, a lower alkyl or the like; R<SP>12</SP>is H, a lower alkyl or the like; R<SP>2</SP>is a lower alkyl, cycloalkyl or the like; R<SP>3</SP>is a halogen, lower alkyl; R<SP>4</SP>is a cycloalkyl, non-aromatic heterocycle or the like; R<SP>5</SP>is H, a halogen or the like; R<SP>6</SP>is H, a halogen or the like; R<SP>7</SP>is H, a halogen or the like; and when Y is C-R<SP>6</SP>, R<SP>2</SP>and R<SP>6</SP>may be integrated to form a lower alkylene or lower alkenylene provided that 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide is excluded). <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel quinolone derivative or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly a platelet aggregation inhibitor or a P2Y12 inhibitor.

（式中の記号は、該公報参照） Platelet has been treated for a long time as a component in blood necessary for hemostasis since it was discovered by Donne in 1842. Today, platelets not only play a leading role in the mechanism of hemostasis, but also are clinically noted for the establishment of arteriosclerosis, circulatory diseases including thrombotic diseases, cancer metastasis, inflammation, rejection after transplantation, and immune response. It has been clarified to show multifunctionality such as involvement.
In general, for thrombotic diseases and ischemic diseases, treatment for resuming blood circulation using drugs or physical methods is performed. However, recently, after revascularization, a phenomenon has been discovered in which platelet activation, adhesion, and aggregation are promoted due to disruption of vascular tissue including endothelial cells or disruption of the fibrinolysis / coagulation balance caused by the drug itself. It is also a clinical problem. For example, after recanalization was obtained by thrombolytic therapy using t-PA or the like, it has become clear that fibrinolytic ability and coagulation ability are activated and the coagulation / fibrinolytic balance of the whole body is disrupted. Clinically, it causes re-occlusion and is a major problem in treatment (Non-patent Document 1).
On the other hand, PTCA therapy and stent placement have rapidly spread to treat diseases based on coronary stenosis and aortic stenosis such as angina pectoris and myocardial infarction. However, these therapies damage the vascular tissue including endothelial cells, causing acute coronary occlusion and further restenosis occurring in the chronic phase. Platelets play an important role in various thrombotic adverse effects (such as reocclusion) after such revascularization therapy. Therefore, although the effectiveness of antiplatelet agents is expected, sufficient effects have not been proven with conventional antiplatelet agents.
Platelet aggregation inhibitors such as aspirin, indomethacin, cilostazol, prostaglandin I ₂ , prostaglandin E ₁ , ticlopidine, and dipyridamole have been used as preventive or therapeutic agents for these cardiovascular diseases. In recent years, GPIIb / IIIa antagonists that inhibit the final stage of platelet aggregation and have strong platelet aggregation inhibitory activity have been developed, but their use is limited to intravenous infusion in the acute phase of thrombosis (Non-patent Document) 2).
In recent years, it has been clarified that ticlopidine, which is used as an antiplatelet agent, exhibits an inhibitory action on platelet aggregation by inhibiting its active metabolite, P2Y12, which is an ADP receptor. Thereafter, triazolo [4,5-D] pyrimidine derivatives (Patent Document 1), piperazine and / or homopiperazine derivatives (Patent Document 2, Patent Document 3) and the like have been reported as compounds having a P2Y12 inhibitory action.
On the other hand, as a quinolone derivative, a compound represented by the formula (A) having an antibacterial action (Patent Document 4) is known, but these derivatives are not known to have a platelet aggregation inhibitory action.

(Refer to this publication for symbols in the formula)

Journal of the American College of Cardiology, 1988, Volume 12, p.616-623 Sogo Clinical, 2003, Vol. 52, pp. 1516-1521 International Publication No. WO 00/34283 Pamphlet International Publication No. WO 02/098856 Pamphlet International Publication No. WO 03/022214 Pamphlet International Publication No. WO 98/23592 Pamphlet

Under such circumstances, the development of an antiplatelet agent having both high safety with less bleeding side effects and clear medicinal effects not only in the acute phase but also in the chronic phase is eagerly desired. Therefore, an object of the present invention is to provide a novel compound useful as a platelet aggregation inhibitor and a P2Y12 inhibitor having a high pharmacological effect and excellent balance between the pharmacological effect and safety.
Therefore, as a result of intensive studies aimed at overcoming the above problems, the present inventors have found that a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, P2Y12 The present invention was completed by discovering that the compound has a novel skeleton exhibiting an inhibitory action.

［式中の記号は、以下の意味を示す。
X：C-R⁷、又はN。
Y：C-R⁶、又はN。
R¹¹：-H、置換されていてもよい低級アルキル、又は置換されていてもよい低級アルキルで置換されていてもよいアミノ。
R¹²：-H、又はそれぞれ置換されていてもよい低級アルキル若しくはアリール。ただし、R¹¹とR¹²は隣接する窒素原子と一体となって、置換されていてもよい環状アミノを形成してもよい。
R²：それぞれ置換されていてもよい低級アルキル、シクロアルキル、アリール若しくはへテロ環。
R³：ハロゲン、低級アルキル、又は-O-低級アルキル。
R⁴：それぞれ置換されていてもよいシクロアルキル若しくは非芳香族へテロ環、又はシクロアルキルで置換されている低級アルキル。ただし、R⁴が置換されていてもよい非芳香族へテロ環を示す場合、環を構成する炭素原子が隣接するNHと結合するものとする。
R⁵：-H、ハロゲン、シアノ、ニトロ、低級アルキル、ハロゲノ低級アルキル、シクロアルキル、アリール、ヘテロ環、-O-低級アルキル、-OH、-NHCO-低級アルキル、-N(低級アルキル)CO-低級アルキル、低級アルキルで置換されていてもよいアミノ、又は置換されていてもよい環状アミノ。
R⁶：-H、ハロゲン、低級アルキル又はハロゲノ低級アルキル。
R⁷：-H、ハロゲン、低級アルキル又はハロゲノ低級アルキル。
ただし、YがC-R⁶を示す場合、R²とR⁶は一体となって、低級アルキレン、又は低級アルケニレンを形成してもよい。ただし、7-(シクロヘキシルアミノ)-1-エチル-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-カルボヒドラジドを除く。］
また、本発明によれば、以下の（２）乃至（２１）の発明が提供される。
（２）Xが、CHである（１）記載の化合物。
（３）R³が、ハロゲンである（２）記載の化合物。
（４）R⁴がシクロアルキルである（３）記載の化合物。
（５）R⁵が、H、-OH、若しくはハロゲンである（４）記載の化合物。
（６）R¹²がQ群より選択される１つ以上の基でそれぞれ置換されている（ただし少なくとも１つはＰ群の基により置換されている)低級アルキルである（５）の化合物。
Ｐ群：-CO₂H、-SO₃H、-P(O)(OH)₂及び-OP(O)(OH)₂
Ｑ群：-F、-OH、-CO₂H、-SO₃H、-P(O)(OH)₂及び-OP(O)(OH)₂
（７）NR¹¹R¹²が一体となってＱ群より選択される１つ以上の基で置換されている（ただし少なくとも１つはＰ群の基により置換されている)環状アミノ基である（５）記載の化合物。
（８）（７）に記載の化合物のうち、
[2-({[7-(シクロヘキシルアミノ)-1-シクロペンチル-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)エチル]ホスホン酸、
(2S)-2-({[7-(シクロヘキシルアミノ)-1-シクロペンチル-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)ブタン二酸、
2-({[7-(シクロヘキシルアミノ)-1-シクロペンチル-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)エチル 二水素 ホスファート、
(2S)-2-({[7-(シクロヘキシルアミノ)-1-シクロペンチル-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)ペンタン二酸、
{2-[({7-(シクロヘキシルアミノ)-6-フルオロ-4-オキソ-1-[(3S)-テトラヒドロフラン-3-イル]-1,4-ジヒドロキノリン-3-イル}カルボニル)アミノ]エチル}ホスホン酸、
{2-[({7-(シクロヘキシルアミノ)-6-フルオロ-4-オキソ-1-[(3R)-テトラヒドロフラン-3-イル]-1,4-ジヒドロキノリン-3-イル}カルボニル)アミノ]エチル}ホスホン酸、
[2-({[7-(シクロヘキシルアミノ)-1-(1-エチルプロピル)-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)-1,1-ジフルオロエチル]ホスホン酸、
{2-[({7-(シクロヘキシルアミノ)-6-フルオロ-1-[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]-4-オキソ-1,4-ジヒドロキノリン-3-イル}カルボニル)アミノ]エチル}ホスホン酸、
[2-({[7-(シクロヘキシルアミノ)-1-エチル-6-フルオロ-4-オキソ-1,4-ジヒドロシンノリン-3-イル]カルボニル}アミノ)エチル]ホスホン酸、
[2-({[7-(シクロヘキシルアミノ)-1-(1-エチルプロピル)-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)エチル]ホスホン酸、
(2S)-2-({[7-(シクロヘキシルアミノ)-1-(1-エチルプロピル)-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)ペンタン二酸、
[2-({[7-(シクロヘキシルアミノ)-1-(1-エチルプロピル)-6-フルオロ-4-オキソ-1,4-ジヒドロシンノリン-3-イル]カルボニル}アミノ)エチル]ホスホン酸、
(2S)-2-({[7-(シクロヘキシルアミノ)-1-(1-エチルプロピル)-6-フルオロ-4-オキソ-1,4-ジヒドロシンノリン-3-イル]カルボニル}アミノ)ペンタン二酸、若しくは、
[2-({[7-(シクロヘキシルアミノ)-1-(2,2-ジメチル-1,3-ジオキサン-5-イル)-6-フルオロ-4-オキソ-1,4-ジヒドロキノリン-3-イル]カルボニル}アミノ)エチル]ホスホン酸
又はその製薬学的に許容される塩。 That is, the present invention relates to a quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

[The symbols in the formula have the following meanings.
X: CR ⁷ or N.
Y: CR ⁶ or N.
R ¹¹ : —H, optionally substituted lower alkyl, or optionally substituted lower alkyl amino.
R ¹² : —H, or lower alkyl or aryl each optionally substituted. However, R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom to form an optionally substituted cyclic amino.
R ² : each optionally substituted lower alkyl, cycloalkyl, aryl or heterocycle.
R ³ : halogen, lower alkyl, or —O-lower alkyl.
R ⁴ : each independently substituted cycloalkyl or non-aromatic heterocyclic ring, or lower alkyl substituted with cycloalkyl. However, when R ⁴ represents an optionally substituted non-aromatic heterocycle, the carbon atoms constituting the ring shall be bonded to the adjacent NH.
R ⁵ : —H, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocycle, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N (lower alkyl) CO— Lower alkyl, amino optionally substituted with lower alkyl, or cyclic amino optionally substituted.
R ⁶ : —H, halogen, lower alkyl or halogeno lower alkyl.
R ⁷ : —H, halogen, lower alkyl or halogeno lower alkyl.
However, when Y represents CR ⁶ , R ² and R ⁶ may be combined to form lower alkylene or lower alkenylene. However, 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide is excluded. ]
Further, according to the present invention, the following inventions (2) to (21) are provided.
(2) The compound according to (1), wherein X is CH.
(3) The compound according to (2), wherein R ³ is halogen.
(4) The compound according to (3), wherein R ⁴ is cycloalkyl.
(5) The compound according to (4), wherein R ⁵ is H, —OH, or halogen.
(6) The compound according to (5), wherein R ¹² is a lower alkyl each substituted with one or more groups selected from group Q (however, at least one is substituted with a group of group P).
Group P: —CO ₂ H, —SO ₃ H, —P (O) (OH) ₂ and —OP (O) (OH) ₂
Q group: -F, -OH, -CO ₂ H, -SO ₃ H, -P (O) (OH) ₂ and -OP (O) (OH) ₂
(7) NR ¹¹ R ¹² is a cyclic amino group which is integrally substituted with one or more groups selected from group Q (however, at least one is substituted with a group of P group) ( 5) The compound described.
(8) Of the compounds described in (7),
[2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
(2S) -2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) butanedioic acid,
2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl dihydrogen phosphate,
(2S) -2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) pentanedioic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-4-oxo-1-[(3S) -tetrahydrofuran-3-yl] -1,4-dihydroquinolin-3-yl} carbonyl) amino] Ethyl} phosphonic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-4-oxo-1-[(3R) -tetrahydrofuran-3-yl] -1,4-dihydroquinolin-3-yl} carbonyl) amino] Ethyl} phosphonic acid,
[2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) -1,1- Difluoroethyl] phosphonic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinolin-3-yl} carbonyl) Amino] ethyl} phosphonic acid,
[2-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
[2-({[7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
(2S) -2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) pentane acid,
[2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) ethyl] phosphonic acid ,
(2S) -2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) pentane Diacid or
[2-({[7- (Cyclohexylamino) -1- (2,2-dimethyl-1,3-dioxane-5-yl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3- Yl] carbonyl} amino) ethyl] phosphonic acid or a pharmaceutically acceptable salt thereof.

  The compound of the present invention has a quinolone skeleton in which the ring atom at the 2-position and / or 8-position may be substituted with a nitrogen atom or may be condensed with a bond between the 1-position and 2-position, It is characterized by chemical structure in that it is substituted with aminocarbonyl and the 7-position is substituted with amino group. In addition, the compound of the present invention has a pharmacological feature in that it has a platelet aggregation inhibitory action.

The excellent platelet aggregation action of the compound of the present invention was confirmed by the following test method.
(1) Human platelet aggregation inhibitory activity measurement test Blood was collected from a healthy person (adult male) with 1/10 volume sodium citrate and centrifuged to separate supernatant platelet-rich plasma (PRP). The number of platelets in PRP was measured with an automatic hemocytometer (MEK-6258, Nihon Kohden), and the platelet count in PRP was adjusted to 3 × 10 ⁸ / ml using platelet poor plasma. ADP, a platelet aggregation inducer, used a product of MC Medical. Platelet aggregation was measured using a platelet aggregometer (MCM Hematracer 212; MC Medical). That is, 80 μl of PRP and 10 μl of the compound solution of the present invention or solvent (10% DMSO) are incubated at 37 ° C. for 1 minute, and then 10 μl of ADP (50 μM) is added to induce platelet aggregation and change the transmitted light. Recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. The results at 10 μM (final concentration) of the compound of the present invention are shown in Table 1.

(2) Substitution test for binding of human P2Y12 to 2-methylthio-ADP (2-MeS-ADP)
C6-15 cells in a 10 cm dish are seeded with DMEM medium to 1 × 10 ⁶ cells and cultured for 1 day, then 8 μg of plasmid pEF-BOS-dhfr-human P2Y12 and 0.8 μg of pEF- BOS-neo (Nucleic Acid Res., 18,5322,1990) was gene-transferred using a transfection reagent (LipofectAMINE 2000; manufactured by GIBCO BRL).
After 24 hours from the above gene transfer operation, the cells into which the gene had been transferred were collected, suspended in DMEM medium containing 0.6 mg / ml G418 (manufactured by GIBCO BRL), then serially diluted to a 10 cm petri dish. Sowed. Colonies that appeared after 2 weeks were individually obtained and used as P2Y12 protein-expressing C6-15 cells in the following experiments (WO 02/36631, Mol. Pharmacol., 60, 432, 2001).
After culturing P2Y12 protein-expressing C6-15 cells, the cells were collected. The cells were washed with PBS, suspended in 20 mM Tris-HCl (pH 7.4) containing 5 mmol / l EDTA and protease inhibitor cocktail set Complete ^™ (Boehringer Mannheim) and homogenized with Polytron. After ultracentrifugation, the precipitate was suspended in 50 mM Tris-HCl (pH 7.4) containing 1 mM EDTA, 100 mM NaCl and Complete ^™ , and this was used as a membrane fraction.

The above-prepared P2Y12 protein-expressing C6-15 cell membrane fraction (100 μg / ml) 100 μl is mixed with the compound solution of the present invention 1.5 μl and 0.75 nM [ ³ H] -2-MeS-ADP (80 Ci / mmol, Amersham Pharmacia Biotech After incubating in 50 mM Tris-HCl (pH 7.4) containing 100 mM NaCl and 50 mM MgCl ₂ for 1 hour at room temperature, it was collected on a glass filter with a cell harvester. A micro scintillator was added to the glass filter, and the radioactivity was measured with a liquid scintillation counter. At the same time, radioactivity was measured by adding the compound to which no compound was added and 1.5 μl of 100 μM 2-MeS-ADP in the above test as the total binding amount and the non-specific binding amount, respectively. The inhibition rate (%) of the compound of the present invention was calculated with the total binding amount and non-specific binding amount being 0% and 100%, respectively. The results for the compound of the present invention at 30 nM (final concentration) are shown in Table 2.

The present invention is described in further detail as follows.
In the present specification, the term “lower” means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified.
Thus, “lower alkyl” means C _1-6 alkyl, specifically, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, or structural isomers such as isopropyl or tert-butyl. And preferably C _1-5 alkyl methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 3-pentyl.

“Lower alkenyl” means C _2-6 alkyl having one or more double bonds at any position, specifically, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, etc. Preferred are C _2-3 alkenyl ethenyl, 1-propenyl, 2-propenyl and 3-propenyl.
“Lower alkynyl” means C _2-6 alkyl having one or more triple bonds at any position.

“Lower alkylene” means a divalent group formed by removing one hydrogen at any position of “lower alkyl”, specifically methylene, methylmethylene, ethylene, trimethylene, propylene, butylene, etc. Preferred are methylene, ethylene and trimethylene.
“Lower alkenylene” means a divalent group formed by removing one hydrogen at any position of “lower alkenyl”, specifically vinylene, 1-propenylene, 2-propenylene, 1-butenylene. 2-butenylene, 3-butenylene and the like, preferably vinylene, 1-propenylene and 2-propenylene.
“Lower alkylidene” means a group in which a free valence formed by removing one hydrogen from a carbon atom having a bond of “lower alkyl” becomes part of a double bond.

“Cycloalkyl” means a monovalent group of a C _3-8 non-aromatic hydrocarbon ring, which may form a bridged ring or a spiro ring, and has a partially unsaturated bond. It may be. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctanedienyl, adamantyl, and norbornyl, with cyclopentyl or cyclohexyl being preferred.
“Aryl” means a monovalent group of a monocyclic to tricyclic C _6-14 aromatic hydrocarbon ring, and specific examples include phenyl, naphthyl, etc., preferably phenyl. .

  “Non-aromatic heterocycle” refers to 3 to 3 having a heteroatom such as nitrogen, oxygen or sulfur which may have a partially unsaturated bond and may be condensed with an aryl or aromatic heterocycle. Means a monovalent group of 10-membered ring, preferably 5- to 7-membered ring, specifically, for example, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholyl, thiomorpholinyl, pyrazolidinyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrofuryl, Examples thereof include dioxanyl, tetrahydrothiopyranyl, tetrahydrothienyl and the like, and preferably pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dioxanyl, tetrahydrothiopyranyl.

  “Heterocycle” is a general term in which “aromatic heterocycle” is added to the above “non-aromatic heterocycle”, and “aromatic heterocycle” is the same selected from the group consisting of nitrogen, oxygen and sulfur. Or a monovalent group of an aromatic heterocycle which may be condensed with a benzene ring, containing 1 to 4 different heteroatoms, specifically, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl , Oxazolyl, thiazolyl, furazanyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazyl, indolyl, isoindolyl, indolizinyl, benzofuryl, benzothienyl, benzoimidazolyl, indazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzooxadiazonyl , Quinolyl, isoquinolyl, chrome , Benzothiopyranyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl, benzodioxinyl, benzodioxepinyl, carbazolyl and the like, and the nitrogen atom constituting these rings and / or The sulfur atom may be oxidized. These rings may be partially saturated. Pyridyl, furyl, thienyl, indolyl, indazolyl, and benzotriazolyl are preferable.

“Halogen” means a monovalent group of a halogen atom, and specific examples thereof include fluoro, chloro, bromo, iodo and the like, preferably fluoro and chloro.
The “halogeno lower alkyl group” means a group in which one or more arbitrary hydrogen atoms of the “lower alkyl group” are substituted with one or more “halogen”, specifically, for example, trifluoromethyl, trifluoro Ethyl etc. are mentioned, Preferably it is trifluoromethyl.
“Cyclic amino” is a monovalent heterocyclic group having a bond to a nitrogen atom and may contain oxygen and sulfur as hetero atoms. Specific examples include pyrrolidino, piperidino, piperazino, homopiperazino, morpholino, thiomorpholino, 3,4-dihydroisoquinolin-2 (1H) -yl, and preferably pyrrolidino, piperidino, piperazino, 3,4-dihydroisoquinoline. -2 (1H) -yl.

In the present specification, the permissible substituent of the word “which may be substituted” may be any substituent as long as it is a commonly used substituent in the technical field. In addition, each group may have one or more substituents which are the same or different.
"Optionally substituted cycloalkyl" in R ^2,; "aryl which may be substituted", together with the nitrogen atom to which R ¹¹ and R ¹² are adjacent "cyclic amino which may be substituted" in R ¹² “Optionally substituted cycloalkyl” in R ⁴ , “optionally substituted aryl”, “optionally substituted non-aromatic heterocycle”, “optionally substituted aromatic heterocycle”; , “Optionally substituted non-aromatic heterocycle”; and “optionally substituted cyclic amino” in R ⁵ are allowed substituents in the following (a) to (h). Group. In addition, “lower alkyl which may be substituted” in R ¹¹ ; “lower alkyl which may be substituted” in R ¹² ; “lower alkyl which may be substituted” in R ² , “which may be substituted” Examples of the substituent allowed in “good lower alkenyl” include the groups shown in the following (a) to (g). R ^Z is —OH, —O-lower alkyl, amino optionally substituted with one or two lower alkyls, —CO ₂ H, —CO ₂ R ^Z , one or two lower Optionally substituted with one or more groups selected from the group consisting of carbamoyl, aryl (which may be substituted with halogen), aromatic heterocycles and halogen which may be substituted with alkyl Lower alkyl is shown.
(A) Halogen.
^{(B) -OH, -OR Z,} -O- aryl, -OCO-R ^Z, oxo _{(= O), - OSO 3} H, -OP (O) (OR Z) 2, -P (O) (OR _{^{Z) 2, -OP (O)}} (OH) (OR Z), - P (O) (OH) (OR Z), - OP (O) (OH) 2, -P (O) (OH) 2.
(C) —SH, —SR ^Z , —S-aryl, —SO—R ^Z , —SO-aryl, —SO ₂ —R ^Z , —SO ₃ H, —SO ₂ -aryl, one or two R Sulfamoyl optionally substituted with ^Z.
(D) amino, —NHCO—R ^Z , —NHCO-aryl, —NHSO ₂ —R ^Z , —NHSO ₂ -aryl, nitro, imino optionally substituted with one or two R ^Z (= NR ^Z ).
(E) —CHO, —CO—R ^Z , —CO ₂ H, —CO ₂ —R ^Z , carbamoyl optionally substituted with one or two R ^Z or aryl, —CO—non-aromatic heterocycle (This non-aromatic heterocycle may be substituted with —CO ₂ H or —CO ₂ —R ^Z ), cyano.
(F) Aryl or cycloalkyl. These groups are --OH, --O-lower alkyl, amino optionally substituted with one or two lower alkyls, --CO ₂ H, --CO ₂ R ^Z , one or two lower alkyls. Each of which may be substituted with one or more groups selected from the group consisting of carbamoyl, aryl, aromatic heterocycle, halogen and R ^Z which may be substituted with
(G) An aromatic heterocycle or a non-aromatic heterocycle. These groups are —OH, —O-lower alkyl, oxo (═O), amino optionally substituted with one or two lower alkyls, —CO ₂ H, —CO ₂ R ^Z , 1 It may be substituted with one or more groups selected from the group consisting of carbamoyl, aryl, aromatic heterocycle, halogen and R ^Z which may be substituted with one or two lower alkyls.
(H) A lower alkyl which may be substituted with one or more groups selected from the substituents shown in the above (a) to (g).

Especially, substitution of the case showing the respective substituents or -NR ¹¹ R ¹² is a cyclic amino group together, the "optionally substituted lower alkyl" and "aryl which may be substituted" in R ¹² The group is preferably one or more substituents selected from the following group Q.
Q group: -F, -OH, -CO ₂ H, -SO ₃ H, -P (O) (OH) ₂ and -OP (O) (OH) ₂
“Amino optionally substituted with an optionally substituted lower alkyl group” means an amino mono- or di-substituted with the above-mentioned “optionally substituted lower alkyl group” and is disubstituted lower alkyl The groups may be the same or different from each other.

In the compound, X is preferably CH.
Y is preferably CH or N, more preferably CH.
R ¹¹ is preferably —H.
R ¹² is preferably lower alkyl or aryl each substituted with one or more groups selected from group Q (but at least one is substituted with group P); more preferably from group Q Methyl, ethyl, propyl or butyl each substituted with one or more selected groups (but at least one is substituted with a group P group).
Here, the P group and the Q group represent the following groups.
Group P: —CO ₂ H, —SO ₃ H, —P (O) (OH) ₂ and —OP (O) (OH) ₂
Q group: -F, -OH, -CO ₂ H, -SO ₃ H, -P (O) (OH) ₂ and -OP (O) (OH) ₂

In the case where —NR ¹¹ R ¹² together represents a cyclic amino group, it is preferably substituted with one or more groups selected from group Q (provided that at least one is substituted with a group of P group) A cyclic amino group.
R ² is preferably a lower alkyl, cycloalkyl or non-aromatic heterocycle which may be substituted.
R ³ is preferably halogen, and more preferably fluoro.
R ⁴ is preferably cycloalkyl, more preferably cyclohexyl.
R ⁵ is preferably —H, —OH or halogen, more preferably H, —OH or fluoro, and still more preferably —H or —OH.
R ⁶ is preferably —H.
R ⁷ is preferably —H.

The quinolone derivative represented by the formula (I) may form a salt and is included in the compound of the present invention as long as the salt is a pharmaceutically acceptable salt. Specifically, inorganic salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, metals such as sodium, potassium, calcium, magnesium Examples thereof include inorganic bases, addition salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and ammonium salts.

  Further, the compound of the present invention may contain an asymmetric carbon atom depending on the type of substituent, and optical isomers based on this may exist. The present invention includes all of these optical isomers and isolated ones. In addition, the compounds of the present invention may have tautomers, but the present invention includes a mixture or a mixture of these isomers. Further, a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioisotope or a non-radioactive isotope is also encompassed in the present invention.

  Furthermore, the present invention includes various hydrates and solvates of the compounds of the present invention and substances having crystal polymorphs. Of course, the compounds of the present invention are not limited to the compounds described in the Examples below, but include all of the derivatives represented by the formula (I) and pharmaceutically acceptable salts thereof. Is.

  The compound of the present invention includes all compounds that are metabolized in vivo and converted into the compound of the present invention, so-called prodrugs. Examples of the group that forms a prodrug of the compound of the present invention include those described in Prog. Med. 5: 2157-2161 (1985), and Yodogawa Shoten 1990 “Development of Drugs” Vol. 7, Molecular Design 163- Examples include the groups described on page 198.

(Production method)
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. A typical production method is illustrated below. Depending on the type of functional group, it is effective in terms of production technology to replace the functional group with a suitable protecting group at the raw material or intermediate stage, that is, a group that can be easily converted to the functional group. There is. Thereafter, the protecting group is removed as necessary to obtain the desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of protective groups thereof include, for example, “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. Can be used as appropriate according to the reaction conditions.

（式中、R¹¹、R¹²、R²、R³、R⁴、R⁵、R⁶、Xは上述の基を示し、Lvはその反応に応じた脱離基を示す。以下同様。） (First manufacturing method)

(In the formula, R ¹¹ , R ¹² , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X represent the above-mentioned groups, and Lv represents a leaving group corresponding to the reaction. The same applies hereinafter.)

(Process A)
This step is a step of producing compound (1c) by condensation / cyclization reaction of compound (1a) and compound (1b).
The condensation / cyclization reaction in this step can be performed without heating or in the presence of a high boiling point solvent (diphenyl ether or the like is preferably used) under heating to heating under reflux.

(Process B)
This step is a step of producing compound (1e) by an alkylation reaction of compound (1c) and compound (1d).
The leaving group Lv in the compound (1d) of this step may be any leaving group commonly used in alkylation reactions, such as halogens such as bromo, iodo and chloro, methanesulfonyloxy, p-toluenesulfonyloxy, Sulfonyloxy such as trifluoromethanesulfonyloxy is preferably used. The method described in J. Med. Chem., 23, 1358-1363, 1980. or a method based thereon can be employed.

(Process C)
In this step, the leaving group of compound (1e) is substituted with the amino group of compound (1f) to produce compound (1g).
The leaving group Lv in the compound (1e) of this step may be any leaving group commonly used in aromatic nucleophilic substitution reactions, and halogens such as fluoro, chloro and bromo; methanesulfonyloxy, p-toluenesulfonyl Preferred examples include sulfonyloxy such as oxy and trifluoromethanesulfonyloxy; sulfonyl such as lower alkylsulfonyl and arylsulfonyl; and the like. When sulfonyl is used as the leaving group Lv in Step C, the compound (1a) having sulfonyl as Lv can be used as a starting material, and the compound (1a) having a corresponding sulfanyl as Lv can be used as a starting material. After the step, for example, step B, Lv can be converted to sulfonyl by an oxidation reaction using, for example, m-chloroperbenzoic acid and the like, and can be used for the substitution reaction in step C.

  The substitution reaction in this step is carried out in the absence of a solvent or aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane; dichloromethane, 1,2-dichloroethane, chloroform, etc. Halogenated hydrocarbons; N, N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); esters such as ethyl acetate (EtOAc); solvents inert to the reaction such as acetonitrile; or methanol (MeOH), ethanol ( EtOH), an alcohol such as 2-propanol, or the like, and equimolar amounts of compound (1e) and compound (1f) can be used in an excess amount, or from room temperature to heating under reflux. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process D)
This step is a step of producing compound (1h) by subjecting compound (1g) to a hydrolysis reaction.
The hydrolysis reaction of this step is based on aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, N, N-dimethylacetamide (DMA), N-methylpyrrolidone, In the presence of acids such as mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, organic acids such as formic acid and acetic acid in solvents inert to reactions such as DMSO, pyridine and water; or lithium hydroxide, sodium hydroxide, The reaction can be performed under cooling to heating under reflux in the presence of a base such as potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia. The reaction temperature can be appropriately selected depending on the compound and the reaction reagent.

(Process E)
This step is a step for producing the compound (Ia) of the present invention by amidation of the compound (1h) or a reactive derivative thereof and the compound (1i).
For the amidation in this step, amidation that can be generally used by those skilled in the art can be employed. In particular, condensing agents such as carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), dicyclohexylcarbodiimide, diphenylphosphoryl azide, diethylphosphoryl cyanide, etc. A method of using a mixed acid anhydride using a method such as isobutyl chloroformate or ethyl chloroformate is preferred. Depending on the reactive derivative and condensing agent used, usually in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF, DMSO, etc. The reaction is carried out at room temperature to heating under reflux.

(Process F)
This step is a step of producing compound (1j) by subjecting compound (1e) to a hydrolysis reaction, and can be performed according to step D.
(Process G)
This step is a step of producing compound (1h) by substituting the leaving group of compound (1j) with the amino group of compound (1f), and can be carried out according to step C.
(Process H)
This step is a step of producing compound (1k) by amidation of compound (1j) or a reactive derivative thereof and compound (1i), and can be performed according to step E.
(Process I)
This step is a step for producing the present compound (Ia) by substituting the leaving group of compound (1k) with the amino group of compound (1f), and can be carried out according to step C.

(Process J)
This step is a step of producing compound (1l) by alkylation of compound (1a).
The alkylation in this step can be performed by a method according to Step B or by reductive alkylation. For reductive alkylation, reductive alkylation which can be usually used by those skilled in the art can be adopted. For example, the method described in “Chemical Experiment Course (4th edition)” volume 20 (1992) (Maruzen) edited by the Chemical Society of Japan can be cited. Usually, using a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, acetic acid, etc. The reaction is preferably performed at room temperature or under reflux with heating. Depending on the compound, it may be advantageous to carry out the reaction in the presence of an acid such as a mineral acid such as sulfuric acid, hydrochloric acid or hydrobromic acid, or an organic acid such as formic acid or acetic acid.
(Process K)
This step is a step of producing compound (1e) by condensation / cyclization reaction of compound (1b) and compound (1l), and can be carried out according to step A.

本製法の工程Ａを経由する製法は、特にtert-ブチル基、アダマンチル基等のR²の嵩高さによって、第一製法工程ＢにおいてR²が導入しにくい場合にも採用しうる製造法である。また、工程Ｂを経由する製法は、R²とR⁶が一体となって環を形成している場合にも採用しうる製造法である。 (Second manufacturing method)

The production method via step A of this production method is a production method that can be employed even when R ² is difficult to introduce in the first production step B due to the bulkiness of R ² such as tert-butyl group and adamantyl group. . Further, the production method via step B is a production method that can be adopted even when R ² and R ⁶ are integrated to form a ring.

(Process A)
This step is a step of producing compound (2c) by an addition / elimination reaction with compound (2b) following a condensation reaction with compound (2a) and orthoformate.
The condensation reaction with orthoformate in this step is carried out using a reagent for capturing alcohols generated from orthoformate such as acetic anhydride as a solvent, or halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO. The reaction can be carried out at room temperature or under reflux with heating by reacting a reagent that captures alcohols generated from orthoformate in a solvent inert to the reaction such as esters such as ethyl acetate (EtOAc), acetonitrile, and the like.
The addition / elimination reaction following the above condensation reaction is carried out in a solvent inert to the reaction such as alcohols, halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc., under cooling, at room temperature to under reflux. Can be done below. The reaction can also be carried out using an excess amount of compound (2b). Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process B)
This step is a step of producing compound (2c) by addition / elimination reaction between compound (2a) and compound (2d).
In this step, the addition / elimination reaction is carried out by equimolarly reacting compound (2a) and compound (2d) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. One of them can be used in an excessive amount under cooling, at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process C)
This step is a step of producing compound (1e) by intramolecular cyclization reaction of the amino group of compound (2c).
The addition / elimination reaction in this step is carried out by heating compound (2c) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc., at room temperature or under reflux with heating. Can be done below. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
Compound (Ib) of this invention can be manufactured by attaching | subjecting the compound (1e) manufactured by this process to the method similar to a 1st manufacturing method.

本製法は、R²とR⁶が一体となって環を形成している場合にも採用しうる製造法である。
（工程Ａ）
本工程は、化合物（3a）と化合物（3b）による縮合反応により、化合物（2c）を製造する工程である。
本工程の化合物（3a）の脱離基Lvはクロロ、ブロモ等のハロゲン、アルコキシ、アシルオキシ、p-トルエンスルホニル等のスルホニルオキシ等が好適に用いられる。また、本工程の化合物(3b)の替わりに二重結合の位置が異性化した化合物（3b'）を用いることも出来る。
本工程の縮合反応は、ハロゲン化炭化水素類、エーテル類、芳香族炭化水素類、DMF、DMSO等の反応に不活性な溶媒中、化合物（3a）と化合物（3b）とを等モル乃至一方を過剰量用いて、冷却下、室温下乃至加熱還流下に行うことができる。化合物によっては、有機塩基（トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、4-(N,N-ジメチルアミノ)ピリジン等が好適に用いられる）、又は金属塩塩基（炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、tert-ブトキシカリウム等が好適に用いられる）の存在下に行うのが有利な場合がある。 (Third manufacturing method)

This production method is a production method that can be employed even when R ² and R ⁶ are combined to form a ring.
(Process A)
This step is a step of producing compound (2c) by a condensation reaction between compound (3a) and compound (3b).
As the leaving group Lv of the compound (3a) in this step, halogen such as chloro and bromo, alkoxy, acyloxy, sulfonyloxy such as p-toluenesulfonyl and the like are preferably used. Moreover, the compound (3b ′) in which the position of the double bond is isomerized can be used instead of the compound (3b) in this step.
The condensation reaction in this step is carried out by mixing equimolar amounts of compound (3a) and compound (3b) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. Can be carried out under cooling at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process B)
This step is a step of producing compound (1e) by cyclization reaction of compound (2c).
The intramolecular cyclization reaction in this step can be performed according to the second production step C. In addition, in this process, in order to advance reaction smoothly, it is advantageous to carry out in presence of metal salt bases, such as sodium hydride.
In addition, depending on the conditions of Step A, (1e) may be obtained from (3a) at once without isolating (2c). Compound (1e) produced by this step is obtained by the same method as in the first production method. To the compound of the present invention (Ic).

本製法は、R⁴NH-を先に導入した後に縮合環を構築する製造法である。
（工程Ａ）
本工程は、化合物（1a）の脱離基を化合物（1f）のアミノ基で置換し、化合物（4a）を製造する工程であり、第一製法工程Ｃに準じて行うことができる。
また、本工程は、パラジウム触媒を用いた置換反応により行うこともでき（この場合、化合物（1a）のLvとしては、ブロモ、ヨード等のハロゲン、トリフルオロメタンスルホニルオキシが好適に用いられる）、Tetrahedron Lett., 38, 6359-6362, 1997.に記載された方法、あるいはそれに準じた方法を採用することができる。 (Fourth manufacturing method)

This production method is a production method in which a condensed ring is constructed after R ⁴ NH— is first introduced.
(Process A)
This step is a step for producing compound (4a) by substituting the leaving group of compound (1a) with the amino group of compound (1f), and can be carried out according to the first production step C.
In addition, this step can also be performed by a substitution reaction using a palladium catalyst (in this case, as Lv of compound (1a), halogen such as bromo and iodo, trifluoromethanesulfonyloxy is preferably used), and Tetrahedron The method described in Lett., 38, 6359-6362, 1997. or a method analogous thereto can be employed.

(Process B)
This step is a step of producing compound (4b) by condensation / cyclization reaction of compound (4a) and compound (1b), and can be carried out according to the first production method step A.
(Process C)
This step is a step of producing compound (4c) by an alkylation reaction of compound (4b) and compound (1d), and can be carried out according to the first production method step B.
(Process D)
This step is a step of producing compound (1h) by subjecting compound (4c) to a hydrolysis reaction, and can be carried out according to the first production step D.
(Process E)
This step is a step of producing the present compound (Id) by amidation of the compound (1h) or a reactive derivative thereof and the compound (1i), and can be carried out according to the first production step E. .

本製法は、式（Ｉ）においてＹがＮである化合物の製造法である。
（工程Ａ）
本工程は、化合物（5a）を、ジアゾ化、引き続きシアノ酢酸エチルを付加して化合物（5b）を製造する工程である。
本工程の第一段階であるジアゾ化反応は、塩酸、硫酸、酢酸等の酸存在下、水、アルコール類等の反応に不活性な溶媒中、亜硝酸ナトリウム、亜硝酸アミル等のジアゾ化試薬と化合物（5a）とを等モル乃至一方を過剰量用い、冷却下に行うことができる。第二段階の付加反応は、第一段階で製造したジアゾ化合物とシアノ酢酸エチルを塩基の存在下、等モル乃至一方を過剰量用い冷却化、室温下乃至加熱還流下で行うことが出来る。塩基としては、有機塩基（トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、4-(N,N-ジメチルアミノ)ピリジン等が好適に用いられる）、又は金属塩塩基（炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、tert-ブトキシカリウム、酢酸ナトリウム等が好適に用いられる）を用いることが出来る。 (Fifth manufacturing method)

This production method is a method for producing a compound in which Y is N in formula (I).
(Process A)
This step is a step of producing compound (5b) by diazotizing compound (5a) and subsequently adding ethyl cyanoacetate.
The diazotization reaction that is the first step of this process is a diazotization reagent such as sodium nitrite and amyl nitrite in a solvent inert to the reaction of water, alcohols, etc. in the presence of acids such as hydrochloric acid, sulfuric acid, and acetic acid. The compound (5a) can be used in an equimolar amount or in an excess amount while cooling with cooling. The addition reaction in the second step can be carried out by cooling the diazo compound prepared in the first step and ethyl cyanoacetate in the presence of a base, using an equimolar amount or an excess amount of one, and from room temperature to heating under reflux. As the base, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used), or metal salt bases (potassium carbonate, cesium carbonate, water) Sodium oxide, potassium hydroxide, sodium hydride, tert-butoxy potassium, sodium acetate and the like are preferably used).

(Process B)
This step is a step of producing compound (5c) by an alkylation reaction of compound (5b) and compound (1d), and can be carried out according to the first production method step B.
(Process C)
This step is a step of producing compound (5d) by subjecting compound (5c) to a hydrolysis reaction, and can be carried out according to the first production step D.

(Process D)
This step is a step of producing compound (5e) by acid halogenation and cyclization of compound (5d).
The first step of this process is acid halogenation in the absence of solvent or in a solvent inert to the reaction such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as ethyl acetate, acetonitrile and the like. Further, the halogenating agent such as thionyl chloride, oxalyl chloride and the compound (5d) can be cooled using an equimolar amount or an excess amount of the halogenating agent, and can be performed at room temperature or under reflux. Depending on the compound, the reaction may proceed advantageously by adding a catalytic amount of DMF or the like. In the second stage cyclization reaction, the acid halide obtained in the first stage is used in the presence of a Lewis acid such as aluminum chloride, in the absence of solvent, or an ester such as aromatic hydrocarbons, halogenated hydrocarbons, ethyl acetate, etc. In an inert solvent such as acetonitrile, the reaction can be carried out by cooling with an excess of equimolar or Lewis acid at room temperature or under reflux with heating.

(Process E)
This step is a step for producing the compound (5f) by substituting the leaving group of the compound (5e) with the amino group of the compound (1f), and can be carried out according to the first production step C.
(Process F)
This step is a step of producing the compound (5d) by subjecting the compound (5f) to a hydrolysis reaction, and can be carried out according to the first production method step D.
(Process G)
This step is a step for producing the present compound (Ie) by amidation of the compound (5g) or a reactive derivative thereof and the compound (1i), and can be carried out according to the first production step E. .

本製法は、式（Ｉ）においてＹがＮである化合物の製造法である。
（工程Ａ）
本工程は、化合物（2a）を、ジアゾ化し化合物（6a）を製造する工程である。
本工程のジアゾ化反応は、ペンタン、ヘキサン等の炭化水素類、芳香族炭化水素類、エーテル類、ハロゲン化炭化水素類、アルコール類、アセトニトリル、水等の反応に不活性な溶媒中、アジ化ナトリウム、アジ化ｐ−トルエンスルホニル等のジアゾ化試薬と化合物（2a）とを等モル乃至一方を過剰量用い、室温乃至加熱還流下に行うことができる。化合物によっては、有機塩基（トリエチルアミン、ジイソプロピルエチルアミン、N-メチルモルホリン、ピリジン、4-(N,N-ジメチルアミノ)ピリジン等が好適に用いられる）、又は金属塩塩基（炭酸カリウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、tert-ブトキシカリウム等が好適に用いられる）の存在下に行うのが有利な場合がある。 (Sixth manufacturing method)

This production method is a method for producing a compound in which Y is N in formula (I).
(Process A)
In this step, compound (2a) is diazotized to produce compound (6a).
The diazotization reaction in this step is carried out in a solvent inert to the reaction such as hydrocarbons such as pentane and hexane, aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, acetonitrile and water. The diazotization reagent such as sodium or p-toluenesulfonyl azide and the compound (2a) can be used in an equimolar amount or in an excess amount and from room temperature to under reflux. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process B)
This step is a step of producing compound (6b) by a reductive intramolecular cyclization reaction of compound (6a).
In this step, trialkylphosphine or triarylphosphine can be used as a reducing agent. As the leaving group Lv in the compound (6a), halogen such as fluoro, chloro and bromo, sulfonyloxy such as p-toluenesulfonyl, nitro and the like are used. In particular, it is preferable to use fluoro. The method described in Chem. Pharm. Bull., 36, 1321-1327, 1988. or a method analogous thereto can be employed.

(Process C)
This step is a step of producing compound (6c) by an alkylation reaction of compound (6b) and compound (1d), and can be carried out according to the first production method step B.
(Process D)
This step is a step of producing the compound (6d) by substituting the leaving group of the compound (6c) with the amino group of the compound (1f), and can be carried out according to the first production step C.
(Process E)
This step is a step of producing the compound (6e) by subjecting the compound (6d) to a hydrolysis reaction, and can be carried out according to the first production method step D.
(Process F)
This step is a step of producing the compound (If) of the present invention by amidation of the compound (6e) or a reactive derivative thereof and the compound (1i), and can be performed according to the first production step E. .

（式中R⁸はアリル、プロパルギル等のβ位に不飽和結合を有する置換されていてもよい低級アルケニル基または置換されていてもよい低級アルキニル基を、R⁹及びR¹⁰はH又は低級アルキル基を示す。或いは、R⁹、R¹⁰は、一体となって低級アルキリデンを示してもよい。m及びnは０〜３を示す。）
本製法は、式（Ｉ）においてR²とR⁶が一体となって環を形成している化合物の製造法である。 (Seventh manufacturing method)

(Wherein R ⁸ is an optionally substituted lower alkenyl group or an optionally substituted lower alkynyl group having an unsaturated bond at the β-position, such as allyl and propargyl, and R ⁹ and R ¹⁰ are H or lower alkyl. Or R ⁹ and R ¹⁰ together may represent a lower alkylidene, and m and n represent 0 to 3.)
This production method is a method for producing a compound in which R ² and R ⁶ are combined to form a ring in formula (I).

(Process A)
This step is a step of producing compound (7b) by an alkylation reaction using compound (1c ′) and compound (7a).
The alkylation reaction in this step is inactive in the absence of solvent or in the reaction with aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as DMF, DMSO, ethyl acetate (EtOAc), acetonitrile, etc. In a solvent such as a solvent or alcohol, the compound (1c ′) and the compound (7a) can be used in equimolar amounts or in excess of one, and at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
(Process B)
This step is a step of producing compound (7c) by intramolecular rearrangement reaction of compound (7b).
The cyclization reaction in this step can be carried out without heating or in the presence of a high boiling point solvent (1,2-dichlorobenzene or the like is preferably used) under heating to heating under reflux.

(Process C)
In this step, when R ⁸ has a leaving group or triple bond such as halogen (chloro and bromo are preferably used), sulfonyloxy (methanesulfonyloxy and p-toluenesulfonyloxy are preferably used), This is a step for producing the present compound (1e ′) by intramolecular cyclization reaction of the compound (7c).
Intramolecular cyclization reaction in this step is carried out by cooling compound (7c) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO without solvent. The reaction can be carried out at room temperature or under reflux. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate, water) It may be advantageous to carry out in the presence of sodium oxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.
Depending on the conditions of step B, (1e ′) may be obtained from (7b) at once without isolating (7c).
Compound (Ig) of this invention can be manufactured by attaching | subjecting the compound (1e ') manufactured by this process to the method similar to a 1st manufacturing method.

Further, some compounds represented by the formula (I) are usually employed by those skilled in the art such as known alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, etc. from the compound of the present invention obtained as described above. It can also be produced by arbitrarily combining the possible processes.
The compound of the present invention produced as described above is isolated or purified as a salt after being free or subjected to a salt formation treatment by a conventional method. Isolation / purification is performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by conventional methods utilizing differences in physicochemical properties between isomers. For example, a racemic mixture can be converted to an optically pure isomer by a general racemic resolution method, such as a method for optical resolution by diastereomeric salts with a general optically active acid such as tartaric acid. The diastereo mixture can be separated by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

For the lyophobic substance containing the compound of the present invention or one or more of pharmaceutically acceptable salts thereof as an efficacy statement, a commonly used pharmaceutical carrier, excipient, and other additives are used. Prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches and the like, and are administered orally or parenterally.
The clinical dose of the compound of the present invention to humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which the compound is applied, but in the case of normal oral administration, the daily dose is about 0.0001 per body weight. ˜50 mg / kg, preferably about 0.001 to 10 mg / kg is appropriate, more preferably 0.01 to 1 mg / kg, which is administered once or divided into 2 to 4 times. In the case of intravenous administration, the daily dose is about 0.0001 to 1 mg / kg, preferably about 0.0001 to 0.1 mg / kg per body weight, and is administered once a day or divided into multiple times. Since the dose varies depending on various conditions, a sufficient effect may be obtained with an amount smaller than the above dose range.

  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. Mixed with magnesium acid etc. The composition contains additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium calcium glycolate, a stabilizer, a solubilizing agent and the like according to a conventional method. May be. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or a gastric or enteric film.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , Ethanol (EtOH). In addition to the inert diluent, the composition may contain adjuvants such as wetting agents and suspending agents, sweeteners, flavors, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80, and the like. Such a composition may further contain auxiliary agents such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, this invention is not restrict | limited at all by these Examples. In addition, the raw material compound used in an Example also contains a novel substance, The manufacturing method from such a raw material compound is demonstrated as a reference example.
The symbols in the table have the following meanings (the same applies hereinafter).
Rf: Reference example number, Ex: Example number (when only the example number is listed in the Ex column, it indicates that the compound is free, and the slash (/) and HCl appear after the example number. If indicated, indicates that the compound is a hydrochloride salt)
Data: physical data (Sal: salt (no indication indicates free form, for example, when HCl is indicated, the compound indicates a hydrochloride))
R, R ¹ , R ² , R ³ , R ⁴ , A: a substituent in the general formula (Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, iBu: isobutyl, sBu: sec-butyl, tBu: tert-butyl, nPen: normal pentyl, cPr: cyclopropyl, cBu: cyclobutyl, cPen: cyclopentyl, cHex: cyclohexyl, cHep: cycloheptyl, cOct: cyclooctyl, Ph: phenyl, Py: pyridyl, fur: furyl, the: thienyl, Bn: benzyl, btria: benzotriazolyl, bimid: benzimidazolyl, pyrr: pyrrolidinyl, pipe: piperidinyl, pipea: piperazinyl, mor: morpholinyl, THF: tetrahydrofuranyl, THP: tetrahydropyranyl, THSP: tetrahydrothio Pyranyl, 2-thiq:, 3,4-dihydroisoquinolin-2 (1H) -yl, Boc: tert-butyloxycarbonyl, Ac: acetyl, Bz: benzoyl tri: tri, di:. di previous figures substituent indicates substitution position, therefore, for example, _{4-EtO 2 C-1-} pipe is a 4-ethoxycarbonyl-1-yl, 2-the- (CH ₂ ) _2- NH- represents 2- (thiophen-2-yl) ethylamino)
Syn: Manufacturing method (number indicates that it was manufactured using the corresponding raw material in the same manner as the example compound having the number as the example number. If two or more numbers are written, write it before It shows that it manufactured by performing the manufacturing method corresponding to an order from a certain number.).

Reference example 1
3-Bromo-4-fluorobenzoic acid is dissolved in toluene, tert-butanol, triethylamine, and diphenylphosphoryl azide are added in that order, followed by stirring at 100 ° C. for 20 hours, and then tert-butyl (3-bromo-4-fluorophenyl ) Carbamate was obtained.
FAB-MS (Neg); 288,290 (M ⁺ -1)

Reference example 2
After dissolving the compound of Reference Example 1 in toluene and adding aniline, cesium carbonate, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, tris (dibenzylideneacetone) dipalladium in order, The mixture was stirred at 110 ° C. for 2 days to obtain tert-butyl (3-anilino-4-fluorophenyl) carbamate. This compound was dissolved in EtOAc, 4M HCl-EtOAc solution was added, and the mixture was stirred at room temperature for 1 day to obtain 4-fluoro-N ³ -phenylbenzene-1,3-diamine.
FAB-MS (Pos); 203 (M ⁺ +1)

Reference example 3
Diethyl ethoxymethylenemalonate was added to 3,4-difluoroaniline at room temperature, followed by stirring at 130 ° C. for 17 hours. Further, diphenyl ether was added to the reaction solution, followed by stirring at 260 ° C. for 1 hour. The solid obtained by allowing the reaction solution to cool to room temperature was collected by filtration to obtain ethyl 6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
In the same manner as in Reference Example 3, Reference Examples 4 to 10 shown in Table 3 were produced using the corresponding raw materials.

Reference Example 11
Ethyl 3- (2-chloro-4,5-difluorophenyl) -3-oxopropanoate prepared according to Organic Preparations and Procedures International, 29, 231-234, 1997. After adding ethyl orthoformate, the mixture was stirred at 150 ° C. for 1 hour and concentrated under reduced pressure. The obtained residue was dissolved in EtOH, cyclopentylamine was added under ice cooling, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue was dissolved in 1,4-dioxane, 60% sodium hydride was added at room temperature, and the mixture was stirred at 80 ° C. for 4 hr, concentrated under reduced pressure, added with aqueous hydrochloric acid and extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in acetic acid, 6M HCl aq was added at room temperature, and the mixture was stirred at 120 ° C. for 5.5 hours to give 1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline. -3-carboxylic acid was obtained.
In the same manner as in Reference Example 11, Reference Examples 12 to 28 shown in Table 4 were produced using the corresponding raw materials.

Reference Example 29
The compound of Reference Example 5 was suspended in DMF, potassium carbonate and ethyl iodide were added in that order under ice cooling, and the mixture was stirred at room temperature for 4 days. Ethyl 7-anilino-1-ethyl-6-fluoro-4 -Oxo-1,4-dihydroquinoline-3-carboxylate was obtained. This compound was suspended in 1M NaOH aq and stirred at 100 ° C. for 1 hour to obtain 7-anilino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos); 327 (M ⁺ +1)

Reference Example 30
The compound of Reference Example 3 was suspended in DMF, and potassium carbonate and ethyl iodide were added in that order under ice cooling, followed by stirring at room temperature for 24 hours, extraction with chloroform, and concentration under reduced pressure. The obtained residue was suspended in acetic acid, 6M HCl aq was added at room temperature, and the mixture was stirred at 120 ° C. for 4 hours, followed by 6,7-difluoro-1-ethyl-4-oxo-1,4-dihydro Quinoline-3-carboxylic acid was obtained.
In the same manner as in Reference Example 30, Reference Examples 31 to 39 shown in Table 5 were produced using the corresponding raw materials.

Reference Example 40
7- (Cyclohexylamino) -1-ethyl was prepared by suspending the compound of Reference Example 30 in DMSO, adding cyclohexylamine at room temperature, stirring at 80 ° C. for 2 hours, and recrystallizing with 80% aqueous acetic acid. -6-Fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
NMR (DMSO-d ₆ ) 1 .; 1.10-1.25 (m, 1H), 1.27-1.50 (m, 7H), 1.60-1.70 (m, 1H), 1.72-1.82 (m, 2H), 1.90-2.00 (m , 2H), 3.55-3.67 (m, 1H), 4.53 (q, J = 7.4Hz, 2H), 6.65 (dd, J = 2.2,8.1Hz, 1H), 6.79 (d, J = 7.4Hz, 1H) , 7.79 (d, J = 11.3Hz, 1H), 8.83 (s, 1H), 15.78 (s, 1H)
In the same manner as in Reference Example 40, Reference Examples 41 to 87 shown in Tables 6 to 7 were produced using the corresponding raw materials.

Reference Example 88
The compound of Reference Example 10 was suspended in DMF, potassium carbonate and ethyl iodide were added in that order under ice cooling, and the mixture was stirred at room temperature for 2 days. Ethyl 1-ethyl-5,6,7-trifluoro- 4-Oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
In the same manner as in Reference Example 88, Reference Examples 89 to 91 shown in Table 8 were produced using the corresponding raw materials.

Reference Example 92, Reference Example 93
The compound of Reference Example 88 was dissolved in DMSO, cyclohexylamine was added, the mixture was stirred at 80 ° C. for 1 hour, and ethyl 7- (cyclohexylamino) -1-ethyl-5,6-difluoro-4-oxo-1,4- Dihydroquinoline-3-carboxylate (Reference Example 92) and ethyl 5- (cyclohexylamino) -1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (Reference Example 93) )
Reference Example 93 FAB-MS (Pos); 379 (M ⁺ +1)
In the same manner as in Reference Example 92, Reference Examples 94 to 103 and Reference Examples 104 to 106 shown in Tables 9 to 10 were produced using the corresponding raw materials.

Reference Example 104
Ethyl 7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 415 (M ⁺ +1)

Reference Example 105
Ethyl 9- (cyclohexylamino) -8-fluoro-6-oxo-6H-pyrido [1,2-a] quinoline-5-carboxylate
FAB-MS (Pos); 383 (M ⁺ +1)

Reference Example 106
Ethyl [7- (cyclohexylamino) -6-fluoro-1-isopropyl-4-oxo-1,4-dihydro-1,8-naphthyridin-3-yl] carboxylate
FAB-MS (Pos); 376 (M ⁺ +1)

Reference Example 107
To a dioxane solution of ethyl 3- (cyclopentylamino) but-2-enoate were added triethylamine and 2,4,5-trifluorobenzoyl chloride under ice cooling, and the mixture was stirred at room temperature for 30 minutes and at 65 ° C. for 1 hour. (Cyclopentylamino) -2- (2,4,5-trifluorobenzoyl) but-2-enoate was obtained.
FAB-MS (Pos); 356 (M ⁺ +1)

Reference Example 108
60% sodium hydride was added to a dioxane solution of the compound of Reference Example 107, and the mixture was stirred at 70 ° C. for 2 hours. Ethyl 1-cyclopentyl-6,7-difluoro-2-methyl-4-oxo-1,4-dihydroquinoline -3-carboxylate was obtained.
FAB-MS (Pos); 336 (M ⁺ +1)

Reference Example 109
Ethyl 3- (2-chloro-4,5-difluorophenyl) -3-oxopropanoate is dissolved in acetic anhydride, ethyl orthoformate is added at room temperature, and the mixture is stirred at 140 ° C. for 12 hours, Concentrated. The obtained residue was dissolved in EtOH, and triethylamine and tetrahydrofuran-3-amine hydrochloride in EtOH were added under ice cooling, followed by stirring for 30 minutes under ice cooling and 1 hour at room temperature. Water was added, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 60% sodium hydride was added to the resulting suspension of 1,4-dioxane, and the mixture was stirred at 80 ° C. for 1.5 hours. Ethyl 6,7-difluoro-4- Oxo-1- (tetrahydrofuran-3-yl) -1,4-dihydroquinoline-3-carboxylate was obtained. This was suspended in DMSO, cyclohexylamine was added, and the mixture was stirred at 100 ° C. for 22 hours. Ethyl 7- (cyclohexylamino) -6-fluoro-4-oxo-1- (tetrahydrofuran-3-yl)- 1,4-dihydroquinoline-3-carboxylate was obtained.
In the same manner as in Reference Example 109, Reference Examples 110 to 125 shown in Table 11 were produced using the corresponding raw materials (however, in Reference Examples 123 and 124, the hydroxyl group in the corresponding raw material was tert-butyldimethyl). A material protected with a silyl group was used as a raw material).

Reference Example 126
Palladium-carbon was added to the trifluoroacetic acid solution of the compound of Reference Example 105, and the mixture was stirred for 12 hours under hydrogen pressure. Ethyl 9- (cyclohexylamino) -8-fluoro-6-oxo-2,3,4,6-tetrahydro -1H-pyrido [1,2-a] quinoline-5-carboxylate was obtained.
FAB-MS (Pos); 387 (M ⁺ +1)

Reference Example 127
The compound of Reference Example 95 was dissolved in methylene chloride, trifluoroacetic acid was added, and the mixture was stirred at room temperature for 24 hours to give [7- (cyclohexylamino) -3- (ethoxycarbonyl) -6-fluoro-4-oxoquinoline. -1 (4H) -yl] acetic acid trifluoroacetate was obtained.
FAB-MS (Pos); 391 (M ⁺ +1)
In the same manner as in Reference Example 127, Reference Example 128 was produced using the corresponding raw material.

Reference Example 128
2- [7- (Cyclohexylamino) -3- (ethoxycarbonyl) -6-fluoro-4-oxoquinolin-1 (4H) -yl] propionic acid
ESI-MS (Pos); 405 (M ⁺ +1)

Reference Example 129
The compound of Reference Example 127 was dissolved in THF, and 1,1′-carbonyldiimidazole was added under ice-cooling, followed by stirring for 1 hour under ice-cooling, and then water was added to the reaction solution, followed by sodium borohydride. And stirred at room temperature for 4 hours to obtain ethyl 7- (cyclohexylamino) -6-fluoro-1- (2-hydroxyethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos); 377 (M ⁺ +1)
In the same manner as in Reference Example 129, Reference Example 130 was produced using the corresponding raw material.

Reference Example 130
Ethyl 7- (cyclohexylamino) -6-fluoro-1- (2-hydroxy-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos); 391 (M ⁺ +1)

Reference Example 131
The compound of Reference Example 129 was dissolved in methylene chloride, pyridinium p-toluenesulfonate and dihydropyran were sequentially added under ice cooling, and the mixture was stirred at room temperature for 3 days. Ethyl 7- (cyclohexylamino) -6-fluoro- 4-Oxo-1- [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] -1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 461 (M ⁺ +1)

Reference Example 132
The compound of Reference Example 127 was dissolved in THF, and 1,1′-carbonylbis-1H-imidazole was added under ice cooling, followed by stirring at room temperature for 2.5 hours. A methylamine aqueous solution was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl 7- (cyclohexylamino) -6-fluoro-1- [2- (methylamino) -2-oxoethyl ] -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 404 (M ⁺ +1)
In the same manner as in Reference Example 132, Reference Examples 133 to 134 were produced using the corresponding raw materials.

Reference Example 133
Ethyl 7- (cyclohexylamino) -6-fluoro-1- [2- (4-methylpiperazin-1-yl) -2-oxoethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 473 (M ⁺ +1)

Reference Example 134
Ethyl 7- (cyclohexylamino) -6-fluoro-1- (2-morpholin-4-yl-2-oxoethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 460 (M ⁺ +1)

Reference Example 135
A 70% aqueous acetic acid solution was added to the compound of Reference Example 110, and the mixture was stirred at 80 ° C. for 18 hours. Ethyl 7- (cyclohexylamino) -6-fluoro-1- [2-hydroxy-1- (hydroxymethyl) ethyl ] -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 407 (M ⁺ +1)
Reference Example 136
The compound of Reference Example 135 was dissolved in DMF, methyl iodide and silver oxide were added, and the mixture was stirred at room temperature for 51 hours. Ethyl 7- (cyclohexylamino) -6-fluoro-1- [2-methoxy-1 -(Methoxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 435 (M ⁺ +1)

Reference Example 137
The compound of Reference Example 129 was dissolved in methylene chloride, triethylamine and methanesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a mesyl form. The mesyl form was dissolved in DMF, sodium azide was added, and the mixture was stirred at room temperature for 5 hours to obtain an azide form. The azide was dissolved in THF, triphenylphosphine was added, and the mixture was stirred at 50 ° C. for 1 hr. To the obtained reaction solution, pyridine and acetic anhydride were added, and the mixture was stirred at room temperature for 3 hours. Ethyl 1- [2- (acetylamino) ethyl] -7- (cyclohexylamino) -6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylate was obtained.
ESI-MS (Pos); 418 (M ⁺ +1)
In the same manner as in Reference Example 137, Reference Examples 138 to 140 were produced using the corresponding raw materials.

Reference Example 138
Ethyl 1- [2- (acetylamino) propyl] -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos); 432 (M ⁺ +1)

Reference Example 139
Ethyl 1- {2- (acetylamino) -1-[(acetylamino) methyl] ethyl} -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 489 (M ⁺ +1)

Reference Example 140
Ethyl 1- [2- (acetylamino) -1-methylethyl] -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos); 432 (M ⁺ +1)

Reference Example 141
The compound of Reference Example 117 was suspended in EtOAc, and a 4M HCl EtOAc solution was added under ice cooling. The mixture was stirred for 1 hour at room temperature overnight and at 50 ° C. overnight, and the insoluble material was collected by filtration at room temperature and dried. Suspend this in methylene chloride, add sodium acetate, formaldehyde solution (36%) and sodium triacetoxyborohydride under ice-cooling, and stir for 45 minutes. Ethyl 7- (cyclohexylamino) -6-fluoro- 1- (1-methylpyrrolidin-3-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 416 (M ⁺ +1)
In the same manner as in Reference Example 141, Reference Examples 142 to 143 were produced using the corresponding raw materials.

Reference Example 142
Ethyl 7- (cyclohexylamino) -6-fluoro-1- (1-methylpiperidin-4-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 430 (M ⁺ +1)

Reference Example 143
Ethyl 7- (cyclohexylamino) -6-fluoro-1- (1-methylazetidin-3-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 402 (M ⁺ +1)

Reference Example 144
Add 5-methoxy-3,4-dihydro-2H-pyrrole and triethylamine to ethyl 3-oxo-3- (2,4,5-trifluorophenyl) propanoate and stir at 60 ° C. for 4 days. -2-Pyrrolidin-2-ylidene-3- (2,4,5-trifluorophenyl) propanoate was obtained.
ESI-MS (Pos); 314 (M ⁺ +1)

Reference Example 145
60% sodium hydride was added to a dioxane solution of the compound of Reference Example 144, and the mixture was stirred at room temperature for 1 hour. Ethyl 7,8-difluoro-5-oxo-1,2,3,5-tetrahydropyrrolo [1,2- a] Quinoline-4-carboxylate was obtained.
ESI-MS (Pos); 294 (M ⁺ +1)

Reference Example 146
To a methylene chloride solution of the compound of Reference Example 130, diethylaminosulfur trifluoride was added at −78 ° C., the temperature was gradually raised to room temperature over 2 hours, and ethyl 7- (cyclohexylamino) -6-fluoro-1- (2 -Fluoro-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
ESI-MS (Pos); 393 (M ⁺ +1)

Reference Example 147
Triethylamine and methanesulfonyl chloride were added to a methylene chloride solution of the compound of Reference Example 130 at 0 ° C. and stirred as it was for 1 hour to obtain a mesyl form. Dissolve the mesyl compound in THF, add potassium tert-butoxide, stir at room temperature for 3 hours, ethyl 7- (cyclohexylamino) -6-fluoro-1-isopropenyl-4-oxo-1,4-dihydroquinoline -3-carboxylate was obtained.
ESI-MS (Pos); 373 (M ⁺ +1)

Reference Example 148
Sodium hydride and methyl iodide were added to a DMF solution of the compound of Reference Example 137 at 0 ° C., and the mixture was stirred for 5 hours. Ethyl 1- {2- [acetyl (methyl) amino] ethyl} -7- (cyclohexylamino) -6-Fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
ESI-MS (Pos); 446 (M ⁺ +1)
In the same manner as in Reference Example 148, Reference Example 149 was produced using the corresponding raw material.

Reference Example 149
Ethyl 1- {2- [acetyl (methyl) amino] -1-methylethyl} -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos); 446 (M ⁺ +1)

Reference Example 150
To the EtOH solution of the compound of Reference Example 102 was added palladium-carbon and concentrated hydrochloric acid, and the mixture was stirred for 12 hours under a hydrogen atmosphere. Ethyl 8- (cyclohexylamino) -7-fluoro-1-methyl-5-oxo-1,2, 3,5-tetrahydropyrrolo [1,2-a] quinoline-4-carboxylate was obtained.
ESI-MS (Pos); 387 (M ⁺ +1)
In the same manner as in Reference Example 150, Reference Example 151 was produced using the corresponding raw materials.

Reference Example 151
Ethyl 9- (cyclohexylamino) -8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido [1,2-a] quinoline-5-carboxylate
ESI-MS (Pos); 401 (M ⁺ +1)

Reference Example 152
Potassium carbonate and iodocyclopentane were added to a DMF solution of ethyl 6,7-difluoro-4-hydroxycinnoline-3-carboxylate, and the mixture was stirred at 80 ° C. for 40 minutes. Ethyl 1-cyclopentyl-6,7-difluoro-4 -Oxo-1,4-dihydrocinnoline-3-carboxylate was obtained.
FAB-MS (Pos); 323 (M ⁺ +1)
In the same manner as in Reference Example 152, Reference Example 153 was produced using the corresponding raw materials.

Reference Example 153
Ethyl 1- (1-ethylpropyl) -6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate
FAB-MS (Pos); 325 (M ⁺ +1)
Reference Example 154, Reference Example 155
Ethyl 3-oxo-3- (2,4,5-trifluorophenyl) propanoate was dissolved in acetic anhydride, ethyl orthoformate was added at room temperature, and the mixture was stirred at 140 ° C. for 3 hr and concentrated under reduced pressure. The obtained residue was dissolved in EtOH, [2-fluoro-1- (fluoromethyl) ethyl] amine hydrochloride and triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. . Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in acetonitrile, potassium carbonate was added at room temperature, and the mixture was stirred at 50 ° C. for 15 hours, further stirred at 80 ° C. for 7 hours, and ethyl 6,7-difluoro-1- [2- Fluoro-1- (fluoromethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate (Reference Example 154) and ethyl 6,7-difluoro-1- [1- (fluoromethyl) vinyl] -4-Oxo-1,4-dihydroquinoline-3-carboxylate (Reference Example 155) was obtained.
Reference Example 154 FAB-MS (Pos); 332 (M ⁺ +1)
Reference Example 155 FAB-MS (Pos); 312 (M ⁺ +1)

Reference Example 156
Add 3-pentanone, acetic acid, sodium triacetoxyborohydride to 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, stir at room temperature for 14 hours, N- (1-ethylpropyl) -3, 4,5-trifluoroaniline was obtained.
EI-MS (Pos); 217 (M ⁺ )

Reference Example 157
Diethyl (ethoxymethylene) malonate was added to the compound of Reference Example 156, and the mixture was stirred at 130 ° C. for 20 hours. Diethyl {[(1-ethylpropyl) (3,4,5-trifluorophenyl) amino] methylene} malonate was added. Obtained.
FAB-MS (Pos); 388 (M ⁺ +1)

Reference Example 158
Polyphosphoric acid was added to the compound of Reference Example 157, and the mixture was stirred at 130 ° C. for 30 minutes. Ethyl 1- (1-ethylpropyl) -5,6,7-trifluoro-4-oxo-1,4-dihydroquinoline-3 -Carboxylate was obtained.
FAB-MS (Pos); 342 (M ⁺ +1)

Reference Example 159
The compound of Reference Example 88 was added to a suspension of lithium methoxide in toluene, and the mixture was stirred at room temperature for 3 days. Ethyl 1-ethyl-6,7-difluoro-5-methoxy-4-oxo-1,4-dihydroquinoline -3-carboxylate was obtained.
ESI-MS (Pos); 312 (M ⁺ +1)
In the same manner as in Reference Example 159, Reference Example 160 was produced using the corresponding raw material.

Reference Example 160
5- (Benzyloxy) -7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
ESI-MS (Pos); 481 (M ⁺ +1)

Reference Example 161
A methylamine aqueous solution was added to a toluene suspension of the compound of Reference Example 88, and the mixture was stirred at 70 ° C. for 20 hours. Ethyl 1-ethyl-6,7-difluoro-5- (methylamino) -4-oxo-1,4 -Dihydroquinoline-3-carboxylate was obtained.
ESI-MS (Pos); 311 (M ⁺ +1)
In the same manner as in Reference Example 161, Reference Example 162 was produced using the corresponding raw materials.

Reference Example 162
Ethyl 5- (benzylamino) -1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos); 387 (M ⁺ +1)

Reference Example 163
3-Methylcyclopent-3-ene-1-carboxylic acid was dissolved in toluene, tert-butanol, triethylamine, and diphenylphosphoryl azide were added in that order, and the mixture was stirred at 90 ° C. for 3 days, and tert-butyl (3-methyl Cyclopent-3-en-1-yl) carbamate was obtained.
NMR (CDCl ₃ ) 臀 och; 1.44 (s, 9H), 1.71 (brs, 3H), 2.02-2.18 (m, 2H), 2.58-2.77 (m, 2H), 4.27 (brs, 1H), 4.69 (brs) , 1H), 5.25 (brs, 1H)

Reference Example 164
The compound of Reference Example 163 was dissolved in methylene chloride, trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours to obtain 3-methylcyclopent-3-en-1-amine trifluoroacetate.
Ethyl 3- (2-chloro-4,5-difluorophenyl) -3-oxopropanoate was dissolved in acetic anhydride, ethyl orthoformate was added, and the mixture was stirred at 150 ° C. for 2 hr and concentrated under reduced pressure. The obtained residue was dissolved in EtOH, triethylamine and 3-methylcyclopent-3-en-1-amine trifluoroacetate were sequentially added under ice cooling, and the mixture was stirred for 18 hours under ice cooling. (2-Chloro-4,5-difluorobenzoyl) -3-[(3-methylcyclopent-3-en-1-yl) amino] acrylate was obtained. The obtained compound was dissolved in 1,4-dioxane, sodium hydride was added, and the mixture was stirred at 50 ° C. for 3 hours. Ethyl 6,7-difluoro-1- (3-methylcyclopent-3-ene- 1-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 334 (M ⁺ +1)

Reference Example 165
The compound of Reference Example 162 was dissolved in EtOH-acetic acid, palladium-carbon (10%) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. Ethyl 5-amino-1-ethyl-6,7-difluoro-4 -Oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 297 (M ⁺ +1)

Reference Example 166
Ethyl 7- (cyclohexylamino) -6-fluoro-1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate in benzene solution P-toluenesulfonic acid monohydrate was added, and the mixture was stirred with heating under reflux for 34 hours. Ethyl 7- (cyclohexylamino) -1- (2,2-diethyl-1,3-dioxane-5-yl) -6 -Fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.
FAB-MS (Pos); 475 (M ⁺ +1)

Reference Example 167
The compound of Reference Example 92 was dissolved in EtOH-THF, 2M NaOH aq was added, and the mixture was stirred at room temperature for 12 hours, and 7- (cyclohexylamino) -1-ethyl-5,6-difluoro-4-oxo-1 1,4-Dihydroquinoline-3-carboxylic acid was obtained.
In the same manner as in Reference Example 167, Reference Examples 168 to 214 shown in Tables 12 to 15 were produced using the corresponding raw materials.

Reference Example 215
LiOH aq was added to an EtOH-THF solution of the compound of Reference Example 104, and the mixture was stirred at 60 ° C. for 24 hours and at 80 ° C. for 24 hours, and then 7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-2-methyl-4- Oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 387 (M ⁺ +1)
In the same manner as in Reference Example 215, Reference Examples 216 to 220 were produced using the corresponding raw materials.

Reference Example 216
9- (Cyclohexylamino) -8-fluoro-6-oxo-6H-pyrido [1,2-a] quinoline-5-carboxylic acid
FAB-MS (Pos); 355 (M ⁺ +1)

Reference Example 217
Ethyl [7- (cyclohexylamino) -6-fluoro-1-isopropyl-4-oxo-1,4-dihydro-1,8-naphthyridin-3-yl] carboxylic acid
FAB-MS (Pos); 348 (M ⁺ +1)

Reference Example 218
Ethyl 9- (cyclohexylamino) -8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido [1,2-a] quinoline-5-carboxylic acid
FAB-MS (Neg); 357 (M ⁺ -1)

Reference Example 219
9- (Cyclohexylamino) -8-fluoro-2-methylene 6-oxo-2,3,4,6-tetrahydro-1H-pyrido [1,2-a] quinoline-5-carboxylic acid
FAB-MS (Pos); 371 (M ⁺ +1)

Reference Example 220
9- (Cyclohexylamino) -8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido [1,2-a] quinoline-5-carboxylic acid
FAB-MS (Pos); 373 (M ⁺ +1)
Reference Example 221
To an aqueous hydrochloric acid solution of 3,4-difluoroaniline, an aqueous sodium nitrite solution was added dropwise under ice cooling, followed by stirring at the same temperature for 1.5 hours. The previous reaction solution was added dropwise to an EtOH-water solution of ethyl cyanoacetate and sodium acetate prepared in a separate reaction vessel under ice-cooling, followed by stirring at room temperature for 2 hours, and ethyl cyano [(3,4-difluoro Phenyl) diazenyl] acetate was obtained.
FAB-MS (Pos); 254 (M ⁺ +1)

Reference Example 222
The compound of Reference Example 221 was suspended in acetonitrile, ethyl iodide and potassium carbonate were added, and the mixture was stirred at 50 ° C. for 7 days. Ethyl 2-cyano [(3,4-difluorophenyl) (ethyl) hydrazono] acetate Got.
FAB-MS (Pos); 282 (M ⁺ +1)

Reference Example 223
The compound of Reference Example 222 was suspended in EtOH, NaOH aq was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours to give 2-cyano [(3,4-difluorophenyl) (ethyl) hydrazono] acetic acid. Got.
FAB-MS (Pos); 254 (M ⁺ +1)

Reference Example 224
The compound of Reference Example 223 was suspended in toluene, thionyl chloride was added, the mixture was stirred at 90 ° C. for 1.5 hr, and concentrated under reduced pressure. Azeotropic distillation with toluene was performed, and hexane was added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was dissolved in dichloroethane, aluminum chloride was added, and the mixture was stirred at 55 ° C. for 24 hours and further refluxed for 23 hours to give 1-ethyl-6,7-difluoro-4-oxo-1,4- Dihydrocinnoline-3-carbonitrile was obtained.
FAB-MS (Pos); 236 (M ⁺ +1)

Reference Example 225
The compound of Reference Example 224 was dissolved in DMSO, cyclohexylamine was added, and the mixture was stirred at 80 ° C. for 3 hours to give 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydro Cinnoline-3-carbonitrile was obtained.
FAB-MS (Pos); 315 (M ⁺ +1)

Reference Example 226
The compound of Reference Example 225 was dissolved in acetic acid, HCl aq was added, and the mixture was stirred at 120 ° C. for 2 days to give 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydro Cinnoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 334 (M ⁺ +1)

Reference Example 227
DMF and N-chlorosuccinimide were added to the compound of Reference Example 40, and the mixture was stirred at 100 ° C. for 14 hours, and then 8-chloro-7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 367 (M ⁺ +1)

Reference Example 228
Cyclohexylamine was added to a DMSO solution of the compound of Reference Example 153 and stirred at 80 ° C. for 14 hours. The reaction solution was cooled to room temperature, water and a saturated aqueous ammonium chloride solution were added, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol, 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hr. 7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo -1,4-Dihydrocinnoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 376 (M ⁺ +1)

Reference Example 229
Water and concentrated hydrochloric acid were added to an acetic acid solution of the compound of Reference Example 154, and the mixture was stirred at 100 ° C. for 5 hours. 6,7-difluoro-1- [2-fluoro-1- (fluoromethyl) ethyl] -4-oxo- 1,4-dihydroquinoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 304 (M ⁺ +1)
In the same manner as in Reference Example 229, Reference Example 230 was produced using the corresponding raw material.

Reference Example 230
6,7-Difluoro-1- [1- (fluoromethyl) vinyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid
FAB-MS (Pos); 284 (M ⁺ +1)

Reference Example 231
The compound of Reference Example 130 was dissolved in methylene chloride, pyridinium p-toluenesulfonate and dihydropyran were sequentially added, and the mixture was stirred overnight at room temperature. Ethyl 7- (cyclohexylamino) -6-fluoro-1- [1-methyl -2- (Tetrahydro-2H-pyran-2-yloxy) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained. The obtained compound was suspended in EtOH-THF, 1M NaOH aq was added, and the mixture was stirred overnight. 7- (Cyclohexylamino) -6-fluoro-1- [1-methyl-2- (tetrahydro-2H-pyran-2 -Iyloxy) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
FAB-MS (Pos); 447 (M ⁺ +1)

Reference Example 232
The compound of Reference Example 40 was suspended in DMF, 1,1′-carbonylbis-1H-imidazole was added at room temperature, and the mixture was stirred at 100 ° C. for 24 hours to give 7- (cyclohexylamino) -1- Ethyl-6-fluoro-3- (1H-imidazol-1-ylcarbonyl) quinolin-4 (1H) -one was obtained.
NMR (CDCl ₃ ) δ; 1.25-1.53 (m, 5H), 1.59 (t, J = 7.6Hz, 3H), 1.65-1.76 (m, 1H), 1.80-1.90 (m, 2H), 2.05-2.15 ( m, 2H), 3.34-3.45 (m, 1H), 4.22 (q, J = 7.6Hz, 2H), 4.57-4.66 (m, 1H), 6.44 (d, J = 6.4Hz, 1H), 7.04-7.05 (m, 1H), 7.51-7.53 (m, 1H), 7.99 (d, J = 12.0Hz, 1H), 8.12 (s, 1H), 8.15-8.16 (m, 1H).

Reference Example 233
From the compound of Reference Example 30, tert-butyl {[(6,7-difluoro-1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl) carbonyl] was prepared in the same manner as in Example 16 described later. Amino} acetate was obtained.
FAB-MS (Pos); 367 (M + 1)
In the same manner as in Reference Example 233, Reference Example 234 was produced using the corresponding raw materials.

Reference Example 234
Ethyl {[(5-amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl) carbonyl] amino} acetate
FAB-MS (Pos); 354 (M ⁺ +1)

Reference Example 235
Acetic anhydride was added to the compound of Reference Example 234, and the mixture was stirred at 120 ° C. for 4 hours. Ethyl ({[5- (acetylamino) -1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline -3-yl] carbonyl} amino) acetate was obtained.
FAB-MS (Pos); 396 (M ⁺ +1)
In the same manner as in Reference Example 235, Reference Example 236 was produced using the corresponding raw materials.

Reference Example 236
Ethyl [5- (acetylmethylamino) -1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl] carboxylic acid
ESI-MS (Pos); 395 (M ⁺ +1)

Reference Example 237
(2-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} ethyl) phosphonic acid was suspended in benzene and benzyl N, N′-dicyclohexylimide carbamate was added, followed by refluxing for 4 hours. Stirring gave dibenzyl (2-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} ethyl) phosphonate.
FAB-MS (Pos); 528 (M ⁺ +1)

Reference Example 238
The compound of Reference Example 237 was dissolved in DMF, diisopropylethylamine was added, and the mixture was stirred at room temperature for 2 days to obtain dibenzyl (2-aminoethyl) phosphonate. Furthermore, dibenzyl (2-aminoethyl) phosphonate oxalate was obtained by adding oxalic acid to the obtained phosphonate.
FAB-MS (Pos); 306 (M ⁺ +1)

Reference Example 239
Add hydrazine monohydrate to a solution of diethyl [2- (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) -1,1-difluoroethyl] phosphonate in methylene chloride and bring to room temperature. For 1 hour to obtain diethyl (2-amino-1,1-difluoroethyl) phosphonate.
ESI-MS (Pos); 218 (M ⁺ +1)

Reference Example 240
Diethylpyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, platinum oxide was added, and the mixture was stirred under hydrogen of 3.4 kgf / cm ² for 120 hours to obtain diethylpiperidin-3-ylphosphonate.
ESI-MS (Pos); 222 (M ⁺ +1)
In the same manner as in Reference Example 240, Reference Example 241 was produced using the corresponding raw materials.

Reference Example 241
Diethyl (piperidin-2-ylmethyl) phosphonate
FAB-MS (Pos); 236 (M ⁺ +1)

Reference Example 242
Benzyl ((3aRS, 4SR, 6RS, 6aRS) -6-{[tert-butyl (dimethyl) silyl] oxy} -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-yl ) To a solution of carbamate in EtOH, palladium-carbon (10%) was added and stirred overnight in a hydrogen atmosphere, and (3aRS, 4SR, 6RS, 6aRS) -6-{[tert-butyl (dimethyl) silyl] oxy} -2 1,2-Dimethyltetrahydro-3aH-cyclopenta [d] [1,3] dioxol-4-amine was obtained.
FAB-MS (Pos); 288 (M ⁺ +1)

Reference Example 243
Platinum (c-HCl) and c.HCl were added to a solution of diethyl (1-cyano-2-phenylethyl) phosphonate in EtOH and stirred overnight in a hydrogen atmosphere to obtain diethyl [2-amino-1- (cyclohexylmethyl) ethyl] phosphonate.
FAB-MS (Pos); 278 (M ⁺ +1)

Example 1
400 mg of the compound of Reference Example 59 was suspended in 5.0 ml of DMF, and 350 mg of 1,1′-carbonylbis-1H-imidazole was added at room temperature, followed by stirring at 100 ° C. for 20 hours. To the resulting reaction solution, 0.2 ml of triethylamine and 180 mg of glycine ethyl ester hydrochloride were sequentially added under ice cooling, and the mixture was further stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallized from EtOH to give ethyl ({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) Acetate 408 mg was obtained.

Example 2
300 mg of the compound of Reference Example 232 was dissolved in 5.0 ml of DMF, 0.2 ml of triethylamine and 120 mg of glycine ethyl ester hydrochloride were sequentially added under ice cooling, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By recrystallizing the resulting solid from EtOH, ethyl ({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) Acetate 219 mg was obtained.

Example 3
The compound of Reference Example 232 was dissolved in 3.0 ml of DMF, 150 mg of O-trimethylsilylhydroxylamine was added under ice cooling, and the mixture was stirred at 50 ° C. for 5.5 hours. The reaction solution was concentrated under reduced pressure, 5.0 ml of MeOH was added, 4.0 ml of 1M HCl aq was added under ice cooling, and the mixture was stirred at room temperature for 2 hours and then at 50 ° C. for 2.5 hours. The solid obtained by cooling to room temperature was washed with EtOAc, and further recrystallized with 80% aqueous acetic acid to give 7- (cyclohexylamino) -1-ethyl-6-fluoro-N-hydroxy-4-oxo-1 1,141 mg of 4-dihydroquinoline-3-carboxamide was obtained.

Example 4
300 mg of the compound of Example 56 was suspended in 5.0 ml of EtOH, 1.0 ml of 3M HCl aq was added under ice cooling, and the mixture was stirred at 50 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, water was added, neutralized with 1M NaOH aq, and extracted with 10% MeOH-chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with EtOH to give 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-N-[(1RS, 2SR, 3RS, 4SR) -2,3,4-tri Hydroxycyclopentyl] -1,4-dihydroquinoline-3-carboxamide 230 mg was obtained.

Example 5
360 mg of the compound of Example 51 was dissolved in 5.0 ml of methylene chloride, and 2.0 ml of trifluoroacetic acid was added under ice cooling, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether to give (4S) -4-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl Carbonyl} amino) -5- [4- (ethoxycarbonyl) piperazin-1-yl] -5-oxopentanoic acid 282 mg was obtained.

Example 6
300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, 0.8 ml of 1M NaOH aq was added under ice cooling, and the mixture was stirred at room temperature for 25 hours. Water was added to the reaction solution and neutralized with 1M HCl aq. The precipitated solid is collected by filtration and washed with EtOH to give ({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} 263 mg of amino) acetic acid was obtained.

Example 7
To a solution of the compound of Example 44 (1.16 g) in chloroform (20 ml) was slowly added trimethylsilane bromide (TMSBr) (2.23 ml) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and 15 ml of MeOH was added. The mixture was concentrated again under reduced pressure, ether and a small amount of MeOH were added, and the resulting insoluble material was collected by filtration. 1M NaOH aq 10 ml, MeOH and water were added to this, and insoluble matter was filtered off. Then 1M HCl aq 11 ml was added, and the resulting precipitate was collected by filtration. Wash with 80% EtOH aq, [2-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] 841 mg of phosphonic acid was obtained.

Example 8
250 mg of the compound of Example 374 was suspended in 2.0 ml of EtOAc, and 2.0 ml of 4M HCl-EtOAc solution was added under ice cooling, followed by stirring at room temperature for 4 days. The precipitated solid is filtered and washed with EtOAc to give ({[1-ethyl-6-fluoro-4-oxo-7- (piperidin-4-ylamino) -1,4-dihydroquinolin-3-yl] Carbonyl} amino) acetic acid hydrochloride 210 mg was obtained.

Example 9
300 mg of the compound of Example 163 was suspended in 5.0 ml of THF, 200 mg of 1,1′-carbonylbis-1H-imidazole was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. To the resulting reaction solution was added 1.0 ml of 28% aqueous ammonia under ice cooling, and the mixture was further stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By recrystallizing the resulting solid from EtOH, N- (4-amino-4-oxobutyl) -7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline- 214 mg of 3-carboxamide was obtained.

Example 10
210 mg of the compound of Example 161 was suspended in 5.0 ml of DMF, and 0.1 ml of ethoxycarbonylpiperazine, 130 mg of WSC · HCl and 100 mg of 1-hydroxybenzotriazole were sequentially added under ice cooling, and then at room temperature for 17 hours. Stir. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. The obtained organic layer was washed successively with saturated NaHCO ₃ aq and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with EtOH to give ethyl 4-[({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} Amino) acetyl] piperazine-1-carboxylate 228 mg was obtained.

Example 11
530 mg of the compound of Example 196 was suspended in a mixed solvent of 10 ml of acetone and 3.0 ml of water, and 0.30 g of N-methylmorpholine-N-oxide and 2.0 ml of OsO ₄ (2.5 wt% in tBuOH) were sequentially added at room temperature. After the addition, the mixture was stirred at room temperature for 1 week. Water was added to the reaction solution, 2.0 g of sodium thiosulfate was added at room temperature, and the mixture was stirred overnight at room temperature. Insoluble matters in the reaction solution were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with water to give ethyl ({[7- (cyclohexylamino) -1- (2,3-dihydroxypropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3- Yl] carbonyl} amino) acetate 190 mg was obtained.

Example 12
423 mg of the compound of Example 72 was suspended in 5 ml of chloroform and 5 ml of MeOH, 126 mg of LiOH.H ₂ O was added, and the mixture was stirred at room temperature for 30 minutes. To the obtained reaction solution, 1.17 g of methyl-1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside uronate was added and stirred at room temperature for 1 hour. Further, 126 mg of LiOH.H ₂ O and 1.17 g of methyl-1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranoside uronate were added and stirred at room temperature for 6 hours. Water (15 ml), MeOH (5 ml) and sodium carbonate (1.0 g) were added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Further, 30 ml of water, 220 ml of MeOH and 1.0 g of sodium carbonate were added and stirred at room temperature for 30 minutes, then neutralized with acetic acid and stirred at room temperature for 12 hours. The resulting insoluble material was removed by filtration, water was added to the filtrate, and the mixture was washed with chloroform. The resulting aqueous solution was concentrated under reduced pressure. The residue was purified by ODS column chromatography and 3-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) As a result, 168 mg of phenyl 秉 och-D-glucopyranoside uronic acid was obtained.

Example 13
The compound of Reference Example 233 (0.20 g) was dissolved in DMSO (5.0 ml), cyclohexylmethylamine (0.2 ml) was added at room temperature, and the mixture was stirred at 80 ° C. for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain tert-butyl [({7-[(cyclohexylmethyl) amino] -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline- 0.23 g of 3-yl} carbonyl) amino] acetate was obtained.
0.23 g of the above tert-butyl ester was dissolved in 5.0 ml of methylene chloride, and 2.0 ml of trifluoroacetic acid was added under ice cooling, followed by stirring at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the solid precipitated by adding water was collected by filtration to give [({7-[(cyclohexylmethyl) amino] -1-ethyl-6-fluoro-4-oxo-1, There were obtained 102 mg of 4-dihydroquinolin-3-yl} carbonyl) amino] acetic acid.

Example 14
To a suspension of 253 mg of the compound of Example 210 in THF 10 ml, sodium acetate 89 mg, formaldehyde solution (37%) 55 μl, and sodium triacetoxyborohydride 177 mg were added and stirred at room temperature for 3 hours. Saturated NaHCO ₃ aq was added, extracted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1- (1-methylpyrrolidin-3-yl) -1,4-dihydroquinoline 146 mg of 3-yl] carbonyl} amino) acetate was obtained.

Example 15
0.45 g of the compound of Example 412 was dissolved in 10 ml of methylene chloride, and 1.0 ml of trimethylsilane bromide was added under ice cooling, followed by stirring at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, MeOH was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, and the solid precipitated by adding EtOH was collected by filtration to give [2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1, 4-Dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid hydrobromide 344 mg was obtained.

Example 16
Suspended in 20 ml of the compound of Reference Example 75, 149 μl of triethylamine and 117 μl of isobutyl chloroformate were added under ice cooling. After stirring for 1 hour, 149 μl of triethylamine and 138 mg of glycine ethyl ester hydrochloride were added, and the mixture was stirred at room temperature for 12 hours. Saturated NH ₄ Cl aq was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, washed with EtOAc, and ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1- (2,2,2-trifluoroethyl)- 227 mg of 1,4-dihydroquinolin-3-yl] carbonyl} amino) acetate were obtained.

Example 17
0.51 g of the compound of Example 200 was dissolved in 5.0 ml of methylene chloride, 0.5 ml of triethylamine and 0.2 ml of methanesulfonyl chloride were sequentially added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mesyl body. The obtained mesyl compound was dissolved in 10 ml of DMF, and 0.10 g of sodium azide was added under ice cooling, followed by stirring at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an azide. The obtained azide was dissolved in 10 ml of THF, 0.40 g of triphenylphosphine was added at room temperature, and the mixture was stirred at 50 ° C. for 1 hour. To the reaction solution, 2.0 ml of water was added and stirred at 80 ° C. for 3.5 hours. The reaction solution was allowed to cool, 0.30 g of di-tert-butyl dicarbonate was added under ice cooling, and the mixture was stirred at room temperature for 27 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain ethyl {[(1- {2-[(tert-butoxycarbonyl) amino] ethyl} -7- (cyclohexylamino) -6-fluoro-4-oxo. 494 mg of 1,4-dihydroquinolin-3-yl) carbonyl] amino} acetate was obtained.

Example 18
407 mg of the compound of Example 589 was dissolved in 5 ml of MeOH, 30 mg of palladium-carbon (10%) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. After adding 1.15 ml of 1M NaOH aq to the reaction solution, the insoluble material was filtered off through Celite. To the filtrate was added 1.15 ml of 1M HCl aq, and the resulting precipitate was collected by filtration and washed with water to give [2-({[7- (cyclohexylamino) -1- (2,2-dimethyl-1,3- There were obtained 220 mg of dioxane-5-yl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid.

Example 19
415 mg of the compound of Example 200 was suspended in 5 ml of methylene chloride, 400 μl of triethylamine and 111 μl of methanesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 10 minutes. Water and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 5 ml of DMF, 948 μl of piperidine was added, and the mixture was stirred at 70 ° C. for 23 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1- (2-piperidin-1-ylethyl) -1,4-dihydroquinoline] was obtained. 202 mg of -3-yl] carbonyl} amino) acetate were obtained.

Example 20
149 mg of the compound of Example 31 was suspended in 5 ml of chloroform, 75 μl of triethylamine was added under ice cooling, and then 30 μl of acetyl chloride was added. After stirring overnight at room temperature, water was added, and the mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain ethyl ({[1- (1-acetylpyrrolidin-3-yl) -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline. 167 mg of -3-yl] carbonyl} amino) acetate was obtained.

Example 21
734 mg of the compound of Example 200 was suspended in 10 ml of methylene chloride, and after adding 708 μl of triethylamine and 197 μl of methanesulfonyl chloride under ice cooling, the mixture was stirred at room temperature for 15 minutes. Water and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 10 ml of DMSO, 100 mg of sodium cyanide was added, and the mixture was stirred at 70 ° C. for 24 hours. Water and saturated brine were added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) acetate 354 mg Got.

Example 22
A 70% aqueous acetic acid solution was added to 146 mg of the compound of Example 18, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with EtOH. The resulting residue was crystallized with EtOH-water and {2-[({7- (cyclohexylamino) -6-fluoro-1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1 96 mg of 1,4-dihydroquinolin-3-yl} carbonyl) amino] ethyl} phosphonic acid was obtained.
Example 23
Methyl (2R) -2-({[7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino)- 374 mg of 3-pyridin-3-ylpropanoate was suspended in 4 ml of EtOAc, 2 ml of 0.5 M HCl in EtOAc was added and stirred for 30 minutes, and then the precipitate was collected by filtration, and methyl (2R) -2- ( {[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) -3-pyridin-3-ylpropa 156 mg of noate hydrochloride was obtained.

Example 24
0.5 ml of 2M NaOH aq was added to 11 mg of the compound of Example 44, and the mixture was stirred at 100 ° C. for 30 minutes. After adding 0.1 ml of 2-propanol and stirring at 100 ° C. for 12 hours, 1.1 ml of 1M HCl aq was added, and the resulting precipitate was collected by filtration. Wash with diethyl ether, ethyl hydrogen [2-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] 7 mg of phosphonate was obtained.

Example 25
148 mg of the compound of Example 31 was suspended in 5 ml of acetonitrile, 67 mg of potassium carbonate, 46 μl of benzyl bromide, and 5 ml of DMF were added and stirred overnight. Water was added, extracted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and ethyl ({[1- (1-benzylpyrrolidin-3-yl) -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline] was obtained. 174 mg of -3-yl] carbonyl} amino) acetate was obtained.

Example 26
183 mg of the compound of Example 220 was suspended in 20 ml of chloroform, 1.35 ml of trimethylsilane bromide was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. After adding 1.35 ml of trimethylsilane bromide and stirring for 3 days, EtOH was added. After evaporating the solvent under reduced pressure, water and saturated NaHCO ₃ aq were added, and the insoluble material was collected by filtration. To this was added saturated NaHCO ₃ aq, extracted with chloroform, and washed with 1M HCl aq, saturated NaHCO ₃ aq, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and ethyl [({7- (cyclohexylamino) -6-fluoro-4-oxo-1-[(1RS, 2SR, 3RS, 4SR) -2,3,4- 54 mg of trihydroxycyclopentyl] -1,4-dihydroquinolin-3-yl} carbonyl) amino] acetate was obtained.

Example 27
Compound 743 mg of Example 15, tetrabutylammonium hydrogen sulfate 226 mg, sodium iodide 102 mg, acetonitrile 10 ml, 1,8-diazabicyclo [5.4.0] -7-undecene 720 μl, pivalic acid chloromethyl 575 μl And stirred at 75 ° C. for 65 hours. Water was added, extracted with EtOAc, and washed with water, saturated NaHCO ₃ aq, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, washed with diethyl ether, and bis {[(2,2-dimethylpropanoyl) oxy] methyl} [2-({[7- (cyclohexylamino) -1-cyclopentyl. 378 mg of -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonate were obtained.

Example 28
273 mg of the compound of Example 544 was suspended in 10 ml of THF, 1.2 ml of 1M LiOH aq was added, and the mixture was stirred at room temperature for 2 days, at 50 ° C. for 3 hours, and at 60 ° C. for 20 hours. After evaporating the solvent under reduced pressure, 1M HCl aq was added, and the resulting precipitate was collected by filtration to give 2-({[7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4- 270 mg of oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) -2-methylpropionic acid was obtained.

Example 29
148 mg of the compound of Example 31 was suspended in 5 ml of chloroform, 75 μl of triethylamine was added, then cooled to −45 ° C., and 32 μl of methanesulfonyl chloride was added. After gradually warming up and stirring at room temperature overnight, water was added, extracted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and ethyl [({7- (cyclohexylamino) -6-fluoro-1- [1- (methylsulfonyl) pyrrolidin-3-yl] -4-oxo-1,4 -Dihydroquinolin-3-yl} carbonyl) amino] acetate 138 mg was obtained.

Example 30
The compound of Example 17 (0.40 g) was suspended in EtOH (5.0 ml), 1M NaOH aq (1.1 ml) was added under ice cooling, and the mixture was stirred at room temperature for 25 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in 20 ml of water. After adding 3.0 ml of concentrated hydrochloric acid under ice cooling, the mixture was stirred at 50 ° C. for 6 hours. The mixture is allowed to cool to room temperature, and the precipitated solid is collected by filtration ({[1- (2-aminoethyl) -7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3 0.15 g of -yl] carbonyl} amino) acetic acid hydrochloride was obtained.

Example 31
Saturated NaHCO ₃ aq, water, and EtOH were added to 1 g of the compound of Example 210 and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1- (pyrrolidin-3-yl) -1,4- 750 mg of dihydroquinolin-3-yl] carbonyl} amino) acetate was obtained.

Example 32
To 50 mg of the compound of Example 241, 2 ml of 6M HCl aq was added and stirred at 80 ° C. for 1.5 hours, and then 2 ml of 6M HCl aq was added and stirred at 80 ° C. for 1 hour. After evaporating the solvent under reduced pressure, water was added and the insoluble material was collected by filtration. By recrystallizing from EtOH, [({7- (cyclohexylamino) -6-fluoro-1- [2-fluoro-1- (fluoromethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3- 18 mg of yl} carbonyl) amino] acetic acid was obtained.

Example 33
52 mg of the compound of Example 348 was suspended in 1 ml of DMSO, 46 μl of triethylamine and 165 μl of 2.0M dimethylamine THF solution were added, and the mixture was stirred at 100 ° C. for 24 hours. Water was added and the resulting precipitate was collected by filtration. This was dissolved in ethyl acetate and washed with water, saturated NH ₄ Cl aq, and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, and ethyl ({[7- (cyclohexylamino) -5- (dimethylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4 -Dihydroquinolin-3-yl] carbonyl} amino) acetate 43 mg was obtained.

Example 34
53 mg of the compound of Reference Example 235 was dissolved in 1.5 ml of DMSO, and 31 μl of cyclohexylamine was added at room temperature, followed by stirring at 80 ° C. for 13 hours and at 100 ° C. for 10 hours. Water was added to the reaction solution, and the resulting precipitate was collected by filtration and washed with water. This was purified by silica gel column chromatography to obtain ethyl ({[5- (acetylamino) -7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline- 51 mg of 3-yl] carbonyl} amino) acetate were obtained.
Tables 16 to 41 below show the structures and physical data of the example compounds.

Hereinafter, Tables 42 to 44 show NMR data of some example compounds.

Tables 45 to 67 show structures of other compounds of the present invention. These can be easily produced by using the production methods described above, the methods described in the examples, methods obvious to those skilled in the art, or variations thereof.

Since the compound of the present invention has an excellent platelet aggregation inhibitory action and P2Y12 inhibitory action, it is useful as a pharmaceutical, particularly a platelet aggregation inhibitor and a P2Y12 inhibitor. Therefore, the compound of the present invention is a cardiovascular disease closely related to thrombus formation by platelet aggregation, for example, unstable angina pectoris, acute myocardial infarction and secondary prevention thereof, hepatic artery bypass surgery, PTCA surgery or stent placement. Ischemic diseases such as postoperative reocclusion and restenosis, promotion of hepatic artery thrombolysis and reocclusion prevention; transient cerebral ischemic attack (TIA) cerebral infarction, subarachnoid hemorrhage (vasospasm) and other cerebrovascular disorders It is useful as a prophylactic and / or therapeutic drug for peripheral arterial disease such as chronic arterial occlusion; and an auxiliary drug in cardiac surgery or vascular surgery.

Claims (8)

A quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof. However, 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide is excluded.

[The symbols in the formula have the following meanings.
X: CR ⁷ or N.
Y: CR ⁶ or N.
R ¹¹ : —H, optionally substituted lower alkyl, or optionally substituted lower alkyl amino.
R ¹² : —H, or lower alkyl or aryl each optionally substituted. However, R ¹¹ and R ¹² may be combined with an adjacent nitrogen atom to form an optionally substituted cyclic amino.
R ² : each optionally substituted lower alkyl, cycloalkyl, aryl or heterocycle.
R ³ : halogen, lower alkyl, or —O-lower alkyl.
R ⁴ : each independently substituted cycloalkyl or non-aromatic heterocyclic ring, or lower alkyl substituted with cycloalkyl. However, when R ⁴ represents an optionally substituted non-aromatic heterocycle, the carbon atoms constituting the ring shall be bonded to the adjacent NH.
R ⁵ : —H, halogen, cyano, nitro, lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocycle, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N (lower alkyl) CO— Lower alkyl, amino optionally substituted with lower alkyl, or cyclic amino optionally substituted.
R ⁶ : —H, halogen, lower alkyl or halogeno lower alkyl.
R ⁷ : —H, halogen, lower alkyl or halogeno lower alkyl.
However, when Y represents CR ⁶ , R ² and R ⁶ may be combined to form lower alkylene or lower alkenylene. ] The compound according to claim 1, wherein X is CH. The compound according to claim 2, wherein R ³ is halogen. The compound according to claim 3, wherein R ⁴ is cycloalkyl. The compound according to claim 4, wherein R ⁵ is -H, -OH, or halogen. 6. The compound according to claim 5, wherein R ¹² is lower alkyl each substituted with one or more groups selected from group Q (wherein at least one is substituted with a group of P group).
Group P: —CO ₂ H, —SO ₃ H, —P (O) (OH) ₂ and —OP (O) (OH) ₂
Q group: -F, -OH, -CO ₂ H, -SO ₃ H, -P (O) (OH) ₂ and -OP (O) (OH) ₂ 6. NR ¹¹ R ¹² is a cyclic amino group which is substituted with one or more groups selected from group Q (provided that at least one group is substituted with a group of P group). Compound.
Group P: —CO ₂ H, —SO ₃ H, —P (O) (OH) ₂ and —OP (O) (OH) ₂
Q group: -F, -OH, -CO ₂ H, -SO ₃ H, -P (O) (OH) ₂ and -OP (O) (OH) ₂ Among the compounds according to claim 7,
[2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
(2S) -2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) butanedioic acid,
2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl dihydrogen phosphate,
(2S) -2-({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) pentanedioic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-4-oxo-1-[(3S) -tetrahydrofuran-3-yl] -1,4-dihydroquinolin-3-yl} carbonyl) amino] Ethyl} phosphonic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-4-oxo-1-[(3R) -tetrahydrofuran-3-yl] -1,4-dihydroquinolin-3-yl} carbonyl) amino] Ethyl} phosphonic acid,
[2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) -1,1- Difluoroethyl] phosphonic acid,
{2-[({7- (Cyclohexylamino) -6-fluoro-1- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinolin-3-yl} carbonyl) Amino] ethyl} phosphonic acid,
[2-({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
[2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) ethyl] phosphonic acid ,
[2-({[7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) ethyl] phosphonic acid,
(2S) -2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) pentane acid,
(2S) -2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl] carbonyl} amino) pentane Diacid or
[2-({[7- (Cyclohexylamino) -1- (2,2-dimethyl-1,3-dioxane-5-yl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3- Yl] carbonyl} amino) ethyl] phosphonic acid or a pharmaceutically acceptable salt thereof.