WO2006077851A1 - Quinolone derivative and salt thereof - Google Patents

Abstract

Disclosed is a compound having an excellent platelet agglutination inhibitory effect. Specifically disclosed is a quinolone derivative characterized by having an amide group at the 3-position which is substituted with a substituent having a carboxylate ester, phosphate ester, sulfate ester or the like, and an amino group at the 7-position which is substituted with a substituent having a ring structure. Also disclosed is a pharmaceutically acceptable salt of such a quinolone derivative. The quinolone derivative and a pharmaceutically acceptable salt thereof have excellent P2Y12 inhibitory effect and platelet agglutination inhibitory effect. Consequently the quinolone derivative and a pharmaceutically acceptable salt thereof are useful as a platelet agglutination inhibitor.

Description

 Specification

 Quinolone derivatives or salts thereof

 Technical field

 [0001] The present invention relates to a novel quinophone derivative or a pharmaceutically acceptable salt thereof useful as a pharmaceutical, particularly a platelet aggregation inhibitor, a P2Y12 inhibitor.

 Background art

 [0002] Since its discovery in 1842 by Donne, platelets have long been treated as a component in blood necessary for hemostasis. Today, platelets not only play a leading role in the mechanism of hemostasis, but also become a clinically recognized arteriosclerosis, cardiovascular disease including thrombotic disease, cancer transition, inflammation, post-transplant rejection, and immune response. It has been clarified to show multifunctionality such as involvement of

 [0003] In general, for thrombotic diseases and ischemic diseases, treatments for resuming blood circulation using drugs or physical methods are performed. However, after recent revascularization, platelet activation, adhesion, and aggregation are promoted due to the breakdown of vascular tissue including endothelial cells or the breakdown of fibrinolysis / coagulation balance caused by the drug itself. This phenomenon has become a clinical problem. For example, after recanalization is obtained by thrombolytic therapy using t-PA etc., fibrinolytic and coagulant activities are activated, and it is clear that the whole body coagulation 'fibrinolytic balance is disrupted. I came. Clinically, it causes re-occlusion and is a major therapeutic problem (Non-Patent Document 1).

 [0004] On the other hand, PTCA therapy and stent placement have rapidly spread to treat diseases based on coronary stenosis such as angina pectoris and myocardial infarction and aortic stenosis, and have achieved certain results. However, these therapies damage vascular tissues including endothelial cells, causing acute coronary occlusion and further restenosis that occurs in the chronic phase. Platelets play an important role in various thrombotic effects (such as reocclusion) after such revascularization therapy. Therefore, the effectiveness S of antiplatelet agents is expected to be effective S, and the effectiveness of conventional antiplatelet agents has not yet been proven.

[0005] Examples of the preventive or therapeutic agent for these cardiovascular diseases include aspirin, cilostazol, Rostaglandin I, prostaglandin E, ticlopidine, clopidogrel, dipyridamo

 twenty one

 Inhibitors of platelet aggregation such as ru have been used. 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 Documents) 2).

 [0006] In recent years, it has been clarified that ticlovidin and clopidogrel, which are used as antiplatelet agents, exhibit an inhibitory action on platelet aggregation by inhibiting P2Y12, an active metabolite, of the ADP receptor. . Subsequently, as compounds having P2Y12 inhibitory action, triazolo [4,5_D] pyrimidine derivatives (Patent Document 1), piperazine and Z or homopiperazine derivatives (Patent Document 2, Patent Document 3), virazolidinedione derivatives (Patent Document 1) Reference 4), isoquinolinone derivatives (Patent Document 5), etc. have been reported.

 On the other hand, Patent Documents 6 and 7 are known as quinolone derivatives.

 In Patent Document 6, a compound represented by the formula (A) having an antibacterial action is known, but it is not known that these derivatives have a platelet aggregation inhibitory action.

 [Chemical 1]

 (See the official gazette for symbols in the formula)

 In Patent Document 7 filed by the present applicant and published after the priority date of the present application, it is reported that the compound represented by the formula (B) has a P2Y12 inhibitory action.

 [Chemical 2]

(See the official gazette for symbols in the formula) [0009] Non-Patent Document 1: “Journal of the American College of Cardiology”, 1988, No. 12, p.616-623 Patent Document 2: "Sogo Clinical", 2003, No. 52, p.1516-1521

 Patent Document 1: International Publication WO 00/34283 Pamphlet

 Patent Document 2: International Publication No. WO 02/098856 Pamphlet

 Patent Document 3: International Publication No. WO 03/022214 Pamphlet

 Patent Document 4: Pamphlet of International Publication No. WO 05/000281

 Patent Document 5: International Publication No. WO 05/035520 Pamphlet

 Patent Document 6: International Publication No. WO 98/23592 Pamphlet

 Patent Document 7: International Publication No. WO 05/009971 Pamphlet

 Disclosure of the invention

 Problems to be solved by the invention

[0010] Under such circumstances, development of an antiplatelet agent having both high safety with less bleeding side effects and clear medicinal effects even in the acute phase or in the chronic phase is eagerly desired. Accordingly, an object of the present invention is to provide a novel compound useful as a platelet aggregation inhibitor and a P2Y 12 inhibitor, which has a good balance between pharmacological effects and safety with high pharmacological effects.

 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 It was found that the compound has a novel skeleton exhibiting an inhibitory action. Furthermore, as a result of intensive studies, it was found that a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, and the present invention was completed.

 Means for solving the problem

[0011] That is, the present invention relates to a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof useful as a P2Y12 inhibitor.

[The symbols in the formula have the following meanings.

Y: CR ⁶ or N.

R ⁶ : _H, halogen, lower alkyl or halogeno lower alkyl.

R ² : lower alkyl, cycloalkyl, aryl or hetero ring each optionally substituted.

R ³ : Neurogen.

R ⁴ : cycloalkyl.

R ⁵ : -H, -〇H or halogen.

R ^U : -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.

R ¹² : lower alkyl which has at least one substituent selected from the P group and may further have a substituent.

Group P: -CO R -SO R -P (0) (OH) (R ^d ), _P (0) (R ^b ) (R ^d ), -OP (0) (OH) (R ^d ) and -OP (0) (

R ^b ) (R ^d ).

R ^e : -R ^xa , lower alkylene-0 (CO) R ^x , lower alkylene-0 (CO) OR ^x , lower alkylene-S (

CO) R ^x, lower alkylene - S (CO) OR ^x or lower alkylene - SS-R ^X.

R ^b : the same or different from each other, ~ OR -NH, -NR -N (R ^a ), _0 (C0) R ^a or a cyclic amino group.

R ^d : the same or different from each other, —0R ^e , —NH, —NHR ^a , —N (R ^a ), —0 (CO) R ^a or a cyclic amino group;

However, in the P group -P (0) (R ^b ) (R ^d ) and -〇P (0) (R ^b ) (R ^d ), R ^b and R ^d are integrated, It is possible to form a group represented by L.

L: _0_lower alkylene-0_, -0-lower alkylene-NH-, -0-lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, _NH_lower alkylene-N (lower alkyl) -, -N (lower alkyl) -lower alkylene- N (lower alkyl)-, -0-lower alkylene-0-CO

-Lower alkylene-0-, -0-lower alkylene-0-CO-, -0-aryl-CO- or -0-heterocyclic-CO- may be formed.

However, -0-lower alkylene in -0_, -0-lower alkylene-NH-, -〇_lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, -NH-lower alkylene- N (lower alkyl)-, -N (lower alkyl) -lower alkylene- N (lower alkyl)-, -0-lower alkylene-0-C0 -lower alkylene-0-, -0-lower alkylene-0-CO- The lower alkylene moiety of each may be substituted with a group selected from group G ^{1. The} -0-aryl-C0- and -0-heterocyclic-CO- aryl and heterocycles are each G ^2. Substituted with a group selected from the group.

R ^a : the same or different from each other, _R ^X , lower alkylene-0 (C〇) R ^x , lower alkylene-〇 (C〇) 0R ^x , lower alkylene-S (C0) R ^x , lower alkylene-S (C0 ) 0R ^x or lower alkylene-SS-R ^x .

R ^x : lower alkyl, cycloalkyl, aryl or heterocycle.

However, in the above, lower alkyl may be substituted with a group selected from group G ¹ , and cycloalkyl, aryl and heterocycle may each be substituted with a group selected from group G ² .

R ^xa : lower alkyl substituted with a group selected from group G ³ (excluding lower alkyl substituted only with -C0 -lower alkyl), -CH ((-0 (C0) _lower alkyl) -Lower alkylene-C0 -lower alkyl, cycloalkyl, aryl or heterocycle.

Provided that the cycloalkyl, aryl and heterocycles in R ^xa are each substituted with a group selected from Group G ² .

G Group ¹ : Halogen, -0H, -0-lower alkyl, -NH, -NH-lower alkyl, -N (lower alkyl), -N (lower alkylene-0H), -N (lower alkyl) -C0- Lower alkylene-aryl, -CO H, -CO -lower alkyl, -〇 (C0) _lower alkyl, -C0NH, -C0NH-lower alkyl, -C0N (lower alkyl), aryl and heterocycle.

However, the aryl and heterocycles in group G ¹ are each substituted with a group selected from group G ^2. May be.

G ² group: halogen, oxo, lower alkyl, halogeno lower alkyl, -OH, -0-lower alkyl, -0-halogeno lower alkyl, -O (CO) -lower alkyl, -CO H, -CO -lower alkyl Kill, lower alkylene-0H, lower alkylene-〇-lower alkyl, lower alkylene-NH

Lower alkylene-NH-lower alkyl, lower alkylene-NH-aryl, lower alkylene-N (lower alkyl), lower alkylene-N (aryl) and lower alkylene-N (lower alkyl) -aryl.

G ³ group: -N (lower alkylene-OH), -〇 (C0) _lower alkyl, -CO -lower alkyl, aryl substituted with a group selected from group G ² (however, aryl substituted only with halogen) heterocycle substituted with a group selected from the excluded) and G ² groups.

However, NR "R ¹² becomes a isomer, has at least one substituent selected from the P group, and further has a substituent to form a cyclic amino group. You can do it.

However, when Y represents CR ⁶ , R ² and R ⁶ may be combined to form lower alkylene or lower alkenylene.

However,

Bis {[(2,2-Dimethylpropanoyl) oxy] methyl} [2-({[7- (Cyclohexylamino) -1-succinyl pentyl-6-fluo-ortho-4-oxo-1,4- Dihydroquinoline-3-yl] carbonyl} amino) chinole] phosphonate,

Pivalic acid {[[2-({[7- (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) ethyl ] (Hydroxy) phosphoryl] oxy} methylol, and

Pivalic acid ({(benzyloxy) [2-({[7- (cyclohexylamino))-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3_yl] carbonyl } Amino) ethyl] phosphoryl} oxy) methinole

except for. The same applies below. ]

The present invention also provides a pharmaceutical composition comprising a quinolone derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in particular, a P2Y12 inhibitor, It also relates to a pharmaceutical composition that is a platelet aggregation inhibitor. That is, (1) a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;

 (2) The pharmaceutical composition according to the above (1), which is a platelet aggregation inhibitor.

 (3) The pharmaceutical composition according to the above (1), which is a P2Y12 inhibitor.

 (4) Use of the compound described in (1) above as a platelet aggregation inhibitor.

 (5) Use of the compound according to (1) above as a P2Y12 inhibitor.

 (6) Use of the compound according to (1) above for producing a platelet aggregation inhibitor.

 (7) Use of the compound described in (1) above for producing a P2Y12 inhibitor.

 The invention's effect

 [0012] 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 healthy individuals (adult males) with 1/10 volume sodium citrate and centrifuged to separate the platelet-rich plasma (PRP) from the supernatant. 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, which is a platelet aggregation inducer, used a product of MMC Medical. Platelet aggregation was measured using a platelet aggregometer (MCM Hematracer 212; Em “Shiichi” Medical). That is, PRP 80 μΐ and the compound solution or solvent of the present invention (10% DMSO) 10 μΐ 37. After incubation at C for 1 minute, platelet aggregation was induced by adding 10 μl of ADP (50 μ50), and the change in transmitted light was recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. Table 1 shows the results of the compound of the present invention at 10 μΜ (final concentration).

[0013] [Table 1] Inhibition of human platelet aggregation

[0014] (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 has been transferred are collected, suspended in DMEM medium containing 0.6 mg / ml G418 (GIBCO BRL), and then diluted serially 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).

 P2Y12 protein expression After C6-15 cells were cultured, the cells were collected. The cells were washed with PBS, suspended in 20 mM Tris-HCl (pH 7.4) containing 5 mmol / 1 EDTA and protease inhibitor cocktail set Complete ™ (manufactured by 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.

[0015] The P2Y12 protein-expressing C6-15 cell membrane fraction (100 μg / ml) produced above was prepared by adding 1.5 μ 1 and 0.75 nM [ ³ H] _2_MeS_ADP (80 Ci / mmol, Amersham Pharm acia Biotech) (50 μl) was added and incubated in 50 mM Tris-HCl (pH 7.4) containing 100 mM NaCl and 50 mM MgCl for 1 hour at room temperature. Collected in a filter. 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 100 μΜ 2-MeS-ADP and adding 1.5 / i 1 to the total binding amount and 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 at 30 nM (final concentration) of the compound of the present invention are shown in Table 2.

[Table 2]

 Inhibitory activity on the binding of P2Y12 and 2-MeS-ADP

(3) Rat platelet aggregation inhibition test

Male SD rats (5-7 weeks old) were orally administered the compound of the present invention using a sonde. Two hours after compound administration, blood was collected using a syringe containing 1/10 volume of 3.8% sodium quenate solution. went. Centrifugation was performed 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, which is a platelet aggregation inducer, used a product of MMC Medical. Platelet aggregation was measured using a platelet aggregometer (MCM Matreaser 212; Em 'Shiichi' Medical). After incubating 90 μ90 of PRP at 37 ° C for 1 min, adding 100 mg of ADP (50 μΜ) induced platelet aggregation, and the change in transmitted light was recorded for 5 min. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. As a result of evaluating the activity after oral administration of the compound of the present invention by this method, Example 653 Was found to have a 50% inhibitory effect on oral administration to rats.

[0018] (4) Monkey platelet aggregation inhibition test

A male male quix (3-6 kg) was held on a holding table, and the compound of the present invention was orally administered using a catheter. Blood is collected from the femoral vein using a syringe containing 1/10 volume of 3.8% sodium citrate solution before administration of the compound and 0.5, 1, 2, 4, 8, 12, 24, 48 hours after administration. It was. Centrifugation was performed 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, which is a platelet aggregation inducer, used a product of M'C'Medical. Platelet aggregation was measured using a platelet aggregometer (MCM Hematracer 212; Em 'Shiichi' Medical). After incubating 90 μ90 of PRP at 37 ° C for 1 minute, platelet aggregation was induced by adding 10 μ1 of ADP (50 μΜ), and the change in transmitted light was recorded for 5 minutes. The inhibition rate was calculated using the area under the platelet aggregation curve as an index. As a result of evaluating the activity of the compound of the present invention after oral administration by this method, it was revealed that the compound has a strong and sustained platelet aggregation inhibitory effect in the oral administration of power quix monkeys.

[0019] The compound (I) of the present invention includes a compound that is metabolized in vivo and exhibits P2Y12 inhibitory activity, a so-called prodrug. For example, a compound selected from the group Ρ is -P (0) (OH) (R ^d ) or -P (0) (R ^b ) (R ^d ), or selected from the group P Among the compounds whose group is —CO 2, there are compounds that are converted to —PO 2 H and —CO 2 H in vivo and exhibit P2Y12 inhibitory activity. The usefulness of such compounds can be confirmed by the above test method (3) or (4), or by combining the following test methods (5) and test methods (1) to (2).

 (5) Measurement of concentration of test compound in rat plasma

The male compound of the present invention was orally administered to male SD rats (5-7 weeks old) using a sonde. Two hours after compound administration, blood was collected using a syringe containing 1/10 volume of a 3.8% sodium citrate solution. Centrifugation was performed to separate supernatant platelet-rich plasma (PRP). PRP was further centrifuged at high speed, and the supernatant from which platelets had been removed was separated as poor platelet plasma (PPP). In order to draw a standard curve, the PPP of SD rats not administered with the compound was also separated, and this PPP Prepare serial dilutions of the parent compound (final concentration 30 μΜ to 0 · 0003 / ι M: select as appropriate depending on the parent compound). An equal amount of distilled water was added to 100 / l of PPP containing the compound of the present invention and PPP containing the diluted parent compound, and further 5% triclonal acetic acid was added and mixed. After standing in ice for 10 minutes, the mixture was centrifuged and the supernatant was collected. The supernatant was neutralized by adding 3 μΐ of 2 M Tris base and mixing. P2Y12 protein expression C6-15 cell membrane fraction (200

50 1 was mixed with 50 μ ト リ (diluted は depending on the compound) that had been treated with acetic acid. Add 50 μ 1 of 0.75 nM [H] -2-MeS-ADP (80 Ci / mmol, Amersham Pharmacia Biotech) and contain 100 mM NaCl and 50 mM MgCl

 2 Incubated in 50 mM Tris-HCl (pH 7.4) at room temperature for 1 hour, and 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. Using the binding inhibition curve of PPP containing the diluted parent compound as a standard curve, the concentration of the parent compound in PPP was converted from the inhibitory activity of PPP of the rat administered with the compound of the present invention. As a result, it was revealed that the compound of the present invention showed good pharmacokinetics.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0020] 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.

 Therefore, “lower alkyl” means alkyl of C, specifically, for example, methyl

 1-6

 , Ethyl, propyl, butyl, pentyl or hexyl, or these structural isomers such as isopropyl or tert-butyl, preferably C alkyl methyl, ethyl,

 1-5

 Propyl, isopropinole, butyl, isobutyl, 3-pentyl.

[0021] "Lower alkenyl" is a C alkyl having one or more double bonds at any position.

 2-6

 Specifically, examples include ethyl, propenyl, butur, pentul, hexenyl, butagenyl, etc., preferably C alkenyl ethenyl, 1-

twenty three

 Propenyl, 2-propenyl and 3-propenyl.

 “Lower alkynyl” is an alkyl of C having one or more triple bonds at any position.

 2-6

It means to do. “Lower alkylene” means a divalent group formed by removing one hydrogen at any position of “lower alkyl”, and specifically includes methylene, methylmethylene, ethylene, trimethylene, propylene, butylene, etc. Preferably, they 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 “lower alkyl” bond becomes part of a double bond.

 [0023] "Cycloalkyl" means a monovalent group of a non-aromatic hydrocarbon ring of C.

 3-10

 It may form a spiro ring or may have a partially unsaturated bond. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctane genyl, adamantyl and norbornyl, and cyclopentyl or cyclohexenole is preferred.

 “Aryl” means a monovalent group of a monocyclic to tricyclic C aromatic hydrocarbon ring.

 6-14

 Specific examples thereof include phenyl and naphthyl, with phenyl being preferred.

[0024] "Non-aromatic heterocycle" means nitrogen, oxygen, sulfur which may be condensed with aryl or aromatic hetero ring which may have a saturated or partially unsaturated bond A monovalent group having 3 to 10 members, preferably 5 to 7 members, having 1 to 4 heteroatoms such as the above. However, the bond is on a saturated or partially unsaturated ring. Specific examples include pyrrolidinyl, piperidinyl, piperazil, azepinyl, monoreforinole, thiomorpholinyl, pyrazolidinyl, dihydropyrrolinole, tetrahydropyranyl, tetrahydrofuryl, dioxanyl, tetrahydrothiopyrael, tetrahydrothenyl and the like. Preferred are pyrrolidinyl, piperidinyl, piperazil, azepinyl, monoreforinole, thiomorpholinyl, tetrahydroviranyl, dioxanyl and tetrahydrothiopyranyl.

“Heterocycle” is a general term in which “aromatic heterocycle” is added to “non-aromatic heterocycle”, and “aromatic heterocycle” is a group consisting of nitrogen, oxygen and sulfur. Containing 1 to 4 of the same or different selected heteroatoms, fused with a benzene ring, or may be aromatic or heteroaromatic. A monovalent group of a ring, specifically, for example, pyrrolyl, furyl, chenyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furazanyl, pyridyl, biranyl, thiopyranyl, pyridazinyl, pyrimidinyl, virazil, indolyl, isoindolyl , Indolizinyl, benzofuryl, benzocenyl, benzimidazolyl, indazolyl, benzotriazolinole, benzoxazolinole, benzothiazolyl, benzoxazizonolinole, quinolinole, isoquinolyl, chromeninole, benzothiobilanyl, phthaladilyl, naphthyridinyl , Cinnolinole, benzodioxolyl, benzodioxur, benzodioxepinyl, carbazolyl, etc., and the nitrogen constituting these rings Kooyobi / or sulfur atom may be oxidized. Also, these rings may be partially saturated. However, the bond is on the aromatic ring. Pyridyl, furyl, chenyl, indolyl, indazolyl and benzotriazolyl are preferred.

 [0026] "Halogen" means a halogen atom, and specific examples thereof include fluoro, black mouth, bromine and iodine, and preferred are fluoro and black mouth.

 The “halogeno lower alkyl group” means a group in which one or more arbitrary hydrogen atoms of the “lower alkyl group” are substituted with the “halogen”, specifically, for example, trifluoromethyl, trifluoroethyl and the like. Preferably, it is trifluoromethyl.

 “Cyclic amino” is a monovalent heterocyclic group having at least one nitrogen atom and having a bond to the nitrogen atom, and may further contain oxygen or sulfur as a heteroatom. Specific examples include pyrrolidino, piperidino, piperazino, homopiperazino, morpholino, thiomorpholine-containing 3,4-dihydroisoquinoline-2 (1H) _yl, etc., preferably pyrrolidone-containing piperidino, piperazino, 3,4 -Dihydroisoquinoline-2 (1H) _yl.

 [0027] The "parent compound" of a prodrug refers to a compound that is released from a prodrug by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo.

 [0028] In the present specification, "which may be substituted" means that it is not substituted, or is substituted with 1 to 5 substituents.

 “Substituted” means substituted with one or more substituents.

The permissible substituents of the words “substituted, may be,” or “substituted,” are the substituents commonly used in the art as the substituent of each group. If any It's okay to slip. In addition, each group may have the same or different substituent power.

Substituents permitted in “substituted les, may be, cycloalkyl”, “substituted les, may be, aryl,” and “optionally substituted heterocycle” in R ² Examples of these include groups represented by the following (a) to (h).

In addition, “lower alkyl which may be substituted” in R ^u , R ^lla , R ^ub and R ^Ue , “substituted ^ret , may les, lower alkyl” in R ¹² , “substituted” in R ² Substituents that are acceptable for “lower alkyl” and “lower alkenyl that may be substituted” include the groups shown in the following (a) to (g): .

Further, substitutions allowed in “cyclic amino” which may have a substituent represented by R ¹¹ and R ¹² , R ^lla and R ^12a , R ^ub and R ^12b, and R ^Ue and R ^12e together with the adjacent nitrogen atom Examples of the group include the P group, Pa group, Pb group, Pc group, and groups shown in the following (a) to (h).

The substituents allowed in the “lower alkyl” optionally having substituents in R ¹² , R ^12a , R ^12b and R ^12e include the P group, Pa group, Pb group, Pc group, and And the groups shown in the following (a) to (g).

Note that i is -OH, -0-lower alkyl, amide-substituted -CO H, -CO R ^z , which may be substituted with one or two lower alkyls, or one or two lower alkyls. May be rubamoyl, aryl (this aryl may be substituted with halogen), aromatic heterocycle and lower alkyl optionally substituted with one or more groups selected from the group consisting of halogen Indicates.

 (a) Halogen.

(b) - OH, -〇- R ^z, -〇- Ariru, - OCO-R ^z, Okiso (= 0), -OSO H, - OP ( 〇) (0-R ^z)

, -P (0) (0-R ^z ), _OP (〇) (〇H) (0-R ^z ), _P (0) (OH) (0_R ^z ), _OP (〇) (OH), -P (0) (〇H)

^{(c) - SH, -SR z} , - S- Ariru, -SO- R ^z, -SO- ^{Ariru, -SO - R z, -SO H} , -SO - § Li Lumpur, one or two R Substituted with ^Z , Les, Moe, and Sulfamoyl.

(d) Ami optionally substituted with one or two R ^Z -NHC0-R ^Z ,-NHC0-arynore, -NHSO—R ^Z , —NHSO—Ariel, nitro, imino (= N—R ^Z ).

(e) - CHO, - CO- R Z, -CO H, -CO - R Z, 1 or 2 R ^Z or optionally substituted with Ariru force Rubamoiru, -CO- (-CO H or -Non-aromatic heterocycle optionally substituted by CO- ^Rz ), Ciano.

(f) aryl or cycloalkyl. In addition, these groups are substituted with _OH, -O_lower alkyl, one or two lower alkyls which may be substituted with amide -CO H, -CO R ^Z , one or two lower alkyls. And optionally substituted one or more groups selected from the group consisting of rubamoyl, aryl, aromatic heterocycle, halogen and ^Rz .

(g) Aromatic heterocycle or non-aromatic heterocycle. These groups are _OH, -O_lower alkyl, oxo (= 0), amino optionally substituted with one or two lower alkyls, -CO H, -CO R ^Z , one or Optionally substituted with two lower alkyl groups, each of which may be substituted with one or more groups selected from the group consisting of ruberinoyl, aryl, aromatic heterocycle, halogen and i. .

 (h) A lower alkyl which may be substituted with one or more groups selected from the substituents shown in the above (a) to (g).

[0029] " ^{Amino optionally} substituted with an ^optionally substituted lower alkyl group" in R ", R" ^a , ^Rllb and R " ^e is the above R", R " ^a , R" ^b and means Amino which is mono- or di-substituted by "optionally substituted lower alkyl group" in R ^"e, lower alkyl group disubstituted may have mutually be the same or different.

 [0030] In the compound of the present invention, Y is preferably CH or N, more preferably CH.

R ¹¹ is preferably —H.

[0031] R ¹² is preferably-(halogen or lower alkyl optionally substituted with -C0H.

 2

) -CO R-(lower alkylene optionally substituted with halogen) _P (0) (〇H) (R ^d ),-(ha

2

A lower alkylene which may be substituted with a rogen) -P (0) (R ^d ).

However, the two R ^d isomers become-0-lower alkylene-0_,-0-lower alkylene-NH-, -0-lower alkylene-N (lower alkyl)-, _NH_lower alkylene-NH- , -NH-lower Alkylene-N (lower alkyl)-, -N (lower alkyl) -lower alkylene-N (lower alkyl)-, -0-lower alkylene-0-CO -lower alkylene-0-, -0-lower alkylene-0- CO-

, -0-aryl-CO- or -0-heterocyclic-CO- may be formed. Where: -0- lower alkylene_0_, -0-lower alkylene-NH-, -〇_lower alkylene-N (lower alkyl)-, _NH_lower alkylene-NH-, -NH-lower alkylene-N (lower Alkyl)-, -N (lower alkyl) -lower alkylene- N (lower alkyl)-, -◦-lower alkylene-0-C0 -lower alkylene _0_, -0-lower alkylene-0-C0 -lower alkylene moiety Is -0H, -0 (C0)

-Les, may be substituted with lower alkyl or aryl. ;

More preferably-(lower alkylene optionally substituted by halogen or -CO H) -CO

R ^qa ,-(lower alkylene optionally substituted with halogen) -P (0) (〇H) (R ^q ),-(lower alkylene optionally substituted with halogen) -P (0) (R ^q ) is a group represented by Where -O_ lower alkylene-0 (C〇) -lower alkyl, -0-lower alkylene-o (co) -cycloalkyl, -0-lower alkylene-0 (C0) -lower alkylene- (one or NH optionally substituted with two lower alkyls), -0-lower alkylene-0 (C0) _lower alkylene-heterocycle,-

0-lower alkylene-o (co) o-lower alkyl, -0-lower alkylene-o (co) o-cycloalkyl, -0-lower alkylene-0 (C0) 0-lower alkylene- (one or two Substituted with lower alkyl, NH), -0-lower alkylene-0 (C0) 0-lower alkylene-heterocycle, NH optionally substituted with one or two lower alkyls,- NH-lower alkylene-COH, -NH-lower alkylene-CO-lower alkyl, -0 (C0) -lower alkyl

, -0- (aryl optionally substituted with (-C0 -lower alkyl)) or -0CH-(5-methyl-2-oxo-1,3-dioxolan-4-yl)] A group (where two R ^q 's become a isomer and are substituted with -0 _ (_ 0 (C0) -lower alkyl, may be, lower alkylene) _0_ or -0-aryl ^-C0- may also be formed.), R ^qa is lower alkylene-0 (C0) _lower alkyl, lower alkylene-o (co) -cycloalkyl, lower alkylene-〇 (co) -lower alkyl Xylene- (optionally substituted with one or two lower alkyls, NH), lower alkylene

-〇 (co) -lower alkylene-heterocycle, lower alkylene-0 (C0) 〇-lower alkyl, lower alkylene-0 (C〇) 0-cycloalkyl, lower alkylene-o (co) o-lower alkylene- ( May be substituted with one or two lower alkyls, NH), lower alkylene-0 (C0) o-lower alkylene-heterocycle, aryl optionally substituted with (-co-lower alkyl) or -OCH- (5-methyl-2-oxo-1,3-dioxolan-4-yl)] More particularly preferably,-(lower alkylene which may be substituted with no, rogen or -CO 2 H) -CO R ^ra ,-(lower alkylene which may be substituted with halogen) _P ( 0) (OH) (),-(lower alkylene optionally substituted with halogen) -P (0) (). Here, -OCH〇 (C〇) -lower alkyl, -〇CH (Me) 〇 (CO) -lower alkyl, -OCH 0 (C

〇) 〇 -Lower alkyl, -OCH (Me) 〇 (C〇) 〇-Lower alkyl, -OCH〇 (C〇) 0-CH CH-

(NH which may be substituted with one or two lower alkyls), -OCH 0 (CO) 0-CH C

H-heterocycle, NH optionally substituted with one or two lower alkyls, -NH-C (Me) -CO lower alkyl, -〇Ph, -0- (2-ethoxycarbonylsulfuric acid ), -OCH-(5-Methyl-2-oxo-1,3-dioxolan-4-yl)] (where two are combined to form -〇-CH ( -〇 (C〇) _Lower alkyl) _ (CH) -〇- or -〇- (Orthophenylene)-

CO-may be formed), R is -CH 0 (C 0) _lower alkyl, -CH (Me) 0 (CO) _lower alkyl, -CH 0 (C 0) 0-lower alkyl, _CH (Me) 0 (CO) 〇-Lower alkyl, -CH〇 (

C〇) 〇-CH CH- (NH optionally substituted with one or two lower alkyl), --CH

〇 (C〇) 〇-CH CH -heterocycle, -Ph,-(2-ethoxycarbophenyl), -CH _ (5-methyl-2-oxo-1,3-dioxolan-4-y ))]. Particularly particularly preferred-(CH) -P (0) (OH) (OPh),-CH CF _P (0) (OH) (OPh),-(CH) -P (0) (OH) [OCH 0 (C

0) Et], -CH CF -P (0) (OH) [OCH 0 (CO) Et],-(CH) _P (0) (OH) [OCH 0 (CO) tertBu

], — CH CF -P (0) (OH) [OCH 0 (CO) tertBu],-(CH) -P (0) (OH) [OCH-(5-Metinole-2

-Oxo-1,3-dioxolan _4-yl;)], -CH CF -P (0) (OH) [OCH-(5-methyl-2-oxo

-1,3-Dioxolan-4-yl)].

When -NR ^U R ^{12 is in the} form of a cyclic amino group, preferably at least one -C 0 R ^c

, -P (0) (◯ H) (R ^d ) and _P (◯) (R ^d ), a cyclic amino group which may have a substituent. However, the two R ^d forms are -O-lower alkylene -O_, _0_lower alkylene -NH-, -0-lower alkylene -N (lower alkyl)-, -NH -lower alkylene. -NH-, -NH-lower alkylene- N (lower alkyl)-, _N (lower alkyl)- Lower alkylene-N (lower alkyl)-, -0-lower alkylene-0-CO-lower alkylene-

0-, -0-lower alkylene-0-CO-, -0-aryl-CO- or -0-heterocyclic-CO- may be formed. Where -0-lower alkylene-0-, -0-lower alkylene-NH-, -〇-lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, -NH-lower alkylene- N (lower alkyl)-, _N (lower alkyl) -lower alkylene-N (lower alkyl)-, -O-lower alkylene-0-C0-lower alkylene-0_, -0-lower alkylene-0-C0-lower The primary alkylene part may be substituted with -0H, _0 (C0) -lower alkyl or aryl. More preferably, having at least one substituent selected from —CO R ^qa , _P (0) (0H) (R ^q ) and —P (◯) (R ^q ), and further having a substituent Cyclic amino group (wherein R ^qa and R ^q are the above-mentioned groups), provided that two R ^q are in the form of _0 _ (-0 (C0) -lower alkyl and May be formed of lower alkylene) -〇_ or -〇 -aryl -CO-. More particularly preferably has at least one substituent selected from —CO R ^ra , _P (0) (0H) (R ^F ) and —P (0) (), and further has a substituent. which may be a cyclic amino group (wherein, R r ^a and R ^F is indicating the foregoing groups.). However, the two isomers may form -0-CH (-0 (C0) -lower alkyl) _ (CH) -0- or-0- (orthophenylene) -CO-. Les. Particularly preferably, at least one substituent is -P (0) (0H) (0Ph), -P (0) (0H) [0CH

○ (C〇) Et], -P (0) (0H) [0CH〇 (C〇) tertBu] and -P (〇) (0H) [〇CH _ (5_methyl_2_oxo-1,3 A cyclic amino group which has a substituent selected from -dioxolan-4-yl)] and may further have a substituent.

[0032] R ² is preferably an optionally substituted lower alkyl, cycloalkyl or non-aromatic heterocycle.

R ³ is preferably halogen, more preferably fluoro.

R ⁴ is preferably cycloalkyl, more preferably cyclohexyleno.

R ⁵ is preferably —H, —OH or halogen, more preferably H, —OH or fluoro.

R ⁶ is preferably -H.

[0033] Another preferred compound in the compound of the present invention represented by the general formula (I) is shown below. (1) A compound of the formula (I) represented by the formula (Ia):

[Chemical 4]

[R ^Ua : -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, and amino.

R ^12a : a lower alkyl having at least one substituent selected from the Pa group and further having a substituent.

Pa Group: - CO R -P (0) ( 〇_H) (R ^d) and - P ^{(〇) (R b) (R d} ). However, R ^b and R ^d may be combined to form L in the case of Pa group -P (◯) (R ^b ) (R ^d ).

However, NR ^Ua R ^12a may integrally form a substituent selected from at least one Pa group and further form a cyclic amino group which may have a substituent. The same applies below. (2) The compound according to (1), which is represented by the formula (Ι-b).

[Chemical 5]

[R ^Ub : -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, and amino.

R ^12b : a lower alkyl having a substituent selected from at least one Pb group and further having a substituent. Pb group: -CO R -P (0) (OH) (R ^d ) and -P (0) (R ^d ). However, Pb group -P

In (0) (R ^d ), two R ^{d s} may be combined to form a group represented by L. However, ^NRllb R ^12b may integrally form a substituent selected from at least one Pb group, and may further form a cyclic amino group that may have a substituent. The same applies below. (3) The compound according to (2), which is represented by the formula (I_c). [Chemical 6]

[R ^Ue : -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.

R ^12e : a lower alkyl which has a substituent selected from at least one Pc group and may further have a substituent. Pc group: -CO R ^e , -P (0) (OH) (R ^e ) and -P (0) (R ^e ).

 twenty two

However, in _P (0) (R ^e ) of the Pc group, two R ^e together form a group represented by L.

 2

You may do it.

R ^e : the same or different, -〇-aryl, -〇_lower alkylene- (_C〇lower alkyl)

2 kill and / or -o (co) -lower alkyl substituted aryl), -◦-lower alkylene -〇 (CO) -R ^xb , _0_lower alkylene-0 (CO) 〇-R ^xb , _0 -CH (aryl substituted by (-0 (CO) _lower alkyl)) -lower alkylene-CO -lower alkyl, _0_lower alkylene-

2

 S (C0) -Lower alkyl, _0-Lower alkylene _S (CO) 0 -Lower alkyl, _0_Lower alkylene -SS-Lower alkyl, -0-Lower alkylene -SS-Lower alkylene _OH, -NH, -NH (

 2 lower alkyl), -N (lower alkyl), -NH-lower alkylene-CO H, -NH-lower al

 twenty two

Xylene-CO-lower alkyl, -o (co) -lower alkyl, cyclic amino group, -0-heterocyclic ring

 2

Others - 0_ lower alkylene - (heterocyclic ring substituted with lower alkyl and / or Okiso) However, in R ^e, -0- lower alkylene - 0 (C0) _ lower alkylene portion content of lower alkyl, and, The aryl part of -0-aryl is -CO-lower alkyl or -o (co) -lower

 2

It ’s replaced with rukill.

R ^ea : the same or different from each other, aryl, lower alkylene-(-C0 lower alkyl and

 2

/ Or -0 (C0) _aryl substituted with lower alkyl), lower alkylene-0 (C0) -R ^xb , lower alkylene-0 (C0) 0-R ^xb , -CH ((-0 (C0) _ Aryl substituted with lower alkyl)) -lower alkylene-CO-lower alkyl, lower alkylene _S (C0) -lower alkyl, Lower alkylene-s (co) o-lower alkyl, lower alkylene-ss-lower alkyl, lower alkylene-SS-lower alkylene-OH,-(CO) -lower alkyl, heterocycle or lower alkylene- (lower alkyl and // Oxo-substituted heterocycle).

However, Slight R ^ea Te, lower alkylene - 0 (C_〇) - lower alkylene moiety of lower alkyl, and, Ariru is -CO - lower alkyl or - 0 (CO) optionally substituted with _ lower alkyl Good.

R ^xb : lower alkyl, cycloalkyl, aryl or heterocycle. However, in R ^xb , the lower alkyl may be substituted with a substituent of group G ⁴ , and the aryl may be substituted with -0 (CO) _lower alkyl.

G ⁴ group: -NH, -NH (lower alkyl), -N (lower alkyl), _N (lower alkylene-OH),-

N (lower alkyl) -CO -lower alkylene -aryl, aryl, heterocycle. However, the aryl may be substituted with _o (co) -lower alkyl, and the heterocycle may be substituted with lower alkyl.

However, NR "3 ^12e may be a isomer having a substituent selected from at least one Pb group, and may further form a cyclic amino group which may have a substituent. The same.] (4) The compound according to (3) represented by the formula (Id).

[Chemical 7]

[R ^12d :-(lower alkylene optionally substituted with halogen or -CO 2 H) _C (◯) R ^f ,-(re substituted with halogen, or may be lower alkylene) -P (○) (OH) (R ^f ) or-(lower alkylene optionally substituted with halogen) -P (0) (R ^f ).

R ^f : _0_lower alkylene-OC (0) _lower alkyl, -0-lower alkylene-OC (〇) 0-lower alkyl, -0-lower alkylene _OC (〇) 0-cycloalkyl or -0_lower alkylene -(5-methyl-2-oxo-1,3-dioxol-4-yl). The same applies below. ]

(5) The compound according to (4), which is represented by the formula (Ie). [Chemical 8]

[R ^12e :-(reduced by halogen, may be, lower alkylene) -P (0) (OH) (R ^f ) or-(lower alkylene optionally substituted by nodogen)- P (◯) (R ^f ). The same applies below. ]

 2

 (7) Pivalic acid {[[2 _ ({[7- (Cyclohexylaminoethylpropyl) -6-fluoro-4_oxo-1,4-dihydroquinoline-3_yl] carbonyl} amino)) _ 1,1- Difluoroethyl] (hydroxy) phosphoryl] oxy} methyl,

 [2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroxyquinoline-3-yl] carbol} amino)- 1,1-difluoroethyl] hydrogen phosphonate [(ethoxycarbonyl) oxy] methyl,

 [2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroxyquinoline-3-yl] carbol} amino)- 1,1-difluoroethyl] phosphonate hydrogen (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, and

Pivalic acid {[[2-({[7- (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino)- 1,1-difluoroethyl] (hydroxy) phosphoryl] oxy} methyl

A compound of the formula (I) or a pharmaceutically acceptable salt thereof selected from the group consisting of: 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, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and other acid addition salts with sodium, potassium, calcium, Examples thereof include inorganic bases containing metals such as gnesium, addition salts with organic bases such as methenoreamine, ethylamine, ethanolanolamine, lysine and onolenitine, and ammonium salts. [0035] 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 encompasses all of these optical isomer mixtures and isolated ones. The compounds of the present invention may have tautomers, but the present invention includes a mixture of these isomers or a mixture thereof. 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.

 [0036] Further, the present invention includes various hydrates and solvates of the compounds of the present invention and substances having crystal polymorphs. It should be understood that the compounds of the present invention include all of the quinolone derivatives represented by the formula (I) and pharmaceutically acceptable salts thereof, which are not limited to the compounds described in Examples below. To do.

 [0037] (Production method)

 The quinolone derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. can do. In addition, the quinolone derivative represented by the formula (I) of the present invention can be easily synthesized from the quinolone derivative represented by the formula (I) by a known method. Hereinafter, typical production methods for the quinolone derivative represented by the formula (I) are exemplified. Depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group at the raw material or intermediate stage, that is, a group that can be easily converted into the functional group. There is a match. Thereafter, the protecting group can be removed as necessary to obtain the desired compound. Examples of such functional groups include a hydroxyl group, a carboxyl group, an amino group, and the like, and examples of their protective groups include those described in “Protective Groups in Organic Synthesis (third edition)” by Greene and Wuts. If you use these as appropriate, depending on the reaction conditions.

[0038] [First manufacturing method]

[Chemical 9]

(In the formula, Lv represents a leaving group corresponding to the reaction. The same shall apply hereinafter.)

[0039] This production process is, Y is the production method of the present invention compounds (I_ 1) which is a CR ^6.

 This step is a step for producing the compound (lc) by a condensation cyclization reaction between the compound (la) and the compound (lb).

 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.

[0040] (Process B)

 This step is a step for producing the compound (le) by an alkylation reaction of the compound (lc) and the compound (Id).

The leaving group Lv in the compound (Id) in this step is commonly used in alkylation reactions. Any leaving group can be used. Halogen such as bromo, iodine, black mouth, sulfonyloxy such as methanesulfonanoloxy, p-tonoleenesulfonyloxy, trifluoromethanesulfonyloxy and the like is preferably used. The method described in J. Med. Chem., 23, 1358-1363, 1980. or a method analogous thereto can be employed.

[0041] (Process C)

 This step is a step for producing the compound (lg) by substituting the leaving group of the compound (le) with the amino group of the compound (If).

 The leaving group Lv in the compound (le) in this step can be any halogen that is commonly used in aromatic nucleophilic substitution reactions, such as halogens such as fluoro, black mouth, and bromo; methanesulfonyloxy, p-toluenesulfonyl Preferred examples include sulfonyloxy such as oxy, trifluoromethanesulfonyloxy, etc .; sulfonyl such as lower alkylsulfonyl, aryl sulfonyl, etc .; When sulfonyl is used as the leaving group Lv in Step C, the compound (la) having sulfonyl as Lv can be used as a starting material, and the compound (la) having a corresponding sulfanyl as Lv can be used as a starting material. Then, after an appropriate step, for example, step B, Lv can be converted to sulfonyl by an oxidation reaction using, for example, m-cloperbenzoic acid, etc., and can be used for the substitution reaction in step C.

[0042] The substitution reaction in this step is carried out in the absence of a solvent or aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as jetyl ether, tetrahydrofuran (THF) and dioxane; dichloromethane, 1,2- Halogenated hydrocarbons such as dichloroethane and chloroform; N, N-dimethylformamide (DMF); dimethyl sulfoxide (DMSO); esters such as ethyl acetate (EtOAc); solvents inert to the reaction such as acetonitrile In a solvent such as methanol (MeO H), ethanol (EtOH), 2_propanol, etc., the compound (le) and the compound (If) are equimolar to one in an excess amount, The reaction can be carried out at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylenomonoreforin, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used), or metal salt bases (carbonic acid) It may be advantageous to carry out in the presence of potassium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like. [0043] (Process D)

 This step is a step for producing compound (lh) by subjecting compound (lg) to a hydrolysis reaction.

 The hydrolysis reaction in this step is based on aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, N, N_dimethylacetamide (DMA), N-methyl for compound (lg). In the presence of acids such as pyrrolidone, DMSO, pyridine, water, mineral acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, organic acids such as formic acid, acetic acid; or lithium hydroxide, water oxidation The reaction can be carried out under cooling to heating under reflux in the presence of a base such as sodium, 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.

[0044] (Process E)

 This step is a step for producing the compound (I 1) by amidation of the compound (lh) or a reactive derivative thereof and the compound (li).

 For the amidation in this step, those skilled in the art can employ a conventional amidation. In particular, carbonyldiimidazole (CDI), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC 'HC1), dicyclohexylcarbodiimide, diphenylphosphoryl azide, jetylphosphoryl cyanide, etc. And a method using a mixed acid anhydride using isotyl chloroformate, ethyl ethyl formate, and the like. 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 or under reflux.

[0045] (Process F)

 This step is a step of producing the compound (lj) by subjecting the compound (le) to a hydrolysis reaction, and can be carried out according to the step D.

 (Process G)

 This step is a step for producing compound (lh) by substituting the leaving group of compound (lj) with the amino group of compound (If), and can be carried out according to step C.

(Process H) This step is a step of producing compound (lk) by amidation of compound (lj) or a reactive derivative thereof and compound (li), and can be performed according to step E.

 (Process I)

 This step is a step for producing compound (I-11) by substituting the leaving group of compound (lk) with the amino group of compound (If), and can be carried out according to step C.

[0046] (禾 ¾ [)

 This step is a step of producing the compound (11) from the alkyl group of the compound (la). The alkylation in this step can be performed by a method according to Step B or by reductive alkylation. For reductive alkylation, those skilled in the art can employ conventional reductive alkylation. For example, the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” 20 (1992) (Maruzen) can be mentioned. Usually, use a reducing agent such as sodium borohydride or sodium triacetoxyborohydride in a solvent inert to the reaction such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, and acetic acid. It is preferable to carry out at room temperature or under heating reflux. 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 for producing compound (le) by a condensation and cyclization reaction between compound (lb) and compound (11), and can be carried out according to step A.

[0047] [Second manufacturing method]

[Chemical 10]

1) HC (OE¾

The production method via step A of this production method is a production method that can be adopted 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. . The production method via Step B is a production method that can also be adopted when R ² and R ⁶ are in the form of a ring to form a ring.

(Process A)

 This step is a step of producing a compound (2c) in which is H by an addition / elimination reaction with the compound (2b) following a condensation reaction with the compound (2a) and orthoformate.

 The condensation reaction with orthoformate in this step is carried out using a reagent that captures alcohol generated from orthoformate such as acetic anhydride as a solvent, or halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO. , In a solvent inert to the reaction such as esters such as ethyl acetate (EtOAc), acetonitrile, etc. Can

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, DMSO, etc., under cooling, at room temperature to It can be carried out under heating to reflux. In addition, reaction using an excess amount of compound (2b) Can also be done. Depending on the compound, organic bases (triethylamine, diisopropylethanolamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (potassium carbonate, cesium carbonate) In the presence of sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, etc.).

[0049] (Process B)

 This step is a step of producing compound (2c) by addition / elimination reaction of compound (2a) and compound (2d).

 The addition / elimination reaction in this step involves equimolar compound (2a) and compound (2d) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. It is possible to carry out by using an excess amount of one side under cooling, at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methylenomonophorin, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used) or metal salt bases (carbonate It may be advantageous to carry out in the presence of potassium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

[0050] (Process C)

 This step is a step of producing compound (le) by intramolecular cyclization reaction of the amino group of compound (2c).

 The addition / elimination reaction in this step involves cooling compound (2c) from room temperature to heating under reflux in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, etc. Can be done below. Depending on the compound, organic bases (triethylamine, disopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridin, etc. are preferably used) or metal salts It may be advantageous to carry out in the presence of a base (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxy potassium etc. are preferably used).

The compound (1-1) can be produced by subjecting the compound (le) produced by this step to the same method as in the first production process. [Third manufacturing method]

[Chemical 11]

(I -0 (1 e) This production method is a method for producing the compound (I 1 1) of the present invention that can be employed even when R ² is formed into a ring 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 black mouth and bromo, alkoxy, vinyloloxy, sulfonyloxy such as p-toluenesulfonyl and the like are preferably used. Further, instead of the compound (3b) in this step, a compound (3b ′) in which the position of the double bond is isomerized can also be used.

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 and the like. 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, sodium hydroxide, potassium hydroxide, sodium hydride © beam, tert- butoxy potassium or the like is when force ^s is advantageously carried out in the presence of a suitable are used).

[0052] (Process

 This step is a step of producing compound (le) by cyclization reaction of compound (2c). The intramolecular cyclization reaction in this step can be performed according to the second production step C. In this step, it is advantageous to carry out the reaction in the presence of a metal salt base such as sodium hydride so that the reaction proceeds smoothly.

 Depending on the conditions of step A, (le) may be obtained from (3a) at once without isolating (2c).

 The compound (1-1) can be produced by subjecting the compound (le) produced by this step to the same method as in the first production process.

[0053] [Fourth manufacturing method]

 [Chemical 12]

(I-1) This production method is a production method of the compound (I1) of the present invention in which a condensed ring is constructed after R ⁴ NH- is first introduced.

 (Process A)

In this step, the leaving group of compound (la) is substituted with the amino group of compound (If) to convert compound (4a) This is a manufacturing process and can be performed according to the first manufacturing process C.

 In addition, this step can also be performed by a substitution reaction using a rhodium catalyst (in this case, as Lv of the compound (la), halogens such as bromo and iodine, and trifluoromethanesulfonyloxy are preferably used). The method described in Tetrahedron Lett., 38, 6359-6362, 1997, or a method equivalent thereto can be employed.

[0054] (Process

 This step is a step of producing compound (4b) by condensation / cyclization reaction of compound (4a) and compound (lb), and can be carried out according to the first production step A.

 (Process.)

 This step is a step for producing compound (4c) by an alkylation reaction of compound (4b) and compound (Id), and can be carried out according to the first production step B.

 (Process D)

 This step is a step of producing compound (lh) 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 compound (I 1) by amidation of compound (lh) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E. .

[0055] [Fifth Manufacturing Method]

[Chemical 13]

This production method is a production method of the compound (I-12) of the present invention in which Y is N in the formula (I).

(Process A)

 This step is a step for producing compound (5b) by diazotizing compound (5a) and subsequently adding cyanoethyl cyanoacetate.

 The diazotization reaction, which is the first step in this process, is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid, in a solvent inert to the reaction such as water or alcohol, and in the presence of an acid such as sodium nitrite or amylnitrite The reaction can be carried out under cooling using an equimolar amount of compounding agent and compound (5a) in an excess amount. The second stage addition reaction can be carried out by cooling the diazo compound prepared in the first stage and cyanoacetyl acetate in the presence of a base, using an equimolar amount or an excess of one, and cooling at room temperature or under reflux. As the base, organic bases (triethylamine, diisopropylethylamine, N-methylolmonoreforin, pyridine, 4- (Ν, Ν-dimethylamino) pyridine, etc. are preferably used), or metal salt bases ( Potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxy potassium, sodium acetate, etc. are preferably used).

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

 (Process.)

 This step is a step for producing compound (5d) by subjecting compound (5c) to a hydrolysis reaction, and can be carried out according to the first production step D.

[0057] (Process D)

 This step is a step for producing compound (5e) by acid halogenation and cyclization of compound (5d).

 The first step of this process, acid halogenation, is carried out in the absence of solvent or in a solvent inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as ethyl acetate, and acetonitrile. The compound (5d) and a halogenating agent such as thionyl chloride and oxalyl chloride can be cooled using an equimolar amount to an excessive amount of a halogenating agent, and can be carried out 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 not used in the reaction without solvent, or in the reaction with aromatic hydrocarbons, halogenated hydrocarbons, acetyl acetate such as acetyl acetate, and acetonitrile. In an active solvent, the reaction can be carried out using an equimolar or excess amount of a Lewis acid such as aluminum chloride and cooled at room temperature or under reflux.

[0058] (Process E)

 This step is a step for producing compound (5f) by substituting the leaving group of compound (5e) with the amino group of compound (If), and can be carried out according to the first production step C.

 (Process F)

 This step is a step for producing compound (5d) by subjecting compound (5f) to a hydrolysis reaction, and can be carried out according to the first production step D.

 (Process G)

 This step is a step for producing compound (I-12) by amidation of compound (5g) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E.

[0059] [Sixth manufacturing method]

[Chemical 14]

 (I-2) This production method is a production method of the compound (I2) of the present invention in which Y is N in the formula (I).

(Process A)

 This step is a step of diazotizing compound (2a) 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. P A diazotization reagent such as toluenesulfonyl and compound (2a) can be used in an equimolar amount or in an excess amount and at room temperature or under reflux with heating. Depending on the compound, organic bases (triethylamine, diisopropylethylamine, N-methinomonomonoline, pyridine, 4- (N, N-dimethylamino) pyridine, etc. are preferably used), or metal salt bases (potassium carbonate, It may be advantageous to carry out in the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

(Process B)

 This step is a step of producing the compound (6b) by a reductive intramolecular cyclization reaction of the compound (6a).

This step uses trialkylphosphine or triarylphosphine as the reducing agent. Can do. As the leaving group Lv in the compound (6a), halogen such as fluoro, black mouth 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 based thereon can be employed.

[0061] (Process C)

 This step is a step of producing compound (6c) by an alkylation reaction of compound (6b) and compound (Id), and can be carried out according to the first production method step B.

 (Process D)

 This step is a step of producing compound (6d) by substituting the leaving group of compound (6c) with the amino group of compound (If), and can be carried out according to the first production method step C.

 (Process E)

 This step is a step for producing compound (6e) by subjecting compound (6d) to a hydrolysis reaction, and can be carried out according to the first production step D.

 (Process F)

 This step is a step of producing compound (I 2) by amidation of compound (6e) or a reactive derivative thereof and compound (li), and can be carried out according to the first production step E.

[0062] [Seventh Manufacturing Method]

[Chemical 15]

CO. Et

Me

 C) (7b)

 Process B

 1

(In the formula, R ⁸ may be substituted with an unsaturated bond at the β-position such as allyl, propargyl, etc., lower alkenyl group or substituted ret, lower alkynyl group, R ⁹ and R ^1Q represents H or a lower alkyl group, or R ⁹ and R ^1Q together may represent a lower alkylidene, and m and n represent 0 to 3.)

This production method is a production method of the compound (I-13) of the present invention in which R ² forms a ring with R ² in formula (I).

(Process A)

 This step is a step of producing compound (7b) by an alkyl reaction between compound (1) and compound (7a).

The alkylation reaction in this step is not carried out in the absence of a solvent or in the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as DMF, DMSO, and ethyl acetate (EtOAc), and acetonitryl. In an active solvent or a solvent such as alcohols, the compound (lc ′) and the compound (7a) can be used in an equimolar amount or in an excess amount 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 a metal salt base (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, tert-butoxypotassium, etc. are preferably used) may be advantageous.

(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 performed without heating or in the presence of a high-boiling solvent (1,2-dichlorobenzene or the like is preferably used) under heating to heating under reflux. (Process.)

In this step, R ⁸ is a leaving group such as halogen (black mouth, bromo is preferably used), sulfonyloxy (methanesulfonyloxy, p-toluenesulfonyloxy is preferably used) or a triple bond Is a step of producing a compound (le ′) by an intramolecular cyclization reaction of the compound (7c).

The intramolecular cyclization reaction in this step involves cooling compound (7c) in a solvent inert to the reaction such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, and 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, It may be advantageous to carry out in the presence of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy and the like.

Depending on the conditions of step B, (le ') may be obtained from (7b) at once without isolating (7c).

 Compound (1-3) can be produced by subjecting compound (le ′) produced in this step to the same method as in the first production process.

[Eighth Manufacturing Method]

[Chemical 16]

 (8a) (G 4)

(In the formula, R ¹³ represents an optionally substituted lower alkylene, -X-OH represents -CO H, -SO H, -P (

 twenty three

0) (OH) or _OP the (〇) (〇_H), R ¹⁴ represents the R ^e and R ^d. )

 twenty two

In this production method, a compound (8a) having -CO H, -SO H, -P (〇) (〇H) or -OP (〇) (〇H) is

 2 3 2 2

This is a production process for producing the compound (I-4) of the present invention by rukylation.

(Process A)

The alkylation reaction in this step is not carried out in the absence of a solvent or in the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as DMF, DMSO, and ethyl acetate (EtOAc), and acetonitryl. In the presence of a base in an active solvent or a solvent such as an alcohol, equimolar amounts of compound (8a) and compound (8b) can be used in an excess amount, or from room temperature to heating under reflux. Bases include organic bases (triethylamine, diisopropylethanolamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, 1,8-diazabicyclo [5.4.0] -7_undecene, etc. Or a metal salt base (carbonic acid lithium, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxy, silver nitrate, silver carbonate, silver oxide, etc. are preferably used. ) Is preferably used. Depending on the compound, it may be advantageous to carry out it in the presence of sodium iodide or tetrabutylammonium.

 Furthermore, the 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 compounds obtained as described above. It can also be produced by arbitrarily combining the possible processes.

The compound of the present invention thus produced can be isolated or purified as it is as it is, or after being subjected to a salt formation treatment by a conventional method. Isolation and purification are 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 using differences in physicochemical properties between isomers . For example, a racemic mixture can be converted to an optically pure heteroisomer by a general racemic resolution method, such as a method of optical resolution by diastereomeric salt 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.

 [0066] A pharmaceutical composition containing the compound of the present invention or one or more of pharmaceutically acceptable salts thereof as an active ingredient includes a carrier, excipient, and other additives that are usually used in a formulation. It is prepared into tablets, powders, fine granules, granules, capsules, pills, solutions, injections, suppositories, ointments, patches, etc. and administered orally or parenterally.

 The clinical dose of the compound of the present invention for humans is appropriately determined in consideration of the symptoms, body weight, age, sex, etc. of the patient to which it is applied. In the case of oral administration, the daily dose is usually about 0.0001 per body weight. ˜50 mg / kg, preferably about 0.001 to 10 mg / kg, more preferably 0.01 to 1 mg / kg, which is administered once or divided into 2 to 4 times. When administered intravenously, the daily dose is about 0.0001 to 1 mg / kg per body weight, preferably about 0.0001 to 0.1 mg / kg, and is administered once to several times a day. Since the dosage varies depending on various conditions, a sufficient effect may be obtained with an amount smaller than the above dosage range.

 [0067] Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl senolate, microcrystalline cellulose, starch, polyvinylinole. Mixed with pyrrolidone, magnesium metasilicate aluminate, etc. The composition contains additives other than inert diluents, for example, lubricants such as magnesium stearate, disintegrating agents such as calcium calcium glycolate, stabilizers, solubilizing agents and the like according to conventional methods. It may be. If necessary, the tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropenoresenololose, hydroxypropenoremethenoresenololose phthalate, or a gastric or enteric film.

[0068] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and are generally used as inert dilutions. Agent, for example Contains 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 aqueous solutions and suspensions 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, emulsifying agents, dispersing agents, stabilizing agents and solubilizing agents. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. They can also be prepared by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

Example

 EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples. Note that the raw material compounds used in the examples include new substances, and the production method from such raw material compounds will be described as a reference example.

 The symbols in the table have the following meanings (the same applies hereinafter).

Rf: Reference example number, Ex: Example number,

 Data: Physical data (Sal: Salt (No indication indicates free form. For example, HC1 indicates that the compound is hydrochloride)), NMI ^ H- Δ (ppm) in NMR.

R,

R ⁵ , A: —Substituents in the general formula (Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, iBu: isobutyl, sBu: sec_butyl, tBu: tert-butyl, nP en: normal Pentyl, cPr: Cyclopropyl, cBu: Cyclobutyl, cPen: Cyclopentyl, cHex: Cyclohexyl, cH: Cycloheptyl, cOct: Cyclooctyl, Ph: Phenyl, Py: Pyridyl, fur: Furyl, the: Chenyl, Bn: Benzyl, btria: benzotriazolyl, bimi d: benzimidazolinole, pyrr: pyrrolidininore, pipe: piperidinole, pipa: piperazinole, mor: morpholinyl, THF: tetrahydrofuranyl, THP: tetrahydroviranyl, THSP : Tetrahi Drothiobilanyl, 2_thiq: 3,4-dihydroisoquinoline-2 (1H) _yl, Bo tert-butyloxycarbonyl, A-acetyl, Bz: benzoyl, aq: aqueous solution. The number in front of the substituent indicates the substitution position, so for example 4-EtO C-1-pipe is 4-ethoxycarbonylbiperidine-1

 2

 -Inole, 2-the_ (CH) _NH- represents 2- (thiophen-2-yl) ethylamino. ),

 twenty two

 Syn: Production method (Numbers indicate that the product was prepared using the corresponding raw material in the same manner as the Example compound having the number as the Example number. If more than one number is written, write it before. It shows that it manufactured by performing the manufacturing method corresponding to a certain numerical power.

) o

 [0070] Reference Example 1

 3-Bromo _4_Fluorobenzoic acid is dissolved in toluene, tert-butanol, triethylamine, diphenylphosphoryl azide are added in that order, and the mixture is stirred at 100 ° C for 20 hours. -Fluorophylzinore) obtained the strength rubamate.

 FAB-MS (Neg); 288,290 (M—-1)

[0071] Reference Example 2

After dissolving the compound of Reference Example 1 in toluene and adding in order, aniline, cesium carbonate, 2,2'-bis (diphenylphosphino) -1,1, -binaphthyl, tris (dibenzylideneacetone) dipalladium, The mixture was stirred at 110 ° C for 2 days to obtain tert-butyl (3-anilino-4-fluorophenyl) force rubamate. This compound was dissolved in EtOAc, 4M HC to EtOAc solution was added, and the mixture was stirred at room temperature for 1 day to obtain 4-fluoro-N ³ -phenylbenzene-1,3-diamin.

FAB-MS (Pos); 203 (M ⁺ +1)

[0072] Reference Example 3

 After adding ethoxymethylene malonate jetyl to 3,4-difluoroaniline at room temperature, the mixture was stirred 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 reaction mixture was allowed to cool to room temperature, and the resulting solid was collected by filtration to obtain ethynole 6,7-difluoguchi-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.

[0073] [Table 3]

 [0074] Reference Example 11

 Ethyl 3- (2-chloro-4,5-difluorophenyl) -3-oxopropanoate, prepared according to Organic Preparations and Procedures International, 29, 231-234, 1997., dissolved in acetic anhydride After ethyl orthoformate was collected at room temperature, the mixture was stirred at 150 ° C. for 1 hour and concentrated under reduced pressure. The obtained residue was dissolved in EtOH, cyclopentylamine was collected under ice-cooling, 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 added to hydrochloric acid form. Extracted with. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in acetic acid, and after 6M HC1 aq was prepared at room temperature, the mixture was stirred at 120 for 5.5 hours. 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.

[0075] [Table 4]

[0076] Reference Example 29

 Suspend the compound of Reference Example 5 in DMF, add potassium carbonate and iodinated chill in order under ice-cooling, and stir 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)

[0077] Reference Example 30

The compound of Reference Example 3 was suspended in DMF, and potassium carbonate and iodinated chill were sequentially added under ice cooling, followed by stirring at room temperature for 24 hours, extraction with black mouth form, and concentration under reduced pressure. The obtained residue was suspended in acetic acid, 6M HC1 aq was added at room temperature, and the mixture was stirred at 120 ° C for 4 hours, and then 6,7-difluoguchi-1-ethyl-4-oxo-1, 4-Dihydroquinoline-3-carboxylic acid was obtained. In the same manner as in Reference Example 30, the reference examples 31 to 39 shown in Table 5 are used as the corresponding raw materials. Manufactured using.

[0078] [Table 5]

 [0079] Reference Example 40

 The compound of Reference Example 30 was suspended in DMSO, added with cyclohexylamine at room temperature, stirred at 80 ° C for 2 hours, and recrystallized with 80% aqueous acetic acid to give 7- (cyclohexylamino)- 1-Ethyl-6-fluoro-4_oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.

 NMR (DMSO-d) δ; 1.10_1.25 (m, lH), 1.27— 1.50 (m, 7H), 1.60— 1.70 (m, lH), 1.72-1

 6

 .82 (m, 2H), 1.90—2.00 (m, 2H), 3.55_3.67 (m, lH), 4.53 (q, J = 7.4Hz, 2H), 6.65 (dd, J = 2.2, 8 · 1Ηζ , 1Η), 6.79 (d, J = 7.4Hz, lH), 7.79 (d, J = 11.3Hz, lH), 8.83 (s, lH), 15.78 (s, lH) Same as the method in Reference Example 40 Reference Examples 41 to 87 shown in Tables 6 to 7 were produced using the corresponding raw materials.

[0080] [Table 6]

S00C / 900Zdf / X3d 9 TS8..0 / 900Z OAV

Reference Example 88

After suspending the compound of Reference Example 10 in DMF and adding potassium carbonate and iodide iodide in order under ice-cooling, the mixture was stirred at room temperature for 2 days, and ethyl 1-ethyl _5,6,7-trifluoro mouth- 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. 0083 Table 8

 [0084] Reference Example 92, Reference Example 93

 The compound of Reference Example 88 is dissolved in DMSO, cyclohexylamine is added, and the mixture is stirred at 80 ° C for 1 hour. 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-difluo-or 4-oxo-1,4-dihydroquinoline-3_carboxylate (Reference Example 93) was obtained.

 Reference Example 93 FAB-MS (Pos); 379 (M ++ 1)

 In the same manner as in Reference Example 92, Reference Examples 94 to 103 shown in Tables 9 to 10 and 103 and Reference Examples 104 to 106 were produced using the corresponding raw materials.

[0085] [Table 9]

[0086] [Table 10]

 [0087] Reference Example 104

 Ethyl Ί- (Cyclohexylamino) -1-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 415 (M ⁺ +1)

[0088] Reference Example 105

 Ethyl 9- (Cyclohexylamino) -8-Fluoro-6-oxo-6H-pyrido [1,2-a] quinoline-5-force Noreboxylate

FAB-MS (Pos); 383 (M ⁺ +1)

[0089] Reference Example 106

 Ethyl [7- (cyclohexylamino) -6_fluoro-1_isopropyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3_yl] carboxylate

FAB-MS (Pos); 376 (M ⁺ +1)

[0090] Reference Example 107

 To the dioxane solution of ethyl 3_ (cyclopentylamino) but-2-enoate under ice-cooling, add triethinoleamine and 2,4,5-trifluorobenzoyl chloride to room temperature for 30 minutes at 65 ° C for 1 hour. Upon stirring, ethyl 3- (cyclopentylamino) -2- (2,4,5-trifluoromethylbenzo) _2-enoate was obtained.

FAB-MS (Pos); 356 (M ⁺ +1)

[0091] Reference Example 108

 60% sodium hydride was added to the 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-difluo-2-methyl-4-oxo-1,4- Dihydroquinoline-3-carboxylate was obtained.

FAB-MS (Pos); 336 (M ⁺ +1) [0092] Reference Example 109

 Ethyl 3- (2-chloro-4,5-difluorophenyl) 3-oxopropanoate was dissolved in acetic anhydride, and ethyl orthoformate was added at room temperature, followed by stirring at 140 ° C for 12 hours And concentrated under reduced pressure. The obtained residue was dissolved in EtOH, and triethylamine, tetrahydrofuran-3-amamine hydrochloride in EtOH was added under ice-cooling, and stirred for 30 minutes under ice-cooling and 1 hour at room temperature. did. 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.

 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, Reference Examples 123 and 124 are the hydroxyl groups in the corresponding raw materials. Those protected with a dimethylsilyl group were used as raw materials).

[0093] [Table 11]

[0094] 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-fluoroxy-6-oxo-2,3,4,6 -Tetrahydro-1H-pyrido [1,2-a] quinoline-5-carboxylate was obtained.

FAB-MS (Pos); 387 (M ⁺ +1)

[0095] Reference Example 127

 The compound of Reference Example 95 was dissolved in methylene chloride, and trifluoroacetic acid was added. The mixture was stirred at room temperature for 24 hours, and [7- (cyclohexylamino) -3- (ethoxycarbonyl) _6_fluoroxy-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.

[0096] Reference Example 128

2- [7- (Cyclohexylamino) -3- (ethoxycarbonyl) -6-fluoro- 4-oxoquinoline-1 ( 4H) -yl] propionic acid

ESI-MS (Pos); 405 (M ⁺ +1)

[0097] Reference Example 129

 The compound of Reference Example 127 was dissolved in THF, and Ι, -carbonyldiimidazole was prepared under ice-cooling, followed by stirring for 1 hour under ice-cooling. Then, water was added to the reaction solution, and borohydride was added. Sodium was added 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.

[0098] Reference Example 130

 Ethyl 7- (Cyclohexylamino) -6_Fluoro-I_ (2-Hydroxy-1-methylethyl) _4-Oxo-1,4-dihydroquinoline-3_carboxylate

ESI-MS (Pos); 391 (M ⁺ +1)

[0099] Reference Example 131

 Dissolve the compound of Reference Example 129 in salt and methylene chloride, add pyridinium p-toluene sulfonate and dihydropyran in this order under ice-cooling, stir at room temperature for 3 days, and then add ethyl 7- (cycloto (Xylamino) -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)

[0100] Reference Example 132

 The compound of Reference Example 127 was dissolved in THF, and Ι, -carbonylbis-1H-imidazole was added under ice cooling, followed by stirring at room temperature for 2.5 hours. To this reaction solution, an aqueous methylamine solution was added under ice-cooling, followed by stirring at room temperature for 1 hour. Ethyl 7- (cyclohexenoreamino) -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. [0101] Reference Example 133

 Ethyl 7- (Cyclohexylamino) -6-Fluoro-l- [2- (4-Methylbiperazine-1-yl) -2-oxoethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 473 (M ⁺ +1)

[0102] Reference Example 134

 Ethyl 7- (Cyclohexylamino) -6_Fluoro- 1- (2_Morpholine-4-yl-2-oxoethyl) -4-oxo-1,4-dihydroquinoline-3_carboxylate

FAB-MS (Pos); 460 (M ⁺ +1)

[0103] 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. Ethenole 7- (cyclohexylamino) -6-fluoro-l-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, and ethyl 7- (cyclohexylamino) -6-fluoroxy-1- [2-methoxy -1- (Methoxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.

FAB-MS (Pos); 435 (M ⁺ +1)

[0104] 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, stirred at 50 ° C for 1 hour, water was added, and the mixture was stirred at 80 ° C overnight. 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_fluorine-4-oxo -1,4-Dihydroquinoline-3-carboxylate was obtained.

ESI-MS (Pos); 418 (M ⁺ +1)

In the same manner as Reference Example 137, Reference Examples 138 to 140 were prepared using the corresponding raw materials. Made.

 [0105] 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)

[0106] Reference Example 139

 Ethyl 1_ {2_ (Acetylamino) -1-[(Acetylamino) methinole] ethyl} -7_ (Cyclohexylamino) -6-Fluoro-4_oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 489 (M ⁺ +1)

[0107] Reference Example 140

 1- [2- (Acetylamino)-1_Methylethyl] -7- (cyclohexylamino) -6-Fluoro-4-oxo-1,4-dihydroquinoline-3_carboxylate

ESI-MS (Pos); 432 (M ⁺ +1)

[0108] Reference Example 141

 The compound of Reference Example 117 was suspended in EtOAc, and a 4M HCl solution in EtOAc was added under ice cooling. The mixture was stirred for 1 hour at room temperature and then at 50 ° C, and then insoluble matter was collected by filtration at room temperature and dried. Suspend this in salt-hethylene, add sodium acetate, formaldehyde solution (36%) and sodium triacetoxyborohydride under ice-cooling and stir for 45 minutes. Ethyl 7- (cyclohexylamino)- 6-Fluoromouth-1- (1-methylpyrrolidine-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.

[0109] Reference Example 142

 Ethyl 7- (Cyclohexylamino) -6_Fluoro-1_ (1-Methylpiperidine-4-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 430 (M ⁺ +1)

[0110] Reference Example 143 Ethyl 7- (cyclohexylamino) -6-fluoro-1- (1-methylazetidine-3-yl) -4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 402 (M ⁺ +1)

[0111] Reference Example 144

 60. Add 5-methoxy_3,4-dihydro-2H-pyrrole and triethylamine to ethyl 3_oxo_3_ (2,4,5-trifluorophenyl) propanoate; The mixture was stirred at C for 4 days to obtain ethyl 3-oxo-2-pyrrolidine-2-ylidene-3- (2,4,5-trifluorophenyl) propanoate.

ESI-MS (Pos); 314 (M ⁺ +1)

[0112] Reference Example 145

 Add 60% sodium hydride to the dioxane solution of the compound of Reference Example 144, stir at room temperature for 1 hour, and ethyl 7,8-difluo-5-oxo-1,2,3,5-tetrahydropyro [l, 2_a] quinoline-4-carboxylate was obtained.

ESI-MS (Pos); 294 (M ⁺ +1)

[0113] Reference Example 146

 Reference Example 130 To a methylene chloride solution of the compound of 130, add dimethylaminosulfur trifluoride at -78 ° C, gradually warm to room temperature over 2 hours, and then ethyl 7- (cyclohexylamino) -6-fluorine -1- (2-Fluoromouth-1-methylethyl) -4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.

ESI-MS (Pos); 393 (M ⁺ +1)

[0114] 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 the mixture was stirred for 1 hour to obtain a mesinole. Dissolve the mesinole compound in THF, add potassium tert-butoxide, stir at room temperature for 3 hours, ethyl 7- (cyclohexylamino) -6_fluoroxy-1-isopropenyl _4_oxo-1,4 -Dihydroquinoline-3-carboxylate was obtained.

ES to MS (Pos); 373 (M ⁺ +1)

[0115] Reference Example 148

Sodium hydride and methyl iodide were added to a DMF solution of the compound of Reference Example 137 at 0 ° C. Stir for 5 hours to obtain ethyl 1- {2- [acetyl (methyl) amino] ethyl} -7_ (cyclohexylamino) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-carboxylate It was.

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.

[0116] 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)

[0117] Reference Example 150

 Palladium-carbon and concentrated hydrochloric acid were added to the EtOH solution of the compound of Reference Example 102, and the mixture was stirred for 12 hours under a hydrogen atmosphere. Ethyl 8- (cyclohexylamino) -7_fluorine-1-methyl-5-oxo-1, 2,3,5_tetrahydropyrrolo [1,2-&] 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 material.

[0118] Reference Example 151

 Ethyl 9- (Cyclohexylamino) -8-Fluoro-2,2-Methyl-6-oxo-2,3,4,6-Tetrahydrin 1H-pyrido [l, 2-a] quinoline-5-carboxylate

ESI-MS (Pos); 401 (M ⁺ +1)

[0119] Reference Example 152

 Add potassium carbonate and iodine cyclopentane to the DMF solution of ethyl 6,7-difluor mouth-4-hydroxycinnoline-3-carboxylate, stir at 80 ° C for 40 minutes, and ethyl 1-cyclopentyl-6 , 7-Difluoguchi-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 material.

[0120] Reference Example 153

 Ethylethylpropyl) -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, stirred at 140 ° C for 3 hours, and concentrated under reduced pressure . The obtained residue was dissolved in EtOH, and [2-fluoro-1- (fluoromethyl) ethylenol] amine hydrochloride and triethylamine were added under ice cooling, followed by stirring at room temperature for 30 minutes and reducing the pressure. The bottom was concentrated. Water was added to the obtained residue and 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-difluo-mouth-1 -[2_Fluoro-1- (fluoromethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3_carboxylate (Reference Example 154) and ethinole 6,7-Difunole 1- [1- ( Fluoromethyl) bul] -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)

[0121] Reference Example 156

 To a 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, add 3-pentanone, acetic acid, sodium triacetoxyborohydride, and stir at room temperature for 14 hours. N- (l-ethylpropyl) -3, 4 Thus, 5-trifluoroaniline was obtained.

EI-MS (Pos); 217 (M ⁺ )

[0122] Reference Example 157

 Jetyl (ethoxymethylene) malonate was added to the compound of Reference Example 156, and the mixture was stirred at 130 ° C for 20 hours to obtain jetylethyl) (3,4,5-trifluorophenyl) amino] methylene} malonate. It was.

FAB-MS (Pos); 388 (M ⁺ +1)

[0123] 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)

[0124] Reference Example 159

 Add the compound of Reference Example 88 to a toluene suspension of lithium methoxide and stir at room temperature for 3 days. Ethyl 1_ethyl-6,7-difluoro-5-methoxy-4-oxo-1,4-dihydro Quinoline-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.

[0125] Reference Example 160

 5- (Benzyloxy) -7- (cyclohexylamino) -ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3_carboxylic acid

ESI-MS (Pos); 481 (M ⁺ +1)

[0126] Reference Example 161

 Methylamine aqueous solution was added to the 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-difluo-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 material.

[0127] Reference Example 162

 Ethyl 5- (Benzylamino) -1-Ethyl-6,7-difluo-or 4-oxo-1,4-dihydroquinoline-3-carboxylate

FAB-MS (Pos); 387 (M ⁺ +1)

[0128] Reference Example 163

 3-Methylcyclopent-3-en-1-carboxylic acid was dissolved in tolylene, tert-butanol, triethylamine, diphenylphosphoryl azide were added in that order, and the mixture was stirred at 90 ° C for 3 days. (3-Methylcyclovent-3-en-1-inore) force rubamate was obtained.

 NMR (CDCl 2) δ; 1.44 (s, 9H), 1.71 (brs, 3H), 2.02-2.18 (m, 2H), 2.58— 2.77 (m, 2H), 4.27

(brs, lH), 4.69 (brs, lH), 5.25 (brs, lH)

[0129] Reference Example 164 Dissolve the compound of Reference Example 163 in salt methylene, add trifluoroacetic acid, stir at room temperature for 4 hours, and then add 3-methylcyclopent-3-ene-1-amamine trifluoroacetate salt. Ethyl 3_ (2_black mouth -4,5-difluorophenyl) -3-oxopropanoate was dissolved in acetic anhydride, ethyl orthoformate was added, and the mixture was stirred at 150 ° C for 2 hours. And concentrated under reduced pressure. The obtained residue was dissolved in EtOH, and triethylamine and 3-methylcyclopent-3-ene_1-amine trifluoroacetate were added in that order under ice cooling, followed by stirring for 18 hours under ice cooling. As a result, ethyl 2_ (2-chloro-4,5-difluorobenzoyl) -3-[(3-methylcyclopent-3-en-1-yl) amino] attalylate 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-methylcyclopenta-3-yl 1_yl) _4_oxo-1,4-dihydroquinoline-3-carboxylate.

FAB-MS (Pos); 334 (M ⁺ +1)

[0130] Reference Example 165

 Dissolve the compound of Reference Example 162 in EtOH-acetic acid, add nodium-carbon (10%), stir at room temperature for 3 hours in a hydrogen atmosphere, and then ethyl 5-amino-1-ethyl-6,7-difluor. Mouth-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.

FAB-MS (Pos); 297 (M ⁺ +1)

[0131] Reference Example 166

 Ethyl 7- (Cyclohexylamino) -6-Fluoro-l- [2-hydroxy-1- (hydroxymethyl) ethyl] -4-oxo-1,4-dihydroquinoline-3-Carboxylate in benzene solution 3 -Pentanone, P-toluenesulfonic acid monohydrate was added, and the mixture was stirred with heating under reflux for 34 hours. Ethyl 7- (cyclohexylamino) -1- (2,2-jetyl-1,3-dioxane-5_ _6_fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained.

FAB-MS (Pos); 475 (M ⁺ +1)

[0132] 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. 7- (Cyclohexylamino) -1-ethyl-5,6-difluorine-4-oxo -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.

[Table 12]

[0134] [Table 13]

 [0135] [Table 14]

 [0136] [Table 15]

 [0137] Reference Example 215

 LiOH aq was added to the 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. -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.

[0138] Reference Example 216 9- (Cyclohexylamino) -8-Fluoro-6-oxo-6H-pyrido [1,2-a] quinoline-5-carboxylic acid

FAB-MS (Pos); 355 (M ⁺ +1)

[0139] 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 + + l)

[0140] Reference Example 218

 Ethyl 9_ (Cyclohexylamino) _8_Fluoro-6_oxo _2,3,4,6_Tetrahydro_1H_pyrid [l, 2-a] quinoline-5-carboxylic acid

 FAB-MS (Neg); 357 (M "-1)

[0141] Reference Example 219

 9- (Cyclohexylamino) -8-Fluoro-2-Methylene 6-oxo-2,3,4,6-Tetrahydro-1H-pyrid [1,2-a] quinoline-5-carboxylic acid

FAB-MS (Pos); 371 (M ⁺ +1)

[0142] Reference Example 220

 9- (Cyclohexylamino) -8-fluoro-2,2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrid [1,2-a] quinoline-5-carboxylic acid

FAB-MS (Pos); 373 (M ⁺ +1)

 Reference Example 221

A sodium nitrite aqueous solution was added dropwise to an aqueous hydrochloric acid solution of 3,4-difluoroaniline 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 cyano ethyl acetate and sodium acetate prepared in a separate reaction vessel under ice-cooling, and the mixture was stirred at room temperature for 2 hours, followed by ethylciano [(3,4-difluoro [Finyl) diazenyl] acetate was obtained. FAB-MS (Pos); 254 (M ⁺ +1)

[0143] Reference Example 222

After suspending the compound of Reference Example 221 in acetonitrile and calcining kyoka til and potassium carbonate, the mixture was stirred at 50 ° C for 7 days, and ethyl 2-ciano [(3,4-difluorophenyl) (ethyl) hydride. Lazono] got the acetate.

FAB-MS (Pos); 282 (M ⁺ +1)

[0144] 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 hrs. 2_Cyano [(3,4-difluorophenyl) (ethyl) hydrazono Acetic acid was obtained. FAB-MS (Pos); 254 (M ⁺ +1)

[0145] Reference Example 224

 The compound of Reference Example 223 was suspended in toluene, and after addition of sodium chloride, the mixture was stirred at 90 ° C. for 1.5 hours and concentrated under reduced pressure. Azeotropically with toluene, hexane was added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was dissolved in dichloroethane, and after the salt and aluminum were prepared, the mixture was stirred at 55 ° C. for 24 hours, and further refluxed for 23 hours. 1-Ethyl-6,7-difluoro-4-oxo-1 , 4-Dihydrocinnoline-3_carbonitryl was obtained.

FAB-MS (Pos); 236 (M ⁺ +1)

[0146] 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. 7- (Cyclohexylamino) -1-ethyl-6-fluoro-4-4-oxo-1 Thus, 4-dihydrocinnoline-3-carbonitrile was obtained.

FAB-MS (Pos); 315 (M ⁺ +1)

[0147] Reference Example 226

 The compound of Reference Example 225 was dissolved in acetic acid, and after HC1 aq was prepared, the mixture was stirred at 120 ° C. for 2 days, and 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1, 4-Dihydrocinnoline-3-carboxylic acid was obtained.

FAB-MS (Pos); 334 (M ⁺ +1)

[0148] Reference Example 227

 DMF, N-chlorosuccinimide is added to the compound of Reference Example 40, and the mixture is 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) [0149] Reference Example 228

 Cyclohexylamine was added to a DMSO solution of the compound of Reference Example 153, and the mixture was stirred at 80 ° C for 14 hours. After cooling the reaction solution 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, 1 N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. 7- (Cyclohexylenoamino) -1- (ethylpropyl) _6 -fluoro _4_ Oxo-1,4-dihydrocinnoline-3-carboxylic acid was obtained.

FAB-MS (Pos); 376 (M ⁺ +1)

[0150] Reference Example 229

 Water and concentrated hydrochloric acid were added to the 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.

[0151] Reference Example 230

 6,7-difluo-one 1- [1- (fluoromethinole) bier] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid

FAB-MS (Pos); 284 (M ⁺ +1)

[0152] Reference Example 231

 Dissolve the compound of Reference Example 130 in salt methylene salt, add pyridinium p-toluenesulfonate and dihydropyran in this order, and then stir at room temperature overnight. Ethyl 7- (cyclohexylamino) -6-fluoro Methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl]-

4-Oxo-1,4-dihydroquinoline-3-carboxylate was obtained. Suspend the obtained compound in EtOH-T HF, add 1M NaOH aq, stir overnight 7_ (cyclohexylamino) -6_fluorine-methyl_2- (tetrahydro-2H-pyran_2_iloxy) ethyl] -4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.

FAB-MS (Pos); 447 (M ⁺ +1)

[0153] 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. 7- (Cyclohexylamino) -1-ethyl-6-fluoro-3- (1Η-imidazol-1-ylcarbonyl) quinolin-4 (1H) _one was obtained

NMR (CDCl) δ; 1.25-1.53 (m, 5H), 1.59 (t, J = 7.6Hz, 3H), 1.65- 1.76 (m, lH), 1.80-1.

 Three

 90 (m, 2H), 2.05-2.15 (m, 2H), 3.34_3.45 (m, lH), 4.22 (q, J = 7.6Hz, 2H), 4.57-4.66 (m, lH), 6.44 (d , J = 6.4Hz, lH), 7.04-7.05 (m, lH), 7.51_7.53 (m, lH), 7.99 (d, J = 12.0Hz, lH), 8. 12 (s, lH), 8.15 -8.16 (m, lH).

[0154] 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] amino} was prepared in the same manner as in Example 16 described later. 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 material.

[0155] Reference Example 234

 Ethyl {[(5-Amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-yl) carbonyl] amino} acetate

FAB-MS (Pos); 354 (M ⁺ +1)

[0156] 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-difluo-or 4-oxo-1,4 -Dihydroquinoline-3-yl] carbo} 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 material.

[0157] Reference Example 236

 Ethyl [5- (Acetylmethylamino) -1_Ethyl-6,7-Difluro-4-4 oxo-1,4-dihydroquinoline-3_yl] carboxylate

ESI-MS (Pos); 395 (M ⁺ +1) [0158] Reference Example 237

 (2-{[(9H-fluorene-9-ylmethoxy) carbonyl] amino} ethyl)) phosphonic acid is suspended in benzene and benzyl Ν, Ν'-dicyclohexylimide carbamate is added, followed by reflux conditions. Under stirring for 4 hours, dibenzyl (2 _ {[(9Η-fluorene_9_ylmethoxy) carbonyl] amino} ethyl) phosphonate was obtained.

FAB-MS (Pos); 528 (M ⁺ +1)

[0159] Reference Example 238

 The compound of Reference Example 237 was dissolved in DMF, and after diisopropylethylamine was prepared, the mixture was stirred at room temperature for 2 days to obtain dibenzyl (2-aminoethyl) phosphonate. Further, dibenzinole (2-aminoethyl) phosphonate oxalate was obtained by adding oxalic acid to the obtained phosphonate.

FAB-MS (Pos); 306 (M ⁺ +1)

[0160] Reference Example 239

 Add hydrazine monohydrate to methylene chloride solution of Jetyl [2- (1,3-Dioxo-1,3-dihydro-2H-isoindole-2-yl) -1,1-difluoroethyl] phosphonate at room temperature. The mixture was stirred for 1 hour to obtain Jetyl (2-amino-1,1-difluoroethyl) phosphonate.

ESI-MS (Pos); 218 (M ⁺ +1)

[0161] Reference Example 240

Jefferies Chill pyridine - dissolved 3- Iruhosuhonato to EtOH- acetic acid, platinum oxide was added, and stirred 3.4kgf / cm ² of hydrogen at 120 hours, Jechirupi Bae lysine - was obtained 3_ Iruhosuhonato

ES to MS (Pos); 222 (M ⁺ +1)

 In the same manner as in Reference Example 240, Reference Example 241 was produced using the corresponding raw material.

[0162] Reference Example 241

 Jetinore (piperidine-2-ylmethyl) phosphonate

FAB-MS (Pos); 236 (M ⁺ +1)

[0163] Reference Example 242

Benzyl ((3 & 1¾, 43 scale, 61¾, 6 & 1¾) -6-¾611_butyl (dimethyl) silyl] oxy} -2,2_dimethyl Pt-Carbonate (10%) is added to EtOH solution of tiltetrahydro-3aH-cyclopenta [d] [l, 3] dioxol_4-yl) power rubamate, and stirred overnight under hydrogen atmosphere, (3aRS, 4SR, 6RS , 6a RS) -6-{[tert-butyl (dimethyl) silyl] oxy} -2,2-dimethyltetrahydro-3aH-cyclopenta [d] [l, 3] dioxol-4-amine.

FAB-MS (Pos); 288 (M ⁺ +1)

[0164] Reference Example 243

 Platinum oxide and concentrated hydrochloric acid were stirred in a EtOH solution of jetyl (1-cyano-2-phenylethyl) phosphonate in a hydrogen atmosphere overnight to obtain jetyl [2-amino- (cyclohexylmethyl) ethyl] phosphonate.

FAB-MS (Pos); 278 (M ⁺ +1)

[0165] Reference Example 244

 To a pyridine-THF solution of benzinole (2-hydroxyethyl) methylcarbamate, add a THF solution of chloromethinole chloroformate under ice-cooling, and stir at room temperature for 14 hours. 2-[[(Benzyloxy) force carbonyl] (Methyl) amino] ethyl chloromethylol carbonate was obtained.

FAB-MS (Pos); 302 (M ⁺ +1)

[0166] Example 1

 400 mg of the compound of Reference Example 59 was suspended in 5.0 ml of DMF, and 350 mg of Ι, -carborubbis-1Η-imidazole was added at room temperature, followed by stirring at 100 ° C. for 20 hours. To the obtained reaction solution, 0.2 ml of triethylamine and 180 mg of glycine ethyl ester hydrochloride were successively added under ice cooling, and then 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 black mouth form. 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-dihydroquinoline-3-yl] carbo Diol} amino) acetate 408 mg was obtained.

[0167] 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, and water was extracted with cake form. The resulting organic layer is anhydrous After drying over sodium sulfate, the mixture was filtered and concentrated under reduced pressure. The resulting solid was recrystallized from EtOH to give ethyl ({[7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl. [Carbonyl} amino) acetate 219 mg.

[0168] Example 3

 After dissolving 400 mg of the compound of Reference Example 232 in 3.0 ml of DMF and adding a solution of 0-trimethylsilylolehydroxyreamine 150 mg in DMF 2.0 ml under ice-cooling, 50. Stirred at 0 for 5.5 hours. The reaction solution was concentrated under reduced pressure, 5.0 ml of MeOH was added, 4.0 ml of 1M HC1 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 after cooling to room temperature was washed with EtOAc and recrystallized with 80% aqueous acetic acid to give 7- (cyclohexylamino) -1-ethyl-6-fluoro-N-hydroxy_4_oxo- 41 mg of 1,4-dihydroquinoline-3-carboxamide was obtained.

[0169] Example 4

 300 mg of the compound of Example 56 was suspended in 5.0 ml of EtOH, and 1.0 ml of 3M HC1 aq was added under ice cooling, followed by stirring at 50 ° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, water was added, neutralized with 1M NaO H aq, and extracted with 10% MeOH-chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. By washing the resulting solid with EtOH, 7- (cyclohexylamino) -1-ethyl-6-fluoro-4-oxo_N-[(1RS, 2SR, 3RS, 4SR) -2,3, 4-trihydroxycyclopentyl] -1,4-dihydroquinoline-3-carboxamide 230 mg was obtained.

[0170] 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 black mouth form. 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_fluoroxy-4-oxo-1,4-dihydroquinoline-3- L] Carbonyl} amino) -5- [4_ (ethoxycarbonyl) piperazine-1-yl] _5_oxopentanoic acid 282 mg was obtained.

[0171] Example 6 300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, and 0.8 ml of 1M NaOH aq was added under ice cooling, followed by stirring at room temperature for 25 hours. Water was added to the reaction solution and neutralized with 1M HC1 aq. The precipitated solid was collected by filtration and washed with EtOH to give ({[7- (cyclohexylamino) -1-cyclopentyl-6-fluoro-4_oxo-1,4-dihydroquinolin-3-yl] Carbon} amino) acetic acid (263 mg) was obtained.

[0172] Example 7

 Compound of Example 44 To a solution of 1.106 g of black mouth form in 20 ml was slowly added trimethylsilane bromide (TMSBr) 2.23 ml under ice cooling, and the mixture was stirred for 30 minutes under ice cooling and at room temperature for 6 hours. The reaction solution 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 filtered off. 1M NaOH aq (10 ml), MeOH and water were added to this product, insolubles were filtered off, 1M HC1 aq (11 ml) was added, and the resulting precipitate was collected by filtration. Washed with 80% EtOH aq, [2-({[7- (cyclohexylamino) _1_ethyl _6_fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino ) Ethyl] phosphonic acid 841 mg was obtained.

[0173] Example 8

 250 mg of the compound of Example 374 was suspended in 2.0 ml of EtOAc, and 2.0 ml of 4M HCFEtO Ac solution was added under ice cooling, followed by stirring at room temperature for 4 days. The precipitated solid was filtered and washed with EtOAc to give ({[1-Ethyl-6-Fluoro-4--4-oxo-7- (piperidine-4-ylamino) -1,4-dihydroquinoline-3- 210 mg of [l] carbonyl} amino) acetic acid hydrochloride was obtained.

[0174] Example 9

 300 mg of the compound of Example 163 was suspended in 5.0 ml of THF, and 1,1′-carbonbis-1H-imidazole (200 mg) was added under ice cooling, followed by stirring 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 black mouthform. 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.

[0175] Example 10 210 mg of the compound of Example 161 was suspended in 5.0 ml of DMF, and 0.1 ml of ethoxycarborubiperazine, 130 mg of WSC-HC1 and 100 mg of 1_hydroxybenzotriazole were added in this order under ice-cooling, followed by 17 at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with black mouth form. The obtained organic layer was washed successively with saturated NaHCO 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_fluor-4_oxo_1,4-dihydroquinoline-3_yl] carbohydrate. 228 mg of (diamino) acetyl) piperazine-1-carboxylate was obtained.

[0176] Example 11

 530 mg of the compound of Example 196 was suspended in a mixed solvent of acetone 10 ml-7X3.0 ml, and N-methylmorpholine-N-oxide 0.30 g OsO (2.5 wt% in tBuOH) 2.0 ml was sequentially added at room temperature. After galling, the mixture was stirred at room temperature for 1 week. Water was added to the reaction mixture, and 2.0 g of sodium thiosulfate was collected at room temperature, followed by stirring 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-4-4-oxo-1,4-dihydroquinoline. 190 mg of 3-yl] carbonyl} amino) acetate was obtained.

[0177] Example 12

 423 mg of the compound of Example 72 was suspended in 5 ml of black mouth form and 5 ml of MeOH, and LiOH.H 0

126 mg was added and stirred at room temperature for 30 minutes. To the obtained reaction solution, 1.17 g of methyl-tobromo-todoxy-2,3,4-tri-0-acetyl-α-D-darcobilanoside uronate was added and stirred at room temperature for 1 hour. In addition, LiOH.H 0 126 mg and methyl-1-bromo-1-deoxy-2,3,4-tri-

○ 1.17 g of acetyl-hi-D-darcoviranoside uronate was added and stirred at room temperature for 6 hours. To the reaction solution, 15 ml of water, 5 ml of MeOH and 1.0 g of sodium carbonate were stirred at room temperature for 1.5 hours. After stirring 30 ml of water, 220 ml of MeOH and 1.0 g of sodium carbonate for 30 minutes at room temperature

The mixture was neutralized with acetic acid and stirred at room temperature for 12 hours. The resulting insoluble material was removed by filtration, and water was added to the filtrate, followed by washing with black mouthform. The resulting aqueous solution was concentrated under reduced pressure. The residue was purified by ODS column chromatography, ₃ _ _({[7 - (Kishiruamino cyclohexylene) - Echiru - ₆ _ Furuo port - ₄ - Okiso 1,4-dihydroquinoline-3-I le] carbo sulfonyl } Amino) Phenyl β -D-Darkovirano 168 mg of douronic acid was obtained.

[0178] Example 13

 The compound of Reference Example 233 (0.20 g) was dissolved in DMSO (5.0 ml), and cyclohexylmethylamine (0.2 ml) was prepared at room temperature, followed by stirring 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 te rt-butinole [({7-[(cyclohexylmethyl) amino] -1-ethyl-6-fluoro-4-oxo-1,4-dihydro Quinoline-3-yl} carbonyl) amino] acetate 0.23 g 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 filtering water was collected by filtration to give [({7- [(cyclohexylmethyl) amino] -1-ethyl-6-fluoro-4_. 102 mg of oxo-1,4-dihydroquinoline-3-yl} carbonyl) amino] acetic acid was obtained.

[0179] Example 14

 Compound of Example 210 In a suspension of 253 mg of THF in 10 ml of THF, 89 mg of sodium acetate, 55 μl of formaldehyde solution (37%), and 177 mg of sodium triacetoxyborohydride were prepared and stirred at room temperature for 3 hours. Add saturated NaHCO aq, extract with black mouth form, and wash with saturated brine.

 Three

 Purified. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain ethyl ({[7_ (cyclohexylamino) -6-fluoro-4-oxo-1- (1-methylpyrrolidine-3-yl) -1,4- 146 mg of dihydroquinoline-3-yl] force rubonylamino) acetate was obtained.

[0180] 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 solution was concentrated under reduced pressure, and MeOH was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the solid precipitated by filtering EtOH was collected by filtration to give [2-({[7_ (cyclohexylamino) -1-cyclopentyl-6-fluoro. -4_oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) ethyl] phosphonic acid hydrobromide 344 mg was obtained. [0181] Example 16

 345 mg of the compound of Reference Example 75 was suspended in 20 ml of methylene chloride, and 149 / il of triethylamine and 117 μΐ of isobutinole black formate were calorieated under ice cooling. After stirring for 1 hour, triethylamine 149 μ1 and glycine ethyl ester hydrochloride 138 mg were added, and the mixture was stirred at room temperature for 12 hours. Saturated NH CI aq was added and extracted with black mouth form. 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 washed with ethyl ({[7- (cyclohexylamino) -6-fluoro_4 -oxo-1_ (2,2,2-trifluoro). Cyl) -1,4-dihydroquinoline-3_yl] carbonyl} amino) acetate was obtained.

[0182] Example 17

 0.51 g of the compound of Example 200 was dissolved in 5.0 ml of sodium chloride and 0.5 ml of triethylenamine and 0.2 ml of methanesulfonyl chloride were sequentially added under ice cooling, followed by stirring for 30 minutes under ice cooling. Water was added to the reaction solution and extracted with black mouth form. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a mesyl form. The obtained mesinole body 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 solution and extracted with black mouth form. 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 solution and extracted with black mouth form. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain ethyl {[(l_ {2 _ [(tert-butoxycarbonyl) amino] ethyl} -7- (cyclohexylamino) -6 -fluoro-4_oxo- 1,4-Dihydroquinoline-3-yl) carbonyl] amino} acetate (494 mg) was obtained.

[0183] 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. 1M NaOH aq 1.15 in the reaction solution After adding ml, the insoluble material was filtered off through Celite. 1M HC1 aq 1.15 ml was added to the filtrate, and the resulting precipitate was collected by filtration and washed with water to give [2-({[7_ (cyclohexylamino) -1- (2,2-dimethyl-1,3 -Dioxane-5-yl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) ethinore] phosphonic acid (220 mg) was obtained.

[0184] Example 19

 415 mg of the compound of Example 200 was suspended in 5 ml of methylene chloride, and 400 μΐ of triethylamine and 111 μΐ of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 10 minutes. Water and saturated brine were added to the reaction solution, and the mixture was extracted with black mouth form. 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, and 948 μL of piperidine was collected, followed by stirring at 70 ° C. for 23 hours. The reaction solution was cooled to room temperature, water was removed, and extraction was performed with black mouth form. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography. Ethenole ({[7- (Cyclohexylamino) -6-Fluoro-4-oxo-1- (2-piperidine-1-yletinole)- 202 mg of 1,4-dihydroquinoline-3-yl] carbonyl} amino) acetate was obtained.

[0185] Example 20

 149 mg of the compound of Example 31 was suspended in 5 ml of black mouth form, triethylamine 75 / il was added under ice-cooling, and 30 μΐ of salty acetyl was collected. After stirring overnight at room temperature, water was added, extracted with black mouth form, 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-acetylethylpyrrolidine-3-yl) -7- (cyclohexylamino) -6-fluoro-4-1-oxo-1]. , 4-Dihydroquinoline-3-yl] carbonyl} amino) acetate (167 mg) was obtained.

[0186] Example 21

734 mg of the compound of Example 200 was suspended in 10 ml of salt methylene chloride, and 708 μl of triethylamine and 197 μm of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 15 minutes. Water and saturated brine were added to the reaction solution, and the mixture was extracted with black mouth form. 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 cyanate was added, and the mixture was stirred at 70 ° C. for 24 hours. Water in reaction, saturated Saline was added and extracted with black mouth form. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography.

Thus, 354 mg of ethyl ({[7- (cyclohexylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-ynole] carbonyl} amino) acetate was obtained.

[0187] 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 obtained residue was crystallized with EtOH-water, and {2-[({7_ (cyclohexylamino) -6-fluoro_1_ [2-hydroxy-1- (hydroxymethinole) ethyl] -4-oxo-1 , 4-Dihydroquinoline-3-yl} carbonyl) amino] ethyl} phosphonic acid 96 mg was obtained.

 Example 23

 Methyl (2R) _2 _ ({[7- (cyclohexylamino) -1- (1_ethylpropyl) -6-fluoro _4 -oxo-1,4-dihydroquinoline-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 solution in EtOAc was added, and the mixture was stirred for 30 minutes. The precipitate was then collected by filtration, and methyl (2R)- 2-({[7- (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino)- 156 mg of 3-pyridine-3-ylpropanoate hydrochloride was obtained.

[0188] Example 24

 0.5 ml of 2M NaOH aq was added to lmg of the compound of Example 44, and stirred at 100 ° C for 30 minutes.

 After adding 0.1 ml of 2-propanol and stirring at 100 ° C. for 12 hours, 1 ml of 1M HC1 aq was added and the resulting precipitate was collected by filtration. Washed with Jetyl ether, Ethyl hydrogen [2-({[7_ (Cyclohexylamino) -1_Ethyl _6_Fluoro-4, 4-oxo-1,4-Dihydroquinoline-3_yl] Carbonyl} Amino) etinore] phosphonate 7 mg was obtained.

[0189] 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 black mouth form, 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 to obtain ethyl ({[1_ (1_ Benzylpyrrolidine-3-yl) -7- (cyclohexylamino) -6-fluoroxy-4-oxo-1,4-dihydroxyquinoline-3-yl] carbonyl} amino) acetate 174 mg was obtained. .

[0190] Example 26

 183 mg of the compound of Example 220 was suspended in 20 ml of black mouth form, and 1.35 ml of trimethylsilane bromide was added under ice cooling, followed by stirring 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, saturated NaHCO aq

 3 Insoluble material was collected by filtration. Add saturated NaHCO aq to this, extract with black mouth form, 1

 Three

 Washed with M HC1 aq, saturated NaHCO aq, and saturated brine. Organic layer with anhydrous sodium sulfate

 Three

 After being dried over, it was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, and ethyl [({7- (cyclohexylamino) -6-fluoro-4-oxo-1-[(1RS, 2SR, 3RS, 43¾_2,3,4 -Trihydroxycyclopentyl] -1,4_dihydroquinoline_3_yl} carbonyl) amino] acetate 54 mg was obtained.

[0191] Example 27

 Compound of Example 15 743 mg, tetraptyl ammonium hydrogensulfate 226 mg, sodium iodide 102 mg, acetonitrile 10 ml, 1,8-diazabicyclo [5.4 · 0] _7-undecene 720 1, chloromethyl bivalate 575 μ μ was removed and stirred at 75 ° C for 65 hours. Water was added, extracted with EtO Ac, and washed with water, saturated NaHCO aq, and saturated brine. Organic layer with anhydrous sulfuric acid mug

 Three

 After drying over Nesym, it was filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography, washed with jetyl ether, and bis {[(2,2-dimethylpropanoyl) oxy] methyl} [2-({[7- (cyclo Hexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) ethyl] phosphonate 378 mg was obtained.

[0192] 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 distilling off the solvent under reduced pressure, 1M HC1 aq was added, and the resulting precipitate was collected by filtration to give 2 _ ({[7_ (cyclohexylamino) -ethylpropyl) -6-fluoro-4_oxo-1,4- Dihydroquinoline-3-yl] carbonyl} amino) -2-methylpropionic acid 270 mg was obtained.

[0193] Example 29 148 mg of the compound of Example 31 was suspended in 5 ml of black mouth form, 75 μΐ of triethylamine was added, the mixture was cooled to −45 ° C., and 32 μ1 of methanesulfonyl chloride was added. After gradually warming up and stirring at room temperature overnight, water was added, extracted with black mouth form and washed with saturated saline. 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-l- [1- (methylsulfonyl) pyrrolidine-3-yl] -4-oxo- 138 mg of 1,4-dihydroquinoline-3-yl} carbonyl) amino] acetate was obtained.

[0194] Example 30

 0.40 g of the compound of Example 17 was suspended in 5.0 ml of EtOH and 1.1 ml of 1M NaOH aq was added under ice cooling, followed by stirring 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 3.0 ml of concentrated hydrochloric acid was added under ice cooling, the mixture was stirred at 50 ° C. for 6 hours. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration. ({[1- (2-Aminoethyl) _7-(cyclohexylamino) -6-fluoroxy-4-oxo-1,4-dihydro 0.15 g of quinoline-3-yl] carbonyl} amino) acetic acid hydrochloride was obtained.

[0195] Example 31

 Saturated NaHCO aq, water and EtOH were added to 1 g of the compound of Example 210 and extracted with black mouth form.

 Three

 did. 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, 750 mg of 4-dihydroquinolin-3-yl] carbonyl} amino) acetate was obtained.

[0196] Example 32

 2 ml of 6M HC1 aq was added to 50 mg of the compound of Example 241 and stirred at 80 ° C for 1.5 hours, and then 2 ml of 6M HC1 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 recrystallization from EtOH, [({7- (cyclohexenoreamino) -6-fluoro_1_ [2-fluoro-1_ (fluoromethyl) ethyl] -4-oxo-1,4-dihydroquinolin-3-yl} 18 mg of forceful sulfonyl) amino] acetic acid was obtained.

[0197] Example 33

52 mg of the compound of Example 348 was suspended in 1 ml of DMSO, 46 μl of triethylamine, 165 μl of 2.0Μ dimethylamine THF solution was added, and the mixture was stirred at 100 ° C for 24 hours. Settling caused by adding water Tono was collected by filtration. Dissolve this in ethyl acetate, water, saturated NH CI aq, saturated saline

 Four

 Washed. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to obtain ethyl ({[7- (cyclohexylamino) -5- (dimethylamino) -1- (1_ethylpropyl) -6_fluoroxy-4-oxo-1, 43 mg of 4-dihydroquinoline_3-yl] carbonyl} amino) acetate was obtained.

[0198] Example 34

 The compound of Reference Example 235 (53 mg) was dissolved in DMSO (1.5 ml), and cyclohexylamine (31 μΐ) 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_ (acetylylamino) -7- (cyclohexenoreamino) -1-ethyl-6-fluoro-4_oxo-1,4-dihydroquinoline- 51 mg of 3-yl] carbonyl} amino) acetate was obtained.

[0199] Example 659

 After adding 8 ml of thionyl chloride to 800 mg of the compound of Example 644 under ice cooling, the mixture was heated to reflux for 30 minutes and concentrated under reduced pressure. A solution of the obtained residue in 3 ml of methylene chloride was added to a solution of 0.44 g of phenol and 0.78 ml of triethylamine in 2 ml of methylene chloride under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography and recrystallized from hexyl monoacetate to give diphenylenole [2-({[7-(cyclohexylamino) -1 There was obtained 407 mg of-(1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinolin-3-yl] carbonyl} amino) -1,1-difluoroethyl] phosphonate.

[0200] Example 665

To 250 mg of the compound of Example 644, 5 ml of EtOH and 0.4 ml of a sodium ethoxide / EtOH solution (20 wt%) were added and stirred at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. Acetonitrile (3 ml) and pivalic anhydride (1 ml) were added to the resulting residue, and the mixture was stirred at room temperature for 5 days. The reaction solution is concentrated under reduced pressure, 1 ml of acetonitrile and 10 ml of jetyl ether are added to the resulting residue, and the resulting insoluble matter is collected by filtration, washed with jetyl ether, and washed with sodium 2,2-dimethylpropyl. Panoyl [2 _ ({[7- (Cyclohexylamino) -ethylpropyl) -6-Fluoroguchi-4-oxo-1,4-dihydroquinoline-3_yl] carbol} amino)) _1, 1 -Difluoroethyl Phosphonate 149 mg was obtained.

[0201] Example 666

 To 300 mg of the compound of Example 644, 5 ml of thionyl chloride and 1 drop of DMF were added, heated to reflux for 30 minutes, and then concentrated under reduced pressure. A 5 ml solution of the resulting residue in methylene chloride was added to a mixed solution of 2.90 ml of 2M ethylamine / THF solution and methylene chloride (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 14.5 hours. Concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography, recrystallized with EtOH-EtOAc, and N- {2- [bis (ethylamino) phosphoryl] -2,2-difluoroethyl} _7- 58 mg of (cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro_4-oxo-1,4-dihydroquinoline-3-carboxamide was obtained.

[0202] Example 673

 300 mg of the compound of Example 644 was dissolved in 1.2 ml of 1M NaOH aq, and a solution of 21.7 mg of silver nitrate in 3 ml of water was prepared at room temperature, followed by stirring at room temperature for 15 minutes. Insoluble material was collected by filtration and washed with water to obtain 393 mg of silver salt. Of this, 300 mg was suspended in 8 ml of toluene, 140 μL of chloromethyl bivalate was added at room temperature, and the mixture was stirred at 80 ° C. for 7 hours. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized from hexane-ethyl acetate to give bis {[(2,2-dimethylpropanoyl) oxy] methyl} [2-({[7- ( Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl] carbonyl} amino) -1,1-difluorochinole] phosphonate 189 mg was obtained.

 Tables 16 to 47 below show the structures and physical data of the example compounds.

[0203] [Table 16]

Blasphemy

18]

19] Blasphemy

06 £ 00ε //: 900ζ1 £ ε∞ OAV

80s

twenty two]

twenty four]

twenty five]

26]

Ex Syn R ¹ R ² R ³ R ⁴ Data

34 34 NHAc FH C0 ₂ Et FAB-MS (Pos); 475 (M ⁺ +1) 23 1 HHH C0 ₂ Et FAB-MS (Pos); 400 (M ⁺ +1) 24 1 H Br H C0 ₂ Et FAB -MS (Pos); 478,480 (M ⁺ + 1) 25 6 HHH CO, H FAB- S (Pos); 372 (M ⁺ +1) 26 6 H Br H C0 ₂ H FAB-MS (Pos); 450,452 ( M ⁺ +1) 27 1 H Me H C0 ₂ Et FAB-MS (Pos); 414 (M ⁺ +1) 28 6 H Me H C0 ₂ H FAB- S (Pos); 386 (M ⁺ +1) 29 1 HF CI C0 ₂ Et FAB-MS (Pos); 452 (M ⁺ +1)

330 6 HF CI C0 ₂ H FAB- S (Pos); 424 (M ⁺ +1)

331 1 H CI H C0 ₂ Et FAB-MS (Pos); 434 ( ⁺ +1)

332 6 H CI H CO, H FAB-MS (Pos); 406 (M + 1)

333 1 HFF CO Et FAB-MS (Pos); 436 (M ⁺ +1)

334 6 HFF CO, H FAB-MS (Pos); 408 (M ⁺ +1)

335 16 FFHC ○ ₂ Et FAB-MS (Pos); 436 (M ⁺ +1)

336 6 F F H CO, H FAB-MS (Pos); 408 (M +1)

337 16 OMe FH C0 ₂ Et ESI-MS (Pos); 448 (M ++ 1)

338 6 OMe FH CO, H FAB-MS (Pos); 420 (M ⁺ +1)

339 16 NH, FH C0 ₂ Et ESI-MS (Pos); 433 (M ⁺ +1)

340 6 NH ₂ FH C0 ₂ H FAB-MS (Pos); 405 (M ⁺ +1)

341 16 NHMe FH C0 ₂ Et FAB-MS (Pos); 447 ( ⁺ +1)

342 6 NHMe FH C0 ₂ H FAB-MS (Pos); 419 (M +1)

343 16 NH (cHex) FH C0 2 Et FAB- S (Pos); 515 (M + + 1)

344 6 NH (cHex) FH C0 ₂ H FAB-MS (Pos); 487 (M ⁺ +1)

345 6 NHAc FH C0 ₂ H FAB-MS (Pos); 447 (M ⁺ +1) 27]

[0216] [Table 29]

[0217] [Table 30]

[0218] [Table 31]

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[0238] Tables 52 to 80 show other structures of the compound represented by the formula (I). 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.

[0239] [Table 52]

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Industrial applicability

 Since the quinolonic acid derivative represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent platelet aggregation inhibitory action, it is a pharmaceutical, particularly a platelet aggregation inhibitor, P2Y12 inhibitor. Useful as an agent. Therefore, the compound of the present invention is a cardiovascular disease closely related to blood clot formation due to platelet aggregation, such as unstable angina pectoris, acute myocardial infarction and its secondary prevention, hepatic artery bypass surgery, PTCA surgery or stent Ischemic diseases such as reocclusion and restenosis after implantation, promotion of hepatic artery thrombolysis and prevention of reocclusion; transient cerebral ischemic attack (TIA) cerebral infarction, subarachnoid hemorrhage (vascular spasm), etc. It is useful as a preventive and Z or therapeutic agent for disorders, peripheral arterial diseases such as chronic arterial occlusion, and the like, and as an adjunct in cardiac surgery or vascular surgery.

Claims

 The scope of the claims

 A quinolonic acid derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof.

 [Chemical 17]

[The symbols in the formula have the following meanings.

Y: CR ⁶ or N.

R ⁶ : —H, halogen, lower alkyl or halogeno lower alkyl.

R ² : lower alkyl, cycloalkyl, aryl or hetero ring each optionally substituted.

R ³ : Halogen.

R ⁴ : cycloalkyl.

R ⁵ : -H, -OH or halogen.

 R ": -H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.

R ¹² : lower alkyl which has at least one substituent selected from the P group and may further have a substituent.

P group: -CO R -SO R _P (0) (〇H) (R ^d ), -P (0) (R ^b ) (R ^d ), -OP (0) (〇H) (R ^d ) and -OP (0) (

R ^b ) (R ^d ).

R ^e : _R ^xa , lower alkylene-0 (CO) R ^x , lower alkylene-0 (C 0) OR ^x , lower alkylene-S (

C 0) R ^X , lower alkylene _S (CO) OR ^x or lower alkylene-SS-R ^X.

R ^b : the same or different from each other, -OR ^a , -NH, _NHR ^a , -N (R ^a ), -〇 (C〇) R ^a or a cyclic amino group.

R ^d : the same or different from each other, —OR ^e , —NH, —NHR ^a , —N (R ^a ), —〇 (CO) R ^a or a cyclic amino group.

However, in the P group -P (0) (R ^b ) (R ^d ) and -0P (0) (R ^b ) (R ^d ), R ^b and R ^d are integrated, It is possible to form a group represented by L.

 L: _0-lower alkylene-0-, -0-lower alkylene-NH-, -0-lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, -NH-lower alkylene-N (lower Alkyl)-, -N (lower alkyl) -lower alkylene-N (lower alkyl)-, _0_lower alkylene-0-CO

 2

-Lower alkylene-0-, -〇-Lower alkylene- o-c〇-, -〇-Areyl- c〇 -or

twenty two

Heterocycle -c0- may be formed.

 2

However, -0-lower alkylene in -0_, -0-lower alkylene-NH-, -〇_lower alkylene-N (lower alkyl)-, -NH-lower alkylene-NH-, -NH-lower alkylene- N (lower alkyl)-, -N (lower alkyl) -lower alkylene-N (lower alkyl)-, -0-lower alkylene-0-CO -lower alkylene-0-, -0-lower alkylene-0-CO- Lower al

twenty two

Killen portion Yogu -0- substituted by a group selected from Group G ^1, respectively Ariru - C_〇 - and - 0- heterocyclic - CO - selected from G ² group respectively hetero ring Ariru and to the Is

twenty two

It may be substituted with a group.

R ^a : Identical or different from each other, _R ^X , lower alkylene-0 (C0) R ^x , lower alkylene-0 (C0) 0R ^x , lower alkylene-S (C0) R ^x , lower alkylene-S (C0) 0R ^x or lower alkylene-SS-R ^x .

R ^x : lower alkyl, cycloalkyl, aryl or heterocycle.

However, in the above, lower alkyl may be substituted with a group selected from group G ¹ , and cycloalkyl, aryl and heterocycle may each be substituted with a group selected from group G ² .

R ^xa : lower alkyl substituted with a group selected from group G ³ (provided that -CO -lower alkyl

 2

Excluding lower alkyl substituted only with. ), _CH ((aryl substituted with (_0 (C0) -lower alkyl))-lower alkylene-CO-lower alkyl, cycloalkyl, aryl or

2

Is a hetero ring.

Provided that the cycloalkyl, aryl and heterocycles in R ^xa are each substituted with a group selected from Group G ² .

G ¹ group: halogen, -0H, -0-lower alkyl, -NH, -NH-lower alkyl, -N (lower alkyl)

2

Kill), -N (lower alkylene-0H), -N (lower alkyl) -C0 -lower alkylene-ary -CO H, -CO -lower alkyl, -O (CO) -lower alkyl, -CONH, -CONH-lower alkyl, -CON (lower alkyl), aryl and heterocycle.

However, the aryl and heterocycles in the G ¹ group may each be substituted with a group selected from the G ² group.

G ² group: halogen, oxo, lower alkyl, halogeno lower alkyl, -OH, _0_lower alkyl, _0 -halogeno lower alkyl, _0 (CO) -lower alkyl, -CO H, -CO -lower alkyl, lower Alkylene-OH, lower alkylene-〇-lower alkyl, lower alkylene-NH

Lower alkylene-NH-lower alkyl, lower alkylene-NH-aryl, lower alkylene-N (lower alkyl), lower alkylene-N (aryl) and lower alkylene-N (lower alkyl) -aryl.

G ³ group: -N (lower alkylene-OH), -〇 (CO) _lower alkyl, -CO -lower alkyl, aryl substituted with a group selected from group G ² (however, aryl substituted only with halogen) heterocycle substituted with a group selected from the excluded) and G ² groups.

However, NR "R ¹² becomes a isomer, has at least one substituent selected from the P group, and further has a substituent to form a cyclic amino group. You can do it.

However, when Y represents CR ⁶ , R ² and R ⁶ may be combined to form lower alkylene or lower alkenylene.

However,

Bis {[(2,2-Dimethylpropanoyl) oxy] methyl} [2-({[7- (Cyclohexylamino) -1-succinyl pentyl-6-fluo-ortho-4-oxo-1,4- Dihydroquinoline-3-yl] carbonyl} amino) chinole] phosphonate,

Pivalic acid {[[2 _ ({[7- (Cyclohexylamino) _1] -cyclopentyl-6_fluro-4-oxo-1,4-dihydroquinoline-3_yl] carbonyl} amino) ethyl] ( Hydroxy) phosphoryl] oxy} methylol, and

Pivalic acid ({(benzyloxy) [2-({[7- (cyclohexylamino))-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3_yl] carbonyl } Amino) ethyl] phosphoryl} oxy) methinole

except for. ] The compound according to claim 1, which is represented by formula (Ia).

[Wherein Y, R ² , R ³ , R ⁴ , R ⁵ , R ^b , R \ R ^d and L have the meanings described in claim 1, and other symbols have the following meanings:

R ^Ua : —H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.

R ^12a : a lower alkyl having at least one substituent selected from the Pa group and further having a substituent.

Pa Group: - CO R -P (0) ( 〇_H) (R ^d) and - P ^{(〇) (R b) (R d} ). However, in -P (◯) (R ^b ) (R ^d ) in the Pa group, R ^b and R ^d may be combined to form L.

However, NR ^Ua R ^12a is united and has at least one substituent selected from the Pa group, and further has a substituent and may form a cyclic amino group. Anyway. ]

 The compound according to claim 2, which is represented by the formula (I_b).

[Chemical 19]

[Wherein Y, R R R R R R ”and L represent the meanings described in claim 1, and the other symbols represent the following meanings.

R ^Ub : —H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally substituted, amino.

R ^12b : a lower alkyl having a substituent selected from at least one Pb group and further having a substituent. Pb group: -CO R -P (0) (OH) (R ^d ) and -P (0) (R ^d ). However, in -P (0) (R ^d ) of the Pb group, the two R ^d may be combined to form a group represented by L.

However, NR ^Ub R ^12b is united and has at least one substituent selected from the Pb group, and further has a substituent, or may form a cyclic amino group, Anyway. ]

 The compound according to claim 3, which is represented by the formula (I_c).

 [Chemical 20]

[Wherein Y, R ² , R ³ , R ⁴ , R ⁵ and L have the meanings described in claim 1 and the other symbols have the following meanings]

R ^lle : —H, optionally substituted lower alkyl, or optionally substituted lower alkyl, substituted, optionally, or amino.

R ^12e : a lower alkyl which has a substituent selected from at least one Pc group and may further have a substituent.

Pc groups: _C_〇 ^{R ea, - P (0)} ( 〇_H) (R ^e) and - P (〇) (R ^e).

However, in _P (0) (R ^e ) of the Pc group, two R ^e may be combined to form a group represented by L.

R ^e : the same or different from each other, -0-aryl, -0-lower alkylene- (aryl substituted with -CO lower alkyl and / or -o (co) -lower alkyl), -0-lower alkylene -0 (CO) -R ^xb , -0-lower alkylene-0 (CO) 0-R ^xb , -0-CH (aryl substituted with (-0 (CO) _lower alkyl)) -lower alkylene-CO -Lower alkyl, -0-lower alkylene-s (co) -lower alkyl, -0-lower alkylene-s (co) o-lower alkyl, -0-lower alkylene-SS-lower alkyl, -0-lower alkylene -SS-lower alkylene-0H, -NH, -NH (lower alkyl), -N (lower alkyl), -NH-lower alkylene-CO H, -NH-lower alkylene-CO-lower alkyl, -o (co ) -Lower alkyl, cyclic amino group, -0-heterocycle or -0-lower alkylene- (heterocycle substituted with lower alkyl and / or oxo) However, in R ^e, -O- lower alkylene - 0 (CO) _ lower alkylene portion content of lower alkyl, and, -0- Ariru portion of Ariru is - CO - lower alkyl or - 0 (CO) _ lower § alkyl It is replaced with les, even les.

R ^ea : the same or different from each other, aryl, lower alkylene _ (-C 0 lower alkyl and

/ Or -0 (C0) -lower alkyl substituted aryl), lower alkylene-0 (CO) -R ^xb , lower alkylene-0 (CO) 0_R ^xb , -CH ((_0 (CO) -lower alkyl) -Lower alkylene-CO-lower alkyl-, lower alkylene _S (C0) -lower alkyl, lower alkylene _S (CO) 〇_lower alkyl, lower alkylene-ss-lower alkyl, lower alkylene- SS-lower alkylene-0H, _ (CO) _lower alkyl, heterocycle or lower alkylene- (heterocycle substituted with lower alkyl and Z or oxo).

However, this is the lower alkylene part of lower alkylene-0 (C〇) -lower alkyl.

And aryl may be substituted with -CO-lower alkyl or -o (co) -lower alkyl.

R ^xb : lower alkyl, cycloalkyl, aryl or heterocycle. However, in R ^xb , the lower alkyl may be substituted with a substituent of group G ⁴ , and the aryl may be substituted with -0 (CO) _lower alkyl.

G ⁴ group: -NH, -NH (lower alkyl), -N (lower alkyl), -N (lower alkylene-OH),-

N (lower alkyl) -CO -lower alkylene-aryl, heteroaryl. However, the aryl may be substituted with -o (co) -lower alkyl, and the heterocycle may be substituted with lower alkyl.

However, it becomes an NR ^lle R ¹² S-form, has at least one substituent selected from the Pc group, and further has a substituent, or may form a cyclic amino group. It ’s okay. ]

 The compound according to claim 4, which is represented by the formula (I_d).

[Chemical 21]

[Y, R ² in the formula,

R ⁴ and R ⁵ have the meanings described in claim 1, and other symbols have the following meanings.

R _^12d: - (halogen or - CO-lower alkylene may be substituted by ^{H) -C (0) R f} , - ( C lower alkylene which may be substituted with androgenic) -P (0) (OH) (R ^f ) or-(lower alkylene optionally substituted with a norogen) -P (0) (R ^f ).

R ^f : _0_lower alkylene-OC (0) _lower alkyl, -0-lower alkylene-OC (〇) 0-lower alkyl, -0-lower alkylene _OC (〇) 0-cycloalkyl or -0_lower alkylene -(5-methyl-2-oxo-1,3-dioxol _4 -yl). ]

 6. The compound according to claim 5, which is represented by the formula (I_e).

 [Chemical 22]

[Y in the formula,

R ⁴ and R ⁵ have the meanings described in claim 1, R ^f has the meaning described in claim 5, and the other symbols have the following meanings.

R ^12e:-( substituted with halogen, may be, lower alkylene) -P (0) (OH) (R ^f ) or-(lower alkylene optionally substituted with halogen) -p ( 0) (R ^f ). ]

Pivalic acid {[[2-({[7- (Cyclohexylamino) -1- (1-ethylpropyl) -6-fluoroxy-4-oxo-1,4-dihydroquinoline-3-yl] carbo Diamino) -1,1-difluoroethyl] (hydroxy) phosphoryl] oxy} methyl,

 [2 _ ({[7- (Cyclohexylaminoethylpropyl) -6-fluoro-4_oxo-1,4-dihydroquinoline-3_yl] carbol} amino)) _1,1-difluoroethyl] phosphonate hydrogen [ (Ethoxycarbonyl) oxy] methyl,

 [2 _ ({[7-(Cyclohexylaminoethylpropyl) -6-fluoro-4_oxo-1,4-dihydroquinoline-3_yl] carbol} amino)) _1,1 -difluoroethyl] phosphonic acid hydrogen ( 5-methyl-2-oxo-1,3-dioxol-4-yl) methyl, and

Pivalic acid {[[2-({[7- (Cyclohexylamino) -1-cyclopentyl-6-fluoro-4-oxo-1 , 4-Dihydroquinoline-3-yl] carbonyl} amino) -1,1-difluoroethyl] (hydroxy) phosphoryl] oxy} methyl

 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of potent forces.

 [8] A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[9] The pharmaceutical composition according to claim 8, which is a platelet aggregation inhibitor.

[10] The pharmaceutical composition according to claim 8, which is a P2Y12 inhibitor.

[11] Use of the compound according to claim 1 as a platelet aggregation inhibitor.

[12] Use of the compound according to claim 1 as a P2Y12 inhibitor.

[13] Use of the compound according to claim 1 for producing a platelet aggregation inhibitor.

[14] Use of the compound according to claim 1 for producing a P2Y12 inhibitor.