CN101622240A - Fused Substituted Aminopyrrolidine Derivatives - Google Patents

Abstract

The present invention provides a quinolone synthetic antibacterial agent having excellent characteristics as a drug having strong antibacterial activity not only against gram-negative bacteria but also against gram-positive cocci (including those having low sensitivity to quinolone antibacterial agents), and also exhibiting high safety and excellent pharmacokinetic characteristics. The present invention also provides a compound represented by formula (I) or a salt thereof or a hydrate thereof. In particular, the present invention provides quinolone derivatives of formula (I), wherein the substituent R⁶And R⁷Taken together with the carbon atoms to which they are attached form a cyclic structure which may contain an oxygen atom as a ring constituent atom, said cyclic structure forming a 5-4, 5-5 or 5-6 fused bicyclic pyrrolidinyl substituent which is bound to a quinolone parent skeleton Q containing a pyridobenzoxazine structure.

Description

Fused Substituted Aminopyrrolidine Derivatives

Background of the invention

field of invention

The present invention relates to quinolones used as medicine, veterinary medicine, fishery medicines or antibacterial preservatives.

Description of related technologies

Since the discovery of norfloxacin, quinolone synthetic antibacterials (including those with a pyridobenzoxazine skeleton) with improved antibacterial activity and pharmacokinetic properties have been developed to be effective against almost all systemic infections chemotherapy drugs, and many of them are currently used clinically (see JP 61-282382 or JP 63-45261 and Clinical Microbiology and Infection, Vol. 11, No. 4, p. 256 (2005)).

However, in recent years, the number of bacterial species with low susceptibility to quinolone synthetic antimicrobials has been clinically increasing. For example, the number of bacterial species resistant to drugs other than quinolone synthetic antibacterials, so-called multidrug-resistant bacteria, such as Gram-positive cocci, including β-lactams Staphylococcus aureus (methicillin-resistant Staphylococcus aureus: MRSA) and pneumococci (penicillin-resistant Streptococcus pneumoniae: PRSP) with low antibiotic susceptibility; and antimicrobials to aminoglycosides Enterococci with low susceptibility (vancomycin-resistant enterococci: VRE) and also low susceptibility to quinolone synthetic antibacterials. Bacterial infections caused by such resistant Gram-positive bacteria are known to be often serious (fatal) and difficult to treat. Therefore, drugs more effective against Gram-positive cocci are particularly needed clinically (see Drugs, Vol. 66, No. 6, p. 751 (2005)).

On the other hand, the antibacterial activity of quinolone-based synthetic antibacterial compounds produced in recent years is much higher than those of the previous ones (see Japanese Patent Laid-Open No. 2-231475 or Japanese Patent Laid-Open No. 3-95176). However, many of these quinolone compounds with high antibacterial activity can cause side effects not observed in previous quinolone synthetic antibacterial drugs based on their physiological and pharmacological effects.

Examples of side effects of quinolone synthetic antibacterials include frequently reported side effects such as convulsions, central action (minor central nervous system disturbances such as shaking, headache, and insomnia; and serious side effects, such as fatal convulsive seizures) and phototoxicity (photosensitivity); and side effects disclosed in recent years, such as hepatotoxicity (severe allergic hepatitis), cardiotoxicity (fatal arrhythmia due to abnormal ECG, observed as QT or QTc prolongation), delayed drug eruption (rash), and abnormal blood glucose levels (see Hiroyuki Kobayashi (ed.), Clinical Application of NewQuinolone Agents, Iyaku (Medicine and Drug) Journal Co., Ltd.; Drugs, Vol. 62, No. 1, p. 13 (2002); Toxicology Letters, Vol. 127, p. 269 (2002); Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)); and International Journal of Antimicrobial Agents, p. 23 Vol. 5, p. 421 (2004)).

Among these side effects, the clinical onset of cardiotoxicity has been particularly problematic in recent years. Significant QT or QTc prolongation has been reported for some commercially available synthetic quinolone antimicrobials (eg, gpafloxacin, sparfloxacin, moxifloxacin, gatifloxacin, and gemifloxacin), as well as Certain serious problems (fatal heart rhythm problems caused by abnormal EKG). The onset of severe allergic hepatitis accompanying liver transplantation (trovafloxacin: see Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)) and abnormal blood sugar levels including fatal hypoglycemia (gatifloxacin : See International Journal of Antimicrobial Agents, Volume 23, No. 5, page 421 (2004)) and other serious side effects are also clinical problems. In addition, in clinical trials, delayed drug eruption (rash) due to repeated administration of quinolones has also been reported (Gatifloxacin: See Clinical Infectious Diseases, Vol. 41, p. 1269 (2005)). Under these circumstances, the administration of certain quinolone synthetic antibacterial drugs is restricted, and the development and use of certain quinolone synthetic antibacterial drugs as human medicines has been prohibited. That is, some quinolone synthetic antibacterials have been observed to have strong antibacterial activity, but are less suitable for use as drugs in view of side effects.

Therefore, there is a need for safer quinolone synthetic antibacterials for human use that have only minimal side effects such as convulsions, central effects, and phototoxicity in combination with NSAIDs, which are considered to be common side effects (photosensitivity); and cardiotoxicity, hepatotoxicity, delayed drug eruption (skin rash), and abnormal blood sugar levels that have become clinical problems in recent years. Therefore, there is a need to develop compounds conceptually different from conventional compounds which have high antibacterial activity but cause side effects and cannot be used as medicines. That is to say, there is a need for quinolones having both strong antibacterial activity and high safety (see The Japanese Journal for History of Pharmacy, Vol. 38, No. 2, p. 161 (2003)).

It is known that the antibacterial activity, pharmacokinetic properties and safety of quinolone synthetic antibacterial drugs are affected by the substituent structure at each position of the quinolone skeleton, especially by the 7-position (corresponding to 10 of the pyridobenzoxazine skeleton). -position) on the influence of substituent structure (see, for example, Clinical Microbiology and Infection, Vol. 11, No. 4, p. 256 (2005)).

The distinctive feature of the compounds of the present invention is that they have a substituent represented by the following formula 1 on the 7-position of the quinolone parent skeleton:

[Formula 1]

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined in claim 1 . That is to say, the 7-position substituent of the compound of the present invention has a fused bicyclic amine structure formed by condensing a pyrrolidine ring with a ring structure formed by ^R6 and ^R7 and the carbon to which they are attached. Atoms are bonded together, and the fused bicyclic amine structure also has an amino group at the bridgehead position. As the quinolone derivative substituted with a substituent at the 7-position having such a structure, the following compounds are known.

For example, Japanese Patent Laid-Open No. 64-56673 discloses pyridonecarboxylic acid derivatives represented by the following general formula 2:

[Formula 2]

Wherein R represents a lower alkyl group, a halogenated lower alkyl group, a lower alkenyl group, a cycloalkyl group or a phenyl group which may have a substituent; X represents a nitrogen atom or C-A, wherein A represents a hydrogen atom or a halogen atom; Y represents a hydrogen atom or Halogen atom; Z represents the group represented by the following formula 3:

[Formula 3]

Wherein R ₁ represents a hydrogen atom, a lower alkoxycarbonyl group or an acyl group which may be substituted by a halogen atom; two of R ₂ , R ₃ , R ₄ and R ₅ are directly combined or linked through a lower alkyl chain to form a ring, and The remaining two of R ₂ , R ₃ , R ₄ and R ₅ each represent a hydrogen atom; n represents 0 or 1, provided that R ₂ and R ₃ are a chemical bond when combined with each other. The definitions of substituents etc. in the compound represented by Formula 2 do not apply to the compound of the present invention although they use the same symbols. However, Japanese Patent Laid-Open No. 64-56673 does not specifically disclose quinolones consistent with the compound of the present invention (wherein R ₄ and R ₅ in Formula 3 are combined to form a 4-7 membered ring and n=0).

EP-A-343524 discloses pyridone carboxylic acid antibacterial drugs represented by the following general formula 4:

[Formula 4]

Wherein R ₁ is hydrogen, hydroxyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, oxo, halogen or amino, which may optionally be replaced by C ₁ -C ₄ alkyl and/or C ₁ - C ₄ alkanoyl substituted; R ₂ is azido, hydroxyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkanoyl or amino, which can be optionally replaced by C ₁ -C ₄ alkyl and/or C ₁ -C ₄ alkanoyl substituted; A is the quinolone structure represented by the following formula 5:

[Formula 5]

R ₃ is hydrogen or carboxyl protecting group; R ₄ is C ₁ -C ₄ alkyl, C ₂ -C ₅ alkenyl, C ₃ -C ₅ cycloalkyl, monofluorophenyl or difluorophenyl, or five-membered or a six-membered heterocyclic ring, which may optionally be substituted by halogen and/or C ₁ -C ₄ alkyl; R ₅ is hydrogen, amino, hydroxyl, or C ₁ -C ₄ alkoxy; R ₆ is halogen; X is CH -(C ₁ -C ₄ alkyl), C=CH ₂ , NH or N-(C ₁ -C ₄ alkyl); Z is CQ or N; Q is hydrogen, C ₁ -C ₄ alkoxy, halogen , C ₁ -C ₄ alkyl or cyano; m is an integer of 0 or 1; n and p are each an integer of 1-3. However, as specific compounds related to the compounds of the present invention, EP-A-343524 only discloses quinolonecarboxylic acid derivatives represented by the following formula 6, that is to say, m is 0 in the derivatives, p is 1, and the substituent R ₂ is an amino group at the bridgehead position of the bicyclic amine:

[Formula 6]

Furthermore, EP-A-343524 does not disclose a compound having a halocyclopropyl group at the 1-position, which is a typical example of the compound of the present invention. In the compound represented by formula 6 disclosed in EP-A-343524, the structure of the 7-position substituent is (1R ^* , 5S ^* )-configuration. This compound is a so-called cis-racemate, and EP-A-343524 does not describe the antibacterial activity of the optical isomer. Furthermore, EP-A-343524 does not describe the safety of the disclosed compounds. In terms of efficacy and safety, stereochemically single compounds are preferred as human medicines. In addition, the compound represented by formula 6 has a fluorine atom at the 8-position of the quinolone skeleton, so it is speculated that it can cause high probability of phototoxicity (photosensitivity) (for example, see Journal ofAntimicrobial Chemotherapy, volume 33, page 683 (1994 )). That is to say, it is not considered that the compound represented by formula 6 is necessarily sufficient as a safe and effective drug for human use. European Journal of Medicinal Chemistry, Vol. 26, p. 889 (1991) only discloses what corresponds to EP-A-343524.

Disclosed in WO 95/21163 is the pyridone carboxylic acid antibacterial drug substituted by bicyclic amino, which is represented by the following general formula 7:

[Formula 7]

Wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom, lower alkyl or amino protecting group; R ₃ and R ₄ are the same or different and each represent a hydrogen atom, halogen atom, cyano, hydroxyl, oxo, lower alkane Oxygen or lower alkyl; N represents the integer of 0 or 1; R ₅ represents lower alkyl, lower alkenyl, lower cycloalkyl, phenyl or heterocyclyl (they can be further substituted); G represents CE, wherein E represents a hydrogen atom or together with R ₅ forms a crosslinking group represented by -S-SE(CH ₃ )-; T represents CZ or a nitrogen atom, where Z represents a hydrogen atom, a halogen atom, a cyano group, a lower alkoxy group, halogenated lower alkoxy group, lower alkyl group or halogenated lower alkyl group or together with R ₅ form a crosslinking group represented by -O-CH ₂ -CH(CH ₃ )-; X represents a hydrogen atom, Halogen, hydroxyl, lower alkyl or amino, which may be protected; D represents CY, wherein Y represents a hydrogen atom or a halogen atom. However, with respect to the compounds of the present invention, for the bicyclic amino group in the 7-position substituent of the quinolone derivative, only the substituent represented by the following formula 8 is specifically disclosed, that is to say that in formula 7, R ₃ and R ₄ are each Hydrogen atom and n is 0:

[Formula 8]

In addition, WO 95/21163 does not specifically disclose the fused substituted aminopyrrolidine derivatives (bicyclic amines) that are characteristic of the present invention, that is to say, in the compound represented by formula 7, the substituents R ₃ and One or both of R ₄ have a substituent other than a hydrogen atom.

WO 96/23782 discloses N ₁ -(halocyclopropyl)-substituted pyridonecarboxylic acid derivatives represented by the following general formula 9:

[Formula 9]

Wherein X ¹ represents a halogen atom or a hydrogen atom; X ² represents a halogen atom; R ¹ represents a hydrogen atom, a hydroxyl group, a thiol group, a halomethyl group, an amino group, an alkyl group or an alkoxy group; R ² represents a substituent of the following formula 10 :

[Formula 10]

Wherein R ³ and R ⁴ each represent a hydrogen atom or an alkyl group, and n represents an integer of 1 or 2; A represents a group of the following formula 11:

[Formula 11]

Wherein ^X represents hydrogen atom, halogen atom, cyano, amino, alkyl, halomethyl, alkoxy or halomethoxy; R represents hydrogen atom, phenyl, acetoxymethyl, pivaloyl Oxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo-1,3-dioxa Cyclopenten-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl, alkoxymethyl or phenyl. The definitions of substituents etc. in the compound represented by Formula 9 do not apply to the compound of the present invention although they use the same symbols. However, with regard to the compound of the present invention, for the bicyclic amino group in the 7-position substituent of the quinolone derivative, only the substituent represented by the following formula 12 is specifically disclosed, that is to say, n is 2 in the formula 10:

[Formula 12]

In addition, WO 96/23782 does not disclose 1-amino-3-azabicyclo[3.2.0]heptane derivatives having substituents other than hydrogen atoms on the bicyclic ring, which are characteristic of the compounds of the present invention one.

Japanese Patent Application Laid-Open No. 8-225567 discloses quinolone-formic acid derivatives or naphthyridone-formic acid derivatives represented by the following general formula 13:

[Formula 13]

T-Q

Wherein Q represents the quinolone structure of following formula 14:

[Formula 14]

Wherein X ¹ represents halogen or nitro; X ² represents hydrogen, halogen, amino, hydroxyl, methoxy, etc.; A and D each represent N or CR ⁷ (wherein R ⁷ =H, F, OCH ₃ , etc.); R ¹ Represents C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, etc.; R ² represents hydroxyl, methoxy, benzyloxy, etc.; R ⁹ represents hydrogen or C ₁ -C ₃ alkyl; R ¹¹ represents hydrogen , methyl or CH ₂ F; and T represents the following formula 15:

[Formula 15]

Wherein B represents amino, hydroxyl, etc.; ^R6 represents hydrogen or methyl. The definitions of substituents etc. in the compound represented by Formula 13 do not apply to the compound of the present invention although they use the same symbols. However, Japanese Patent Application Laid-Open No. 8-225567 discloses only a compound represented by the following formula 16, which is a derivative in which B is an amino group.

[Formula 16]

In addition, Japanese Patent Application Laid-Open No. 8-225567 does not disclose specific compounds relevant to the present invention.

Summary of the invention

Therefore, the object of the present invention is to provide quinolone synthetic antibacterial drugs and drugs for treating infections, which have strong activity against Gram-positive bacteria (including those with low sensitivity to quinolones) and Gram-negative bacteria. Broad-spectrum antibacterial activity, and also has high safety.

The inventors of the present invention have conducted studies on compounds having 3-aminopyrrolidinyl at the 7-position of quinolone compounds or its corresponding position (eg, 10-position of pyridobenzoxazine compounds). The inventors of the present invention have found that quinolone derivatives having fused substituted aminopyrrolidinyl substituents represented by the following formula 17 are effective against Gram-positive bacteria (especially drug-resistant Gram-positive cocci, such as multi- Drug-resistant (including quinolone-resistant pneumococci) and Gram-negative bacteria have strong broad-spectrum antibacterial activity:

[Formula 17]

The substituents at the 3- and 4-positions of 3-aminopyrrolidinyl are combined with the carbon atoms to which they are attached to form a 4-7-membered ring structure that may contain double bonds and may contain oxygen or sulfur atoms , this ring structure forms a fused ring (bicyclic) structure together with the pyrrolidine ring. Various preclinical evaluations have shown that these quinolone compounds not only have such a high antibacterial activity, but also cause only low probability of conventionally known side effects of quinolone antibacterial drugs (such as causing convulsions and phototoxicity (photosensitivity)) and have been used in clinical practice in recent years. Side effects reported above (such as cardiotoxicity (QT prolongation), abnormal blood glucose levels, and delayed drug eruption). It is also clear that these quinolones exhibit good oral absorption and organ permeability. According to the contents disclosed in the above patent documents, these results are very unexpected.

Finally, the inventors of the present invention have found that quinolones represented by formula (I) described subsequently and their corresponding salts and hydrates all have excellent drug properties such as high antibacterial activity and safety and show Quinolones synthetic antibacterials with excellent pharmacokinetic properties. These findings have led to the completion of the present invention.

Specifically, the present invention provides compounds represented by the following formula (I), salts or hydrates thereof:

[Formula 18]

Wherein ^R represents a hydrogen atom, an alkyl group with 1-6 carbon atoms, a cycloalkyl group with 3-6 carbon atoms, or a substituted carbonyl group derived from an amino acid, dipeptide or tripeptide; the alkyl group may have One or more substituents selected from the group consisting of hydroxyl, amino, cyano, halogen, alkylthio with 1-6 carbon atoms and alkoxy with 1-6 carbon atoms, and the cycloalkane The group may have one or more substituents selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an amino group, a hydroxyl group and a halogen atom;

R ² represents a hydrogen atom, an alkyl group with 1-6 carbon atoms or a cycloalkyl group with 3-6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of hydroxyl, amino, a halogen atom, an alkylthio group having 1-6 carbon atoms, and an alkoxy group having 1-6 carbon atoms, and the cycloalkyl group may have one or more substituents selected from the group consisting of 1-6 Alkyl, amino, hydroxyl and halogen atoms of carbon atoms;

R ³ and R ⁴ each independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms, and the alkyl group may have one or more substituents selected from the group consisting of a halogen atom and a group having 1-6 carbon atoms Atom alkoxy;

R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group having 1-6 carbon atoms, an alkoxy group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkenyl group having 2-6 carbon atoms Alkynyl group having 3-6 carbon atoms and may have a substituent, aryl group having 6-10 carbon atoms and may have a substituent or heteroaryl group which may have a substituent, the alkyl , alkenyl and alkynyl can be straight or branched, and the alkyl can have one or more substituents selected from the group consisting of hydroxyl, amino, halogen, alkylthio with 1-6 carbon atoms and 1 - an alkoxy group with 6 carbon atoms, and the alkenyl group may have one or more substituents selected from the group consisting of a halogen atom and an alkoxy group with 1-6 carbon atoms;

R ⁶ and R ⁷ are combined with the carbon atoms to which they are attached to form a 4-7 membered ring structure, which represents a partial structure that forms a fused ring (bicyclic) structure with the pyrrolidine ring, and the 4- The 7-membered ring structure may contain double bonds and may contain oxygen or sulfur atoms as constituent atoms of the ring,

^R may be methylene, which may be combined with R to form part of a ³ -membered fused cyclic structure, and the ring formed as described above may be located elsewhere in the fused cyclic (bicyclic) structure, and the The 4-7 membered ring structure may have one or more substituents selected from the group consisting of an alkyl group having 1-6 carbon atoms which may have a substituent, an alkyl group having 1-6 carbon atoms which may have a substituent Oxygen, an alkenyl group having 2 to 6 carbon atoms which may have substituents, an alkynyl group having 2 to 6 carbon atoms which may have substituents, a cycloalkane group having 3 to 6 carbon atoms which may have substituents group, an exomethylene group that may have a substituent, a spiroalkyl group that may have a substituent, an aryl group that may have 6 to 10 carbon atoms and may have a substituent, a heteroaryl group that may have a substituent, Alkoxyimino groups, halogen atoms, hydroxyl groups, cyano groups, and hydroxyimino groups having 1 to 6 carbon atoms and which may have substituents; or polymethylene chains having 2 to 5 carbon atoms may be combined to form spiro ring system; and

Q represents a partial structure represented by the following formula (II):

[Formula 19]

Wherein R represents ^{an alkyl} group with 1-6 carbon atoms, an alkenyl group with 2-6 carbon atoms, a halogen-substituted alkyl group with 1-6 carbon atoms, a group with 3-6 carbon atoms and may have Substituent cycloalkyl, optionally substituted halogen-substituted phenyl, optionally substituted halogen-substituted heteroaryl, alkoxy having 1-6 carbon atoms, or having 1-6 carbon atoms Alkylamino;

R ⁹ represents a hydrogen atom or an alkylthio group having 1-6 carbon atoms, or R ⁹ and R ⁸ are combined with their attached atoms to form a ring structure which may contain a sulfur atom as a ring component atom, and may have an alkyl group containing 1-6 carbon atoms or a halogen-substituted alkyl group containing 1-6 carbon atoms as a substituent;

R ¹⁰ represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalein, 5- Alkyl-2-oxobutyl, alkyl having 1-6 carbon atoms, alkoxymethyl having 2-7 carbon atoms, or alkylene and phenyl having 1-6 carbon atoms And the phenylalkyl formed;

R ¹¹ represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halomethyl group or an alkyl group having 1-6 carbon atoms, and the amino group may have one or two substituents selected from the group consisting of formyl, with Alkyl groups with 1-6 carbon atoms and acyl groups with 2-5 carbon atoms;

X ¹ represents a halogen atom or a hydrogen atom;

^A represents a nitrogen atom or a partial structure represented by the following formula (III):

[Formula 20]

Wherein ^X represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, an alkoxy group having 1-6 carbon atoms, a cyano group, a halogen atom, a halogen-substituted methyl group or a halomethoxy group, or X ² and ^R are combined with their parent skeleton linking moieties to form a ring structure which may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom of the ring, and may be composed of 1-6 carbon atoms and may be substituted with an alkyl substituent; and

A ² and A ³ each represent a nitrogen atom or a carbon atom, and A ¹ , A ² , A ³ , R ⁸ and A ² combine with the carbon atom to which A ³ is connected to form the following partial structure:

>C＝C(-A ¹ ＝)-N(-R ⁸ )-

or the following partial structure:

>NC(-A ¹ =)=C(-R ⁸ )-.

The present invention also provides a medicament comprising a compound represented by formula (I), a salt or a hydrate thereof as an active ingredient.

The present invention also provides a method for treating diseases, the method comprising administering a compound represented by formula (I), a salt or a hydrate thereof. The present invention further provides the use of the compound represented by formula (I), its salt or hydrate in the production of medicine.

The present invention can provide quinolone synthetic antibacterial drugs with excellent drug properties, and these drugs have strong antibacterial effects not only on Gram-negative bacteria but also on Gram-positive cocci (which have low sensitivity to quinolone antibacterial drugs) activity, and exhibited high safety and excellent pharmacokinetic properties.

Brief description of the drawings

Figure 1 shows (3S)-3-(3-hydroxyl-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3 obtained in Reference Example 24 - ORTEP diagram of the X-ray crystallographic structure of tert-butyl formate.

Figure 2 shows (3S)-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3 obtained in Reference Example 24 - Absolute configuration of tert-butyl formate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

R ¹ represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, or a substituted carbonyl group derived from amino acid, dipeptide or tripeptide. The alkyl group may have one or more substituents selected from the group consisting of hydroxyl, amino, cyano, halogen, alkylthio having 1 to 6 carbon atoms and alkoxy having 1 to 6 carbon atoms, and The cycloalkyl group may have one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, an amino group, a hydroxyl group and a halogen atom.

R ² represents a hydrogen atom, an alkyl group having 1-6 carbon atoms or a cycloalkyl group having 3-6 carbon atoms. The alkyl group may have one or more substituents selected from hydroxyl group, amino group, halogen atom, alkylthio group having 1-6 carbon atoms and alkoxy group having 1-6 carbon atoms. The cycloalkyl group may have one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, an amino group, a hydroxyl group and a halogen atom.

When R ¹ or R ² is an alkyl group, the alkyl group can be linear or branched, and is preferably methyl, ethyl, propyl or isopropyl, more preferably methyl or ethyl, still more preferably methyl.

When R ¹ or R ² is an alkyl group having hydroxyl, amino or cyano group as a substituent, the alkyl group may be a straight or branched chain alkyl group having 1 to 6 carbon atoms, and preferably at the terminal carbon of the alkyl group Atoms are substituted by substituents. The alkyl group having a hydroxyl group is suitably an alkyl group having up to 3 carbon atoms and is preferably 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl. The alkyl group having an amino group is suitably an alkyl group having up to 3 carbon atoms and is preferably 2-aminoethyl, 2-aminopropyl or 3-aminopropyl. The alkyl group having a cyano group is suitably an alkyl group having 2 to 4 carbon atoms and is preferably 2-cyanoethyl or 2-cyano-2,2-dimethylethyl.

When R ¹ or R ² is an alkyl group having a halogen atom as a substituent, the alkyl group may be a linear or branched chain alkyl group having 1-6 carbon atoms, and the halogen atom is preferably a fluorine atom. Alkyl groups can be monofluoro-substituted to perfluoro-substituted. Suitable examples of halo-substituted alkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.

When R ¹ or R ² is an alkyl group having an alkylthio group or an alkoxy group as a substituent, the alkyl group may be straight or branched, and the alkyl moiety in the alkylthio group or alkoxy group may also be Straight or branched. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group, an alkylthioethyl group or an alkylthiopropyl group, and the alkylthio group preferably has 1 to 3 carbon atoms. More preferable examples of the alkyl group having an alkylthio group include methylthiomethyl, ethylthiomethyl and methylthioethyl. The alkyl group having an alkoxy group is preferably an alkoxymethyl group, an alkoxyethyl group or an alkoxypropyl group, and the alkoxy group preferably has 1 to 3 carbon atoms. More preferable examples of the alkyl group having an alkoxy group include methoxymethyl group, ethoxymethyl group and methoxyethyl group.

When R ¹ or R ² is cycloalkyl, the cycloalkyl is preferably cyclopropyl or cyclobutyl, more preferably cyclopropyl. The cycloalkyl group may have one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, an amino group, a hydroxyl group and a halogen atom. Specifically, the substituent is preferably a methyl group, an ethyl group, an amino group, a hydroxyl group, a fluorine atom or a chlorine atom.

A preferred combination of R ^{and R} is wherein ^R is selected from a hydrogen atom, an alkyl, a cycloalkyl and a substituted carbonyl derived from an amino acid, a dipeptide or a tripeptide; and ^R is hydrogen. A more preferred combination of ^R1 and ^R2 is wherein ^R1 is selected from a hydrogen atom, an alkyl group and a cycloalkyl group, and ^R2 is hydrogen. Alkyl is preferably methyl or ethyl, especially preferably methyl. Cycloalkyl is preferably cyclopropyl or cyclobutyl, especially preferably cyclopropyl. Still more preferred combinations are those wherein both ^R1 and ^R2 are hydrogen atoms, or wherein one of ^R1 and ^R2 is a hydrogen atom and the other is methyl, ethyl, fluoroethyl or cyclopropyl.

A quinolone derivative in which R ¹ is a substituted carbonyl group derived from an amino acid, dipeptide or tripeptide and R ² is a hydrogen atom can be used as a prodrug. The amino acids, dipeptides or tripeptides used to provide such prodrugs are those that form a peptide bond between the carboxyl group and the amino group to which ^R1 and ^R2 bind and form a free amine compound after cleavage in vivo. Examples of substituted carbonyl groups useful to provide such prodrugs include those derived from amino acids such as glycine, alanine and aspartic acid; dipeptides formed from glycine, alanine or asparagine such as glycine-glycine, glycine-alanine, and alanine-alanine); tripeptides formed from glycine, alanine, or asparagine (such as glycine-glycine-alanine and glycine-alanine-alanine acid).

^R3 and ^R4 independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms. The alkyl group may have one or more substituents selected from halogen atoms and alkoxy groups having 1 to 6 carbon atoms.

When ^R3 and ^R4 are independently alkyl groups, the alkyl groups can be straight or branched, and are preferably methyl, ethyl, propyl or isopropyl, more preferably methyl or ethyl, still more Methyl is preferred.

When ^R3 and ^R4 are independently an alkyl group, the substituent may be a group selected from a halogen atom and an alkoxy group having 1-6 carbon atoms. The halogen atom is preferably a fluorine atom. Alkyl groups can be monofluoro-substituted to perfluoro-substituted. Suitable examples of halo-substituted alkyl include monofluoromethyl, difluoromethyl and trifluoromethyl. Preferable examples of the alkoxy group having 1 to 6 carbon atoms include methoxymethyl, ethoxymethyl and methoxyethyl. When ^R3 and ^R4 are independently substituted alkyl, the group is especially preferably fluoromethyl.

A preferred combination of ^R3 and ^R4 is that one of ^R3 and ^R4 is a hydrogen atom and the other is methyl or fluoromethyl. A more preferred combination of ^R3 and ^R4 is that both ^R3 and ^R4 are hydrogen atoms.

R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group having 1-6 carbon atoms, an alkoxy group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, an alkenyl group having 2-6 carbon atoms Alkynyl, cycloalkyl having 3-6 carbon atoms (which may have substituents), aryl having 6-10 carbon atoms (which may have substituents) or heteroaryl (which may have substituents ).

When R ⁵ is alkyl, alkenyl or alkynyl, the group may be straight or branched. The alkyl group may have one or more substituents selected from hydroxyl group, amino group, halogen atom, alkylthio group having 1-6 carbon atoms and alkoxy group having 1-6 carbon atoms. The alkenyl group may have one or more substituents selected from halogen atoms and alkoxy groups having 1 to 6 carbon atoms.

When R ⁵ is a halogen atom, the halogen atom is preferably a fluorine atom or a chlorine atom, especially preferably a fluorine atom.

When R ⁵ is an alkyl group having 1-6 carbon atoms, the alkyl group is preferably methyl, ethyl, propyl or isopropyl. The alkyl group is more preferably a methyl group or an ethyl group, especially preferably a methyl group.

The alkyl group may have one or more substituents selected from hydroxyl group, amino group, halogen atom, alkylthio group having 1-6 carbon atoms and alkoxy group having 1-6 carbon atoms.

When a hydroxy or amino group is a substituent on an alkyl group, the substituent is preferably on the terminal carbon atom of the alkyl group. The alkyl group having a hydroxyl group is preferably a hydroxymethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group or 3-hydroxypropyl group. The alkyl group having an amino group is preferably aminomethyl, 2-aminoethyl, 2-aminopropyl or 3-aminopropyl. The alkyl group having a hydroxyl group or an amino group is preferably a methyl group or an ethyl group, more preferably a hydroxymethyl group, an aminomethyl group having a hydroxyl group, or an amino group on a methyl group.

When the alkyl group has a halogen atom as a substituent, the alkyl group may be a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is more preferably a methyl group or an ethyl group, especially preferably a methyl group. The halogen atom is preferably a fluorine atom. Alkyl groups can be monofluoro-substituted to perfluoro-substituted. Examples of halogen-substituted alkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. Especially preferred is monofluoromethyl, difluoromethyl or trifluoromethyl.

When the alkyl group has an alkylthio group or an alkoxy group as a substituent, the alkyl group may be straight or branched, and the alkyl moiety in the alkylthio or alkoxy group may also be straight or branched. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group or an alkylthioethyl group, and the alkylthio group preferably has 1 to 2 carbon atoms. More preferable examples of the alkyl group having an alkylthio group include methylthiomethyl, ethylthiomethyl and methylthioethyl. The alkyl group having an alkoxy group is preferably an alkoxymethyl group or an alkoxyethyl group, and the alkoxy group preferably has 1 to 2 carbon atoms. More preferable examples of the alkyl group having an alkoxy group include methoxymethyl group, ethoxymethyl group and methoxyethyl group. Among them, methylthio and methoxymethyl are still more preferred.

When R ⁵ is an alkoxy group having 1-6 carbon atoms, the alkoxy group is preferably an alkoxy group having 1-3 carbon atoms, especially methoxy or ethoxy.

When R ⁵ is an alkenyl group having 2-6 carbon atoms, the alkenyl group preferably contains one double bond and there is no specific limitation on the position of the double bond. Alkenyl is preferably vinyl, propenyl or butenyl, especially preferably eg vinyl.

The alkenyl group may have one or more substituents selected from halogen atoms and alkoxy groups having 1 to 6 carbon atoms.

The halogen atom is preferably a fluorine atom. When an alkenyl group has a halogen atom as a substituent, the alkenyl group is preferably an alkenyl group having 2 to 3 carbon atoms, more preferably a vinyl group having a fluorine atom, especially preferably a fluorovinyl group.

When an alkenyl group has an alkoxy group as a substituent, the alkenyl group preferably has 2 or 3 carbon atoms. Examples of the alkenyl group having an alkoxy group include alkoxyvinyl group and alkoxypropenyl group, especially methoxyvinyl group and ethoxyvinyl group. Methoxyvinyl is especially preferred.

When R ⁵ is an alkynyl group having 2-6 carbon atoms, the alkynyl group preferably contains one triple bond and the triple bond may be in any position. Alkynyl is preferably ethynyl, propynyl or butynyl, especially preferably ethynyl.

When R ⁵ is a cycloalkyl group (which may have a substituent) having 3 to 6 carbon atoms, the cycloalkyl group is preferably a cyclopropyl group or a cyclobutyl group, more preferably a cyclopropyl group.

The cycloalkyl group may have one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halogen atom, an amino group and a hydroxyl group. Specifically, the substituent is preferably a methyl group, an ethyl group, a phenyl group, a fluorine atom or a chlorine atom, more preferably a methyl group or a fluorine atom.

When R ^is an aryl group (which may have a substituent) or a heteroaryl group (which may have a substituent) having 6-10 carbon atoms, the heteroaryl group is a 5-membered ring or a 6-membered ring and may contain 1-4 heteroatoms arbitrarily selected from nitrogen atom, oxygen atom and sulfur atom, and the aryl or heteroaryl group may have one or more substituents selected from the following: halogen atom, amino group, hydroxyl group, cyano group, nitrate group group, carboxyl group, carbamoyl group, alkyl group having 1-6 carbon atoms, alkoxy group having 1-6 carbon atoms, alkoxycarbonyl group having 2-6 carbon atoms and alkoxycarbonyl group having 2-5 carbon atoms Atoms of the acyl group. The alkyl group, alkoxy group, alkoxycarbonyl group or acyl group may have one or more substituents selected from a halogen atom, a hydroxyl group and an alkoxy group having 1 to 6 carbon atoms.

The substituents on the aryl or heteroaryl are preferably halogen atoms, amino, hydroxyl, cyano, carboxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or 2- Alkoxycarbonyl of 6 carbon atoms.

A halogen atom as a preferable substituent is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

Alkyl as preferred substituent may be straight-chain or branched with 1 to 6 carbon atoms and is for example methyl, ethyl, propyl, isopropyl or tert-butyl, preferably methyl or ethyl . The substituent on the alkyl group is preferably a halogen atom, more preferably a fluorine atom. Examples of halogen-substituted alkyl groups include fluoromethyl and trifluoromethyl.

Alkoxy as preferred substituent is preferably alkoxy having 1 to 3 carbon atoms, especially methoxy or ethoxy, particularly preferably methoxy. The substituent on the alkoxy group is preferably a halogen atom, more preferably a fluorine atom. Examples of halogen-substituted alkoxy include trifluoromethoxy.

Alkoxycarbonyl as a preferred substituent is preferably an alkoxycarbonyl group having up to 3 carbon atoms. Preferable examples of the alkoxycarbonyl group include methoxycarbonyl and ethoxycarbonyl. The substituent on the alkoxycarbonyl group is preferably a halogen atom, more preferably a fluorine atom. Examples of halogen-substituted alkoxycarbonyl include trifluoromethoxycarbonyl.

R ⁶ and R ⁷ combine with the carbon atoms to which they are attached to form a 4-7 membered ring structure, and the ring structure represents a partial structure forming a fused ring (bicyclic) structure together with the pyrrolidine ring. The 4- to 7-membered ring structure moiety formed in this manner may contain an oxygen atom or a sulfur atom as a constituent atom of the ring. These fused cyclic amines are represented by the formula:

[Formula 21]

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1; D ¹ , D ² , D ³ , D ⁴ and D ⁵ each represent a carbon atom (which may have a substituent), an oxygen atom or a sulfur atom, provided that when 2 or more of D ¹ , D ² , D ³ , D ⁴ and D ⁵ are each an oxygen atom or a sulfur atom, the adjacent two of them are not simultaneously oxygen atoms or a sulfur atom, and the sulfur atom may be an oxidized sulfur atom, such as S=O or S(=O) ₂ ; Y represents a substituent on the ring (described below); n represents an integer of 0-3.

R ⁶ and R ⁷ form a 4-7 membered ring structure when taken together with the carbon atom to which they are attached. Preferred examples of fused cyclic amines are listed below:

[Formula 22]

The 4-7 membered ring structure formed by combining R ⁶ and R ⁷ with the carbon atoms to which they are attached may contain a ring double bond as a constituent structure. When the ring structure contains a double bond as a constituent structure, the R ⁶ part (carbon atom substituted on the pyrrolidine ring) and R ⁵ can be combined to form a double bond part structure, which together with R ⁷ forms 5 represented by the following formula -7-membered ring structure:

[Formula 23]

However, the double bond partial structure and R ⁷ preferably form a 5-membered or 6-membered ring structure. Preferred examples of dicyclic amines are listed below:

[Formula 24]

The 4-7 membered ring structure may have a substituent selected from an alkyl group having 1-6 carbon atoms (which may have a substituent), an alkoxy group having 1-6 carbon atoms (which may have a substituent group), an alkenyl group having 2-6 carbon atoms (which may have a substituent), an alkynyl group having 2-6 carbon atoms (which may have a substituent), a cycloalkyl group having 3-6 carbon atoms (which may have a substituent), heterocycloalkyl having 3 to 6 carbon atoms (which may have a substituent), exomethylene (which may have a substituent), spiroalkyl (which may have a substituent) , an aryl group having 6-10 carbon atoms (which may have a substituent), a heteroaryl group (which may have a substituent), a halogen atom, a hydroxyl group, a cyano group, a hydroxyimino group, and an aryl group having 1-6 carbon atoms Alkoxyimino group (which may have a substituent).

The alkyl group (which may have a substituent) having 1 to 6 carbon atoms may be linear or branched. Specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, tert-butyl, fluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoro Substituted t-butyl, hydroxymethyl, 2-hydroxyethyl, 2-cyanoethyl, methoxymethyl and 2-methoxyethyl. Alkyl is preferably methyl, ethyl, isopropyl, fluoromethyl, 2-cyanoethyl or methoxymethyl.

The alkoxy group having 1 to 6 carbon atoms (which may have a substituent) may be an alkoxy group derived from the above-mentioned alkyl group, and is preferably an alkoxy group having 1 to 3 carbon atoms, specifically, methyl Oxy or Ethoxy.

The alkenyl group (which may have a substituent) having 2 to 6 carbon atoms preferably contains one double bond and the position of the double bond is not limited. Alkenyl is preferably ethenyl, propenyl or butenyl. The substituent on the alkenyl group is preferably a halogen atom or an alkoxy group, and the halogen atom is preferably a fluorine atom. Examples of substituted alkenyl groups include fluorovinyl and methoxyvinyl.

The alkynyl group (which may have a substituent) having 2 to 6 carbon atoms preferably contains one triple bond and the triple bond may be at any position. Alkynyl is preferably ethynyl, propynyl or butynyl. Preferred alkynyl groups have no substituents other than hydrogen atoms.

The cycloalkyl group (which may have a substituent) having 3 to 6 carbon atoms is preferably a cyclopropyl group or a cyclobutyl group. The cycloalkyl group may be substituted with one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, a halogen atom, an amino group and a hydroxyl group. Specifically, the substituent is preferably a methyl group, an ethyl group, a fluorine atom or a chlorine atom.

The heterocycloalkyl group (which may have a substituent) having 3 to 6 carbon atoms is preferably oxetan-3-yl, thioxetan-3-yl (thioxetan-3-yl), Tetrahydrofuryl, tetrahydropyranyl or 2,2-dimethyl-1,3-dioxan-4-yl.

The exomethylene group (which may have a substituent) is preferably an exomethylene group having no substituent except a hydrogen atom. The substituent other than a hydrogen atom is preferably an amino group, a fluorine atom, a chlorine atom, a methylthio group or a methoxy group.

The spiroalkyl group (which may have a substituent) is preferably a spirocyclopropyl group or a spirocyclobutyl group. Spiroalkyl groups are composed of alicyclic components and form a spirocyclic ring system. The spirocycloalkyl group may be substituted with one or more substituents selected from an alkyl group having 1 to 6 carbon atoms, a halogen atom, an amino group and a hydroxyl group. Specifically, the substituent is preferably a methyl group, an ethyl group, a fluorine atom or a chlorine atom.

When the substituent on the 4-7 membered ring structure is an aryl group (which may have a substituent) or a heteroaryl group (which may have a substituent) having 6-10 carbon atoms, the heteroaryl is 5 A membered ring or a 6-membered ring and may contain 1 to 4 heteroatoms arbitrarily selected from nitrogen atoms, oxygen atoms and sulfur atoms. The aryl or heteroaryl group may have one or more substituents selected from the group consisting of halogen atoms, amino groups, hydroxyl groups, cyano groups, nitro groups, carboxyl groups, carbamoyl groups, alkyl groups with 1-6 carbon atoms, Alkoxy groups having 1-6 carbon atoms, alkoxycarbonyl groups having 2-6 carbon atoms, and acyl groups having 2-5 carbon atoms (ie, alkylcarbonyl groups having 2-5 carbon atoms). The alkyl group, alkoxy group, alkoxycarbonyl group or acyl group may have one or more substituents selected from a halogen atom, a hydroxyl group and an alkoxy group having 1 to 6 carbon atoms. The substituents on the aryl or heteroaryl are preferably halogen atoms, amino, hydroxyl, cyano, carboxyl, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms or 2- Alkoxycarbonyl of 6 carbon atoms. Particularly preferred substituents on aryl or heteroaryl include fluorine atom, chlorine atom, methyl, fluoromethyl, methoxy, ethoxy, methoxycarbonyl and ethoxycarbonyl.

When the substituent is a halogen atom, the halogen atom is preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom.

Preferable examples of the alkoxyimino group (which may have a substituent) having 1 to 6 carbon atoms include methoxyimino and ethoxyimino.

Preferred examples of the above substituents include methyl, ethyl, fluoromethyl, 2-fluoroethyl, methoxymethyl, cyanoethyl, methoxy, cyclopropyl, spirocyclopropyl, phenyl, Oxazolyl group, fluorine atom, hydroxyl group, hydroxyimino group and methoxyimino group. Among them, methyl group, fluoromethyl group, methoxymethyl group, methoxy group, fluorine atom, cyanoethyl group and methoxyimino group are particularly preferred.

The polymethylene chains combined to form the spiro ring system preferably have 2 to 3 carbon atoms, more preferably 2 carbon atoms.

R ⁵ may be a methylene group, which combines with R ⁶ to form a 3-membered fused ring structure, and the ring structure constitutes a fused bicyclic structure by combining R ⁶ and R ⁷ into a tricyclic ring system. In addition, the third ring system derived from ^R5 and ^R6 may be located on another part of the fused bicyclic ring system derived from ^R6 and ^R7 . In other words, a fused bicyclic substituent at the 7-position can form a tricyclic ring system by incorporating a cyclopropane ring on either part of the bicyclic ring structure.

Q represents a partial structure represented by the following formula:

[Formula 25]

Wherein A ² and A ³ each represent a nitrogen atom or a carbon atom, and A ¹ , A ² , A ³ , R ⁸ and A ² together with the carbon atom to which A ³ is connected represent the following partial structure:

>C＝C(-A ¹ ＝)-N(-R ⁸ )-

or the following partial structure:

>NC(-A ¹ ＝)＝C(-R ⁸ )-

Wherein ">" means that there are two bonds connecting nitrogen atoms or carbon atoms (the same below).

Q preferably represents a fused heterocyclic ring system moiety represented by the following formula:

[Formula 26]

Or the partial structure of the fused heterocyclic ring system represented by the following formula:

[Formula 27]

Wherein R represents ^{an alkyl} group having 1-6 carbon atoms, an alkenyl group having 2-6 carbon atoms, a halogen-substituted alkyl group having 1-6 carbon atoms, a cycloalkane group having 3-6 carbon atoms group (which may have a substituent), a halogen-substituted phenyl group which may have a substituent, a halogen-substituted heteroaryl group which may have a substituent, an alkoxy group having 1-6 carbon atoms, or an alkoxy group having 1-6 carbon atoms Atoms of alkylamino groups.

When R ⁸ is an alkyl group having 1-6 carbon atoms, the alkyl group may be straight or branched. Specific examples of the alkyl group include methyl, ethyl, isopropyl, sec-butyl and tert-butyl. Among them, ethyl group and tert-butyl group are preferable.

When R ⁸ is an alkenyl group having 2-6 carbon atoms, the alkenyl group may be straight or branched. Preferable specific examples of alkenyl include ethenyl and isopropenyl.

When R ⁸ is a halogen-substituted alkyl having 1-6 carbon atoms, the alkyl moiety may be straight or branched. Specific examples of the alkyl moiety include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Among them, ethyl group and tert-butyl group are preferable. The halogen atom substituent on the alkyl group is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. Examples of halogen-substituted alkyl include fluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-dimethyl-2- Fluoroethyl, 1-methyl-1-(fluoromethyl)-2-fluoroethyl and 1,1-(difluoromethyl)-2-fluoroethyl. Among them, 2-fluoroethyl and 1,1-dimethyl-2-fluoroethyl are preferable.

When R ⁸ is a cycloalkyl group (which may have a substituent) having 3 to 6 carbon atoms, examples of the cycloalkyl group include cyclopropyl, cyclobutyl and cyclopentyl. Among them, cyclopropyl is preferred. The substituent on the cycloalkyl group is preferably a halogen atom, a methyl group or a phenyl group, more preferably a halogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom, particularly preferably a fluorine atom. The number of substituents may be 1 or 2, but is preferably 1. Specifically, the cycloalkyl group which may have a substituent is preferably a monofluorocyclopropyl group, more preferably a 1,2-cis-2-fluorocyclopropyl group, and especially preferably a (1R,2S)-2-fluorocyclopropyl group.

When R ⁸ is a halogen-substituted phenyl group which may have a substituent, the halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. The number of halogen atom substituents is preferably 1 or 2. The substituent on the halogen-substituted phenyl is preferably amino, hydroxy or methyl. Examples of the halogen-substituted phenyl group which may have a substituent include 2-fluorophenyl, 4-fluorophenyl, 2,4-fluorophenyl and 5-amino-2,4-difluorophenyl. Among them, 2,4-difluorophenyl and 5-amino-2,4-difluorophenyl are preferable.

When ^R is a halogen-substituted heteroaryl group which may have a substituent, the heteroaryl group may be a 5-membered or 6-membered aromatic heteroaryl group containing one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Ring base. The heteroaryl group is preferably a 5-membered or 6-membered nitrogen-containing aromatic heterocyclic group containing 1 or 2 nitrogen atoms. Specific examples of heteroaryl include pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, thiazolyl and oxazolyl. Among them, pyridyl is preferred. The halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. The number of halogen atoms is preferably 1 or 2. Preferable examples of the substituent on the halogen-substituted heteroaryl group include amino, hydroxy and methyl. The halogen-substituted heteroaryl group which may have a substituent is preferably 6-amino-3,5-difluoropyridin-2-yl.

When R ⁸ is an alkoxy group having 1-6 carbon atoms, the alkoxy group is preferably a methoxy group.

When R ⁸ is an alkylamino group having 1-6 carbon atoms, the alkylamino group is preferably methylamino group.

The aforementioned R ⁸ is preferably cyclopropyl or 1,2-cis-2-fluorocyclopropyl, more preferably (1R,2S)-2-fluorocyclopropyl.

R ⁹ represents a hydrogen atom or an alkylthio group having 1-6 carbon atoms. R ⁹ and the above R ⁸ may combine with the parent skeleton (including the carbon atom to which R ⁹ is attached and A ² ; the same below) to form a ring structure. The ring formed in this way may contain a sulfur atom as a constituent atom of the ring, and may have an alkyl group having 1 to 6 carbon atoms or a halogen-substituted alkyl group having 1 to 6 carbon atoms as a substituent. The rings thus formed may be 4 to 6 membered and may be saturated, partially saturated or unsaturated. The fused ring structure formed in this way can be represented by the following structural formula:

[Formula 28]

R ¹⁰ represents a hydrogen atom, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalein, 5- Alkyl-2-oxobutyl, an alkyl group having 1-6 carbon atoms, an alkoxymethyl group having 2-7 carbon atoms, or an alkylene group having 1-6 carbon atoms and a phenyl group Formed phenylalkyl.

R ¹⁰ is preferably a hydrogen atom.

R ¹¹ represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halomethyl group or an alkyl group having 1 to 6 carbon atoms. The amino group may have one or two substituents selected from formyl, alkyl having 1 to 6 carbon atoms, and acyl having 2 to 5 carbon atoms.

When R ¹¹ is an alkyl group having 1-6 carbon atoms, the alkyl group may be linear or branched and is preferably methyl, ethyl, propyl or isopropyl, especially preferably methyl.

When R ¹¹ is halomethyl, the halogen atom is preferably a fluorine atom, and the number of halogen atoms may be 1 to 3.

When R ¹¹ is an amino group, a hydroxyl group or a thiol group, this group can be protected by a commonly used protecting group.

Examples of such protecting groups include: (substituted) alkoxycarbonyl such as tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; (substituted) aralkoxycarbonyl such as benzyloxy ylcarbonyl, p-methoxybenzyloxycarbonyl and p-nitrobenzyloxycarbonyl; (substituted) acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, methyl Acyl and benzoyl; (substituted) alkyl or (substituted) aralkyl, such as tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl and triphenylmethyl; (substituted ) ethers such as methoxymethyl, tert-butoxymethyl, tetrahydropyranyl and 2,2,2-trichloroethoxymethyl; and (alkyl- and/or aralkyl- ) substituted silyl groups such as trimethylsilyl, isopropyldimethylsilyl and tert-butyldiphenylsilyl. Compounds having substituents protected by such protecting groups are especially preferred as production intermediates.

In the above examples, R ¹¹ is preferably a hydrogen atom, an amino group, a hydroxyl group or a methyl group, especially preferably a hydrogen atom or an amino group.

X ¹ represents a halogen atom or a hydrogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. X ¹ is preferably a fluorine atom or a hydrogen atom.

^A represents a nitrogen atom or a partial structure represented by the following formula (III):

[Formula 29]

Wherein X ² represents a hydrogen atom, an alkyl group having 1-6 carbon atoms, an alkoxy group having 1-6 carbon atoms, a cyano group, a halogen atom, a halomethyl group or a halomethoxy group, X ² and R ⁸ may be combined with the parent backbone moiety to which they are attached (including the carbon atom to which X ² is attached and A ² ) to form a ring structure, and rings formed in this manner may contain oxygen, nitrogen or sulfur atoms as rings constituent atoms, and the ring may be substituted by an alkyl group having 1 to 6 carbon atoms which may have a substituent.

When A ¹ is a partial structure represented by formula (III) and X ² is an alkyl group having 1-6 carbon atoms, the alkyl group may be straight or branched, and is preferably methyl, ethyl, Propyl or isopropyl, more preferably methyl or ethyl, still more preferably methyl.

When X ² is an alkoxy group having 1 to 6 carbon atoms, the alkoxy group may be an alkoxy group derived from the above-mentioned alkyl group. The alkoxy group is preferably an alkoxy group having 1 to 3 carbon atoms, particularly preferably a methoxy group.

When X ² is a halogen atom, the halogen atom is preferably a fluorine atom or a chlorine atom. When the above R ¹¹ is a hydrogen atom, X ² is preferably a chlorine atom; when R ¹¹ is an amino group, a hydroxyl group or a methyl group, X ² is preferably a fluorine atom.

When X ² is a halomethyl group, the halogen atom is preferably a fluorine atom. Preferable examples of halomethyl include fluoromethyl, difluoromethyl and trifluoromethyl.

When X ² is a halomethoxy group, the halogen atom is preferably a fluorine atom, as in the above case. Specific examples of halomethoxy include fluoromethoxy, difluoromethoxy and trifluoromethoxy. Among them, difluoromethoxy is more preferred.

When A ¹ is a partial structure represented by formula (III), X ² and R ⁸ can form a ring structure, including the quinolone skeleton part [X ² is connected to the carbon atom, R ⁸ is connected to A ² (wherein A ² is a nitrogen atom or a carbon atom), and the carbon atom and the skeleton ring carbon atom to which A ² is connected]. The ring thus formed is preferably a 5- to 7-membered ring and may be saturated or unsaturated. The ring structure may contain an oxygen atom, a nitrogen atom or a sulfur atom, and may be substituted with an alkyl group having 1 to 6 carbon atoms or a halomethyl group described in ^X2 . The fused ring structure formed in this way can be represented by the following structural formula:

[Formula 30]

When A ¹ is a partial structure represented by formula (III) and the substituent X ² does not form a ring structure, X ² is preferably methyl, ethyl, methoxy, difluoromethoxy, cyano or A chlorine atom is especially preferably a methyl, methoxy, difluoromethoxy or cyano group. Such substituents are particularly preferred when A is a partial structure represented by the formula:

[Formula 31]

In addition, when Q is a partial structure represented by the following formula 1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid skeleton, more Particular preference is given to such substituents:

[Formula 32]

When A ¹ is a partial structure represented by formula (III) and the substituent X ² forms a ring structure, it is preferable to form 2,3-dihydro-3-methyl (or fluoromethyl)-7-oxo- 7H-Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid skeleton. The 3-(S)-picoline benzoxazine skeleton represented by the following formula (the compound of Y is ^methyl ) is particularly preferred:

[Formula 33]

The compound of the present invention is characterized in having the substituent of the representative structure on the 7-position (or its corresponding position) of the quinolone skeleton:

[Formula 34]

Specifically, the substituent of the compound of the present invention has an amino group at the corresponding position of the pyrrolidinyl 3-position, and the substituent R ⁷ (which is substituted by an amino group on a carbon atom) and the substituent R ⁶ (which is at the pyrrolidinyl group) 4-positions) and together with the carbon atoms they are connected to form a 4-7 membered ring structure. That is, the substituent of the compound of the present invention is a fused substituted aminopyrrolidine structure as shown below, wherein the cyclic structure and the pyrrolidine ring together form a fused cyclic (bicyclic) structure represented by the following formula, wherein the fused The ring structure is replaced by an amino group at the bridgehead position:

[Formula 35]

In addition, the substituents of the compounds of the present invention have a ring structure represented by the following formula, wherein the ring structure formed by combining the substituents ^R6 and ^R7 with the carbon atoms to which they are attached is a 5-membered ring or a 6-membered ring ring, and R ⁵ and R ⁶ combine to form a double bond partial structure,

As follows:

[Formula 36]

A bicyclic amino group contains an asymmetric carbon atom and has stereoisomerism (optical isomerism). This stereoisomerism will now be described. In addition, there are two types of bridgehead positions substituted by amino groups:

[Formula 37]

Here, preference is given to the following structures in which the amino group is in the β-configuration:

[Formula 38]

In addition, when the substituents ^R5 and ^R6 are not combined to form a double bond, for the asymmetric carbon atom replaced by ^R5 , there are the following 4 types:

[Formula 39]

Generally, structure 1 is more preferred than structure 2, and structure 3 is more preferred than structure 4; however, which structure is preferred depends on the structure of the substituent R ⁵ . In general, structure 1 is more preferred than structure 3 when substituents ^R6 and ^R7 form a 4-membered ring, and structure 3 is more preferred than structure 1 when substituents ^R6 and ^R7 form a 6-membered ring; however, preferred What kind of structure depends on the size of the ring formed by the substituents ^R6 and ^R7 . The present invention includes all of the above types.

Preferred parent skeletons are listed as follows, for example, the basic skeleton of quinolonecarboxylic acid (or pyridobenzoxazinecarboxylic acid) having the above-mentioned substituents at the 7-position (or its corresponding position):

[Formula 40]

Preferred examples of the substituent at the 7-position (or its corresponding position) are listed below:

(1) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.2.0]heptane-3-yl;

(2) (1S, 5S, 6R)-1-amino-6-fluoro-3-azabicyclo[3.2.0]heptane-3-yl;

(3) (1S, 5S, 6S)-1-amino-6-fluoro-3-azabicyclo[3.2.0]heptane-3-yl;

(4) (1S, 5S)-1-amino-6,6-difluoro-3-azabicyclo[3.2.0]heptane-3-yl;

(5) (1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl;

(6) (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl;

(7) (1S, 5R, 6R)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl;

(8) (1S, 5R, 6S)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl;

(9) Spiro[(1S,5S)-1-amino-3-azabicyclo[3.2.0]heptane-6,1'-cyclopropane]-3-yl;

(10) (1S, 5R)-1-amino-3-azabicyclo[3.3.0]octane-3-yl;

(11) (1S, 5S)-1-amino-3-azabicyclo[3.3.0]octane-3-yl;

(12) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl;

(13) (1R, 5R)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl;

(14) (1S, 5R, 6S)-1-amino-6-fluoro-3-azabicyclo[3.3.0]octane-3-yl;

(15) (1S,5R)-1-amino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3-yl;

(16) (1S, 5R, 7S)-1-amino-7-fluoro-3-azabicyclo[3.3.0]octane-3-yl;

(17) (1S, 5R, 7R)-1-amino-7-fluoro-3-azabicyclo[3.3.0]octane-3-yl;

(18) (1S, 5R)-1-amino-3-azabicyclo[3.3.0]oct-7-en-3-yl;

(19) (1S, 5R)-1-amino-7-methyl-3-azabicyclo[3.3.0]oct-7-en-3-yl;

(20) (1S)-1-amino-3-azabicyclo[3.3.0]oct-5-en-3-yl;

(21) (1S)-1-amino-6-methyl-3-azabicyclo[3.3.0]oct-5-en-3-yl;

(22) (1R, 5R)-1-amino-3-oxa-5-azabicyclo[3.3.0]octane-5-yl;

(23) (1R, 5S)-1-amino-3-oxa-5-azabicyclo[3.3.0]octane-5-yl;

(24) (1R, 5R)-1-amino-4-oxa-5-azabicyclo[3.3.0]octane-5-yl;

(25) (1R, 5S)-1-amino-4-oxa-5-azabicyclo[3.3.0]octane-5-yl;

(26) 6-amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl;

(27) (1S, 5R)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl;

(28) (1S, 5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl;

(29)(1S,5S)-1-amino-3-azabicyclo[4.3.0]non-7-en-3-yl;

(30) (1S, 5S)-1-amino-3-azabicyclo[4.3.0]non-8-en-3-yl;

(31) (1S)-1-amino-3-azabicyclo[4.3.0]non-5-en-3-yl;

(32) (1R, 6S)-1-amino-5-oxa-8-azabicyclo[4.3.0]nonan-8-yl;

(33) (1S, 6S)-1-amino-4-oxa-8-azabicyclo[4.3.0]nonan-8-yl; and

(34) (1S,6S)-1-Amino-3-oxa-8-azabicyclo[4.3.0]nonan-8-yl.

[Formula 41]

Still more preferred examples of the substituent at the 7-position (or its corresponding position) are listed below:

[Formula 42]

Therefore, preferred compounds of the present invention are compounds each having the above-exemplified quinolonecarboxylic acid skeleton substituted with the above-exemplified 7-position substituent (a combination of the above-exemplified parent skeleton and the above-exemplified substituent). In the above formula, the configuration of the 3-position (or its corresponding position) substituted by amino group on the pyrrolidine ring is preferably β-configuration. The absolute configuration at the 3-position (or its corresponding position) can be 3S or 3R, depending on the type of substituent at the 4-position. The compounds of the invention are preferably stereochemically single compounds.

Preferred examples of compounds of the invention (which may be in the form of salts or hydrates) are listed below:

(1) 7-[(1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(2) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(3) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(4) 10-[(1S,5R,6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]heptane-3-yl]-9-fluoro-2,3-di Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(5) 7-[(1S, 5R, 6S)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[( 1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(6) 7-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(7) 10-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-9-fluoro-2,3-di Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(8) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(9) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(10) 10-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-9-fluoro-2,3-di Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(11) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(12) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-6-fluoro-1-[(1R ,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(13) 10-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorobicyclo[3.2.0]heptane-3-yl]-9-fluoro-2,3-di Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(14) 7-[(1S, 5R)-1-amino-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(15) 10-[(1R,5S)-1-amino-3-aza-5-fluorobicyclo[3.3.0]octane-3-yl]-9-fluoro-2,3-dihydro-3 -(S)-Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(16) 7-[(1R, 5S)-1-amino-3-aza-5-fluorobicyclo[3.3.0]octane-3-yl]-8-chloro-6-fluoro-1-[( 1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(17) 7-[(1R, 5S)-1-amino-3-aza-5-fluorobicyclo[3.3.0]octane-3-yl]-8-cyano-6-fluoro-1-[ (1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(18) 7-[(1R, 5S)-1-amino-3-aza-5-fluorobicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(19) 7-[(1R, 5S)-1-amino-3-aza-5-fluorobicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(20) 7-[(1R, 5S)-1-amino-3-aza-5-chlorobicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(21) 7-[(1R, 5S)-1-amino-3-aza-5-chlorobicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S) -2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(22) 7-[(1S, 5R)-1-amino-3-azabicyclo[3.3.0]oct-7-en-3-yl]-6-fluoro-1-[(1R, 2S)- 2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(23) 7-[(1S, 5R)-1-amino-3-azabicyclo[3.3.0]oct-7-en-3-yl]-6-fluoro-1-[(1R, 2S)- 2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(24) 7-[(1S)-1-amino-3-azabicyclo[3.3.0]oct-5-en-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(25) 7-[(1S)-1-amino-3-azabicyclo[3.3.0]oct-5-en-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(26) 7-[(1S)-1-amino-5-methyl-3-azabicyclo[3.3.0]oct-5-en-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(27) 10-[6-Amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl Base-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(28) 7-[6-Amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl]-8-cyano-6-fluoro-1-[(1R,2S)- 2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(29) 7-[6-Amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(30) 7-[6-Amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(31) 7-[(1S, 5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl]-8-cyano-6-fluoro-1-[(1R, 2S )-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(32) 7-[(1S, 5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(33) 7-[(1S, 5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl]-1-[(1R,2S)-2-fluorocyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(34) 7-[(1S, 5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(35) 10-[(1S,5S)-1-amino-3-azabicyclo[4.3.0]nonan-3-yl]-9-fluoro-2,3-dihydro-3-(S) -Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid;

(36) 7-[(1S, 6S)-1-amino-8-aza-3-oxabicyclo[4.3.0]nonan-8-yl]-8-chloro-6-fluoro-1-[ (1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(37) 7-[(1S, 6S)-1-amino-8-aza-3-oxabicyclo[4.3.0]nonan-8-yl]-8-cyano-6-fluoro-1- [(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid;

(38) 7-[(1S, 6S)-1-amino-8-aza-3-oxabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R, 2S )-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid;

(39) 7-[(1S, 6S)-1-amino-8-aza-3-oxabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R, 2S )-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid;

(40) 10-[(1S,6S)-1-amino-8-aza-3-oxa-bicyclo[4.3.0]nonan-8-yl]-9-fluoro-2,3-dihydro -3-(S)-Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.

Next, the substituents at the 7-position (or corresponding positions) of the quinolone skeleton related to the compounds of the present invention will be described. Specifically, the substituent has an amino group at the corresponding position of the 3-position of pyrrolidinyl, and the substituent R on the carbon atom substituted by the amino group is ⁷ and the substituent R ⁶ (on the corresponding position of the 4-position of the pyrrolidinyl group) ) are combined with the carbon atoms to which they are attached to form a 4-7 membered ring structure. More specifically, the substituent is a fused substituted aminopyrrolidine derivative in which the cyclic structure together with the pyrrolidine ring forms a fused cyclic (bicyclic) structure represented by the following formula, wherein the fused cyclic structure is at the bridgehead position Substituted by amino on:

[Formula 43]

In addition, the substituent is a fused substituted aminopyrrolidinyl substituent having a ring structure represented by the following formula, wherein the ring structure formed by combining the substituents ^R6 and ^R7 with the carbon atoms to which they are attached is 5-membered ring or 6-membered ring, and R ⁵ and R ⁶ combine to form a double bond partial structure:

[Formula 44]

Preferred compounds of the invention (which may also be in the form of their salts or hydrates) are exemplified below:

[1] A compound represented by the formula (I), wherein it is a compound represented by the following formula:

[Formula 45]

Or a compound represented by the following formula:

[Formula 46]

[2] A compound represented by the formula (I), wherein it is a compound represented by the following formula:

[Formula 47]

[3] A compound wherein, in the compound represented by formula (I), Q represented by formula (II) has a structure represented by the following formula:

[Formula 48]

Or the structure represented by the following formula:

[Formula 49]

[4] A compound wherein, in the compound represented by the formula (I), Q represented by the formula (II) has a structure represented by the following formula:

[Formula 50]

[5] A compound wherein in formula (I), R ¹ and R ² are each a hydrogen atom.

[6] A compound, wherein in formula (I), one of R ^{and R} is a hydrogen atom, and the other is a substituent selected from the group consisting of methyl, ethyl, isopropyl, fluoroethyl, cyanide ethyl, cyclopropyl and cyclobutyl.

[7] A compound wherein in formula (I), R ³ and R ⁴ are each a hydrogen atom.

[8] Compounds, wherein in formula (I), R ⁵ is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a fluoromethyl group, a fluoroethyl group, a trifluoromethyl group methoxymethyl, vinyl, ethynyl, methoxy, phenyl or oxazol-2-yl.

[9] A compound, wherein in formula (I), the ring structure formed by combining R ⁶ and R ⁷ with the carbon atoms to which they are attached is a 4-membered ring, which may be substituted by one or more substituents .

[10] Compounds, wherein in formula (I), the ring structure formed by combining R ⁶ and R ⁷ with the carbon atoms to which they are attached is a 5-membered ring or a 6-membered ring, which can be replaced by one or more A substituent is substituted.

[11] The compound, wherein in the formula (I), the ring structure formed by combining ^R6 and ^R7 with the carbon atoms to which they are attached is a 5-membered ring or a 6-membered ring containing a double bond as a constituent structure , which may be substituted by one or more substituents.

[12] The compound, wherein in ^the formula (I), the ring structure formed by combining R ^and R with the carbon atoms to which they are attached is a 5-membered ring or a 6-membered ring containing an oxygen atom as a constituent atom , which may be substituted by one or more substituents.

[13] A compound wherein in formula (I), the ring structure formed by combining R and R with the carbon atoms to which they are attached is a 5 ^{- membered} ring or a 6-membered ring and is fused to a pyrrolidine ring And form the cis-condensed bicyclic structure represented by the following formula:

[Formula 51]

[14] A compound wherein in formula (I), the ring structure formed by combining R and R with the carbon atoms to which they are attached is a 5 ^{- membered} ring or a 6-membered ring and is fused to a pyrrolidine ring And form the trans-condensed bicyclic structure represented by the following formula:

[Formula 52]

[15] The compound, wherein in the formula (I), the ring structure formed by combining R ⁶ and R ⁷ with the carbon atoms to which they are attached is a 5-membered ring or a 6-membered ring, and R ⁵ and R ⁶ are combined Together to form a double bond partial structure, the resulting ring structure is represented by the following formula:

[Formula 53]

[16] A compound wherein, in the partial structure Q represented by the formula (II) in the formula (I), X ¹ is a hydrogen atom or a fluorine atom.

[17] A compound wherein, in the partial structure Q represented by the formula (II) in the formula (I), X ¹ is a fluorine atom.

[18] A compound wherein, in the partial structure Q represented by the formula (II) in the formula (I), A ¹ is a nitrogen atom.

[19] A compound wherein, in the partial structure Q represented by the formula (II) in the formula (I), A ¹ is a partial structure represented by the formula (III).

[20] A compound wherein in formula (III), X ² is a methyl group, an ethyl group, a methoxy group, a difluoromethoxy group, a cyano group or a chlorine atom.

[21] A compound wherein in formula (III), X ² is methyl or methoxy.

[22] A compound wherein in the partial structure Q represented by the formula (II) in the formula (I), R ⁸ is 1,2-cis-2-halocyclopropyl.

[23] A compound wherein, in the partial structure Q represented by the formula (II) in the formula (I), R ⁸ is a stereochemically single 1,2-cis-2-halocyclopropyl group.

[24] The compound, wherein in the partial structure Q represented by the formula (II) in the formula (I), the 1,2-cis-2-halocyclopropyl group of ^R is (1R, 2S)-2 - halocyclopropyl.

[25] The compound, wherein in the partial structure Q represented by the formula (II) in the formula (I), the (1R, 2S)-2- ^{halocyclopropyl} of R is (1R, 2S)-2 - Fluorocyclopropyl.

[26] A compound wherein, among the compounds represented by the formula (I), Q is a compound represented by the following formula:

[Formula 54]

wherein Y ⁰ is methyl or fluoromethyl.

[27] A compound wherein in the partial structure Q represented by the formula (II) in the formula (I), R ⁹ is a hydrogen atom.

[28] A compound wherein, among the compounds represented by the formula (I), Q is a compound represented by the following formula (IV):

[Formula 55]

wherein Y ⁰ is methyl or fluoromethyl.

[29] A compound wherein in formula (IV), Y ⁰ is methyl.

[30] A compound wherein in the partial structure Q represented by the formula (II) in the formula (I), R ¹⁰ is a hydrogen atom.

[31] A compound wherein the compound represented by the formula (I) is a stereochemically single compound.

The synthesis of pyrrolidine compounds required to introduce substituents into the quinolone parent skeleton will be described below. There are several possibilities for the synthesis of fused substituted aminopyrrolidine derivatives. Several examples of representative synthetic methods performed by the inventors of the present invention are summarized below (see details described in the Reference Examples in the "Examples" section). However, the synthesis method of the fused substituted aminopyrrolidine derivatives of the present invention is not limited thereto.

The inventors of the present invention utilized a 1,3-dipolar cycloaddition reaction represented by the following scheme with a β-electron-withdrawing group-substituted α,β-unsaturated cyclic or acyclic compound and an imine Using azomethine ylide as a reactive element, an important synthetic intermediate was synthesized through appropriate reaction steps, and a fused substituted aminopyrrolidine derivative was synthesized:

[Formula 56]

In this process, EWG is an electron-withdrawing group; PG is an amino protecting group; R ³¹ , R ⁴¹ , R ⁵¹ , R ⁶¹ and R ⁷¹ are each a hydrogen atom or a substituent suitable for an intermediate; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y and n are as defined above.

The β-electron withdrawing group-substituted α,β-unsaturated compound used in this reaction can be cyclic or acyclic. Bicyclic pyrrolidine derivatives can be synthesized from cyclic compounds in one step. Acyclic compounds can be converted to bicyclic pyrrolidine derivatives by subjecting suitable synthetic intermediates to suitable cyclization or ring closure reactions, such as carbon-carbon bond formation via carbanion nucleophilic reactions or carbon -Oxygen (or sulfur) bond forming reactions; ether (or thioether) ring forming reactions by intramolecular Mitsunobu reactions; ring-forming esterification or ring-forming amidation known as lactone or lactam forming reactions; Molecule Internal condensation ring closure reactions such as aldol condensation, Dieckmann condensation, acyloin condensation, Wittig condensation or Reformatsky reaction ; ring-closing metathesis (RCM); Diels-Alder reaction; deoxycoupling cyclization reactions, such as the McMurry reaction (McMurryreaction); free radical cyclization reactions; coupled ring closures using metal complexes reaction; or photocyclization reaction.

In addition, the electron-withdrawing group (EWG) in the β-electron-withdrawing gene-substituted α,β-unsaturated compound used in the above reaction can be converted into an amino group or an amino group protected by a suitable protecting group by one or several steps . Examples of such groups include ester, cyano, acyl, carbamoyl, carboxy and nitro groups. After conversion to a carboxyl group (carboxylic acid) by hydrolysis, an ester group or a cyano group can be converted to an amine derivative by a Curtius rearrangement reaction. After conversion to carbamoyl groups, cyano or carboxyl groups can be converted to amine derivatives by Hofmann rearrangement. After conversion into hydroxyimino group, the acyl group can be converted into an amine derivative by Beckmann rearrangement reaction or the like. The nitro group is converted to an amine derivative by a reduction reaction.

On the other hand, by adding a catalytic amount of trifluoroacetic acid or a catalytic amount of silver fluoride to the reagent N-benzyl-N-(methoxymethyl)trimethylsilylmethanamine, the An imine ylide used as a reaction element in the reaction, for example [see Journal of Organic Chemistry, Vol. 52, No. 2, p. 235 (1987)]. In the above reaction formula, PG in the methylimine ylide represents a suitable amino protecting group. In the above-mentioned reagents used to produce amethymine ylides, the protecting group is benzyl, but a preferred example is 1-phenylethyl having optical activity. The amino-protecting group (PG) and the amino-protecting group produced by converting an electron-withdrawing group in a later step can be the same or different; the protecting group can be suitably selected from commonly used amino-protecting groups as long as they do not affect the reaction, e.g. Does not inhibit each reaction step and is easily deprotected at a later stage.

基、(2′S)-莰烷-10，2-磺内酰胺基或(S)-4-苄基-2-噁唑烷酮基)；对映体选择的1，3-偶极环加成反应，使用具有不对称的元素的甲亚胺叶立德(例如分子中的(1R)-1-苯乙基)；或非对映体选择的1，3-偶极环加成反应，使用不对称的亲偶极试剂和不对称的甲亚胺叶立德[参见Journal of the Chemical Society PerkinTransactions 1，第1076页(2002)]。此外，可通过不对称的1，3-偶极环加成反应，用不对称的金属络合物或盐作为催化剂，得到旋光环加合物[参见Angewandte Chemie International Edition，第44卷，第6272页(2005)]。Next, synthesis of an optically active substance will be described. Optically active substances can be synthesized, for example, by optical resolution of appropriate intermediates. Specific examples of optical resolutions include HPLC resolution using chiral columns and preferential crystallization of diastereomeric salts for appropriate intermediates; and conversion of intermediates to diastereomers by combining chiral elements with appropriate intermediates , followed by a suitable separation technique such as silica gel chromatography to separate the diastereomers and remove the chiral element to convert the diastereomers into optically active substances. Optically active substances can also be synthesized from chiral building blocks as starting materials. Specifically, optically active cycloadducts can be obtained by enantioselective 1,3-dipolar cycloaddition reactions using dipolarophiles with asymmetric elements (e.g. asymmetric functional groups such as 1-

group, (2′S)-bornane-10,2-sultamyl or (S)-4-benzyl-2-oxazolidinonyl); enantiomerically selected 1,3-dipolar ring Addition reactions, using an imine ylide with an asymmetric element (such as (1R)-1-phenylethyl in the molecule); or diastereoselective 1,3-dipolar cycloaddition reactions, using Asymmetric dipolarophiles and asymmetric azimine ylides [see Journal of the Chemical Society Perkin Transactions 1, p. 1076 (2002)]. In addition, optically active cycloadducts can be obtained by asymmetric 1,3-dipolar cycloaddition reactions using asymmetric metal complexes or salts as catalysts [cf. Angewandte Chemie International Edition, Vol. 44, No. 6272 p. (2005)].

The inventors of the present invention adopted the 1,3-dipolar cycloaddition reaction of β-electron-withdrawing group-substituted α,β-unsaturated compounds as the key reaction and carried out the fused substituted amino Synthesis of pyrrolidine derivatives, which will be specifically described using the synthesis of 1-amino-3-azabicyclo[3.3.0]octane derivatives as an example:

[Formula 57]

In the above scheme, Boc represents tert-butoxycarbonyl, Cbz represents benzyloxycarbonyl, provided that these substituents can be the same or different commonly used amino protecting groups; and R represents an alkyl group having ^1-6 carbon atoms .

Step 1 is a synthetic step of 1-alkoxycarbonyl-3-azabicyclo[3.3.0]octane derivatives (which are fused substituted pyrrolidine derivatives) using 1-cyclopentene-1 - 1,3-Dipolar cycloaddition of esters and use of an imine ylide as the reaction element. For example, by adding a catalytic amount of trifluoroacetic acid or a catalytic amount of silver fluoride to the reagent N-benzyl-N-(methoxymethyl)trimethylsilylmethanamine as described above, the formazan Amine ylide response element. The reaction solvent may be any solvent that does not inhibit the generation of amethymine ylide and the 1,3-dipolar cycloaddition reaction, but is preferably dichloromethane or 1,2-dichloroethane. The reaction can be carried out at -20°C to solvent reflux temperature, but preferably at room temperature to solvent reflux temperature.

Step 2 is the step of converting the benzyl at the 3-position of the 3-azabicyclo[3.3.0]octane ring into a protecting group. This step is performed to facilitate the extraction, isolation and purification of carboxylic acid derivatives produced after hydrolysis of the 1-position ester (if the benzyl group is not converted, the formation, isolation and purification of amino acid derivatives will be difficult). The protecting group at the 3-position is preferably one that is normally distinguishable from the protecting group at the 1-position amino group produced after conversion of the 1-position carboxylic acid during the deprotection step, but can also be distinguished from the protecting group at the 1-position amino group. same. The protecting group at the 3-position is preferably benzyloxycarbonyl or tert-butoxycarbonyl, especially preferably benzyloxycarbonyl. Benzyloxycarbonylation reactions, i.e. direct transformations via the von Braun reaction, can usually be carried out using solvents such as benzyl chloroformate in dichloromethane; or on catalysts such as palladium-carbon Catalytic hydrogenolysis is followed by reacting benzyl chloroformate in a suitable solvent in the presence of a base.

Step 3 is the hydrolysis step of the ester at the 1-position of the 3-azabicyclo[3.3.0]octane ring. Esters are alkyl esters having 1 to 6 carbon atoms, preferably methyl, ethyl or tert-butyl esters. The hydrolysis reaction is carried out by using an ordinary method using a base or an acid which does not affect the protecting group at the 3-position. In the hydrolysis of methyl or ethyl esters, the ester is reacted with a base solution (such as sodium hydroxide in ethanol or water, potassium hydroxide in ethanol or water, or barium hydroxide in ethanol or water) and then reacted with a solution that does not affect the 3-position. Acidification with a suitable acid for the protecting group, followed by separation and purification. The tert-butyl ester is hydrolyzed in a suitable solvent in which the ester can be dissolved under acidic conditions or in the presence of an acidic catalyst. Preferred acids include hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.

Step 4 is the step of converting the carboxylic acid at the 1-position of the 3-azabicyclo[3.3.0]octane ring into an amine. This step is usually carried out by a rearrangement reaction from the carboxylic acid to the amine. For example, when the rearrangement is a Curtius rearrangement, using a reagent such as sodium azide, trimethylsilyl azide or diphenoxyphosphoryl azide in a suitable solvent such as toluene Nitrogen (DPPA) converts carboxylic acid to acyl azide, then heats the reaction solution to form isocyanate, which is converted to amine by hydrolysis using hydrochloric acid or the like.

Step 5 is a step in which the amino group at the 1-position of the 1-amino-3-azabicyclo[3.3.0]octane ring is protected; however, the subsequent steps can be performed without this protection. The protecting group for the 1-position amino group may be a commonly used amino protecting group, but is preferably a protecting group that can be distinguished from the 3-position protecting group in the deprotection step. Specific examples of protecting groups include tert-butoxycarbonyl, acetyl and trifluoroacetyl. The inventors of the present invention chose tert-butoxycarbonyl.

By rearrangement reaction, step 4 and step 5 can be carried out in one step using a suitable solvent. For example, 1-(tert-butoxycarbonyl)amino-3-aza can be prepared by Curtius rearrangement using diphenoxyphosphoryl azide (DPPA) in tert-butanol Bicyclo[3.3.0]octane derivatives.

Step 6 is the optical resolution step of 1-amino-3-azabicyclo[3.3.0]octane derivative. This can be resolved by HPLC, using a suitable chiral column for this step. As a result of this optical resolution, it has been found that the antibacterial activity of quinolonecarboxylic acid derivatives derived from the resulting enantiomers of 1-amino-3-azabicyclo[3.3.0]octane derivatives having positive optical activity, Superior to quinolonecarboxylic acid derivatives derived from the resulting enantiomer with negative optical rotation (see "Examples" section). The inventors of the present invention have chosen tert-butoxycarbonyl as the protecting group for the amino group at the 1-position; however, optical split. For example, when the amino group at the 1-position is unprotected or protected by a protecting group such as benzyl or t-butyl (in which case the protected amino group is basic), conversion of an appropriate optically active acid to method for diastereomeric salts and preferential crystallization of diastereomeric salts, in addition to HPLC optical resolution with a suitable chiral column. In this case, optically active 1-amino-3-azabicyclo[3.3.0]octane derivatives can be obtained by converting the preferentially crystalline diastereomeric salts into the free base. In addition, when the amino group at the 1-position is unprotected, the following method can be used: incorporation of a chiral element to convert the derivative into diastereomers, followed by separation of the diastereomers using a suitable separation technique such as silica gel chromatography, and migration Diastereomers are converted to optically active species by removal of chiral elements.

The inventors of the present invention have described a specific optical resolution method in this step; however, when a suitable synthetic intermediate can be optically resolved, the intermediate can be appropriately selected and optically resolved as described above .

Step 7 is the deprotection step of 3-position of 1-amino-3-azabicyclo[3.3.0]octane derivative. The deprotection reaction can be carried out under any conditions without changing other functional groups and configurations. Therefore, since the protecting group at the 1-position of the compound of the present invention is benzyloxycarbonyl, the deprotection reaction is carried out under usual deprotection conditions, for example, under conditions using a catalyst such as palladium-carbon, or using ammonium formate, on The deprotection reaction proceeds by catalytic hydrogenolysis in a protic polar solvent. When the 3-azabicyclo[3.3.0]octane derivative has a carbon-carbon unsaturated bond in the molecule, the carbon-carbon unsaturated bond must be retained while performing deprotection. Therefore, since the 3-protecting group of the compound of the present invention is benzyloxycarbonyl, deprotection under strong acid conditions (such as hydrobromic acid-acetic acid, trifluoroacetic acid or trifluoromethanesulfonic acid-trifluoroacetic acid) The carbon-carbon unsaturation in the 3-azabicyclo[3.3.0]octane ring is also preserved, ie by using sodium-liquid ammonia (Birch reducing conditions) or by using eg barium hydroxide.

In addition, condensed substituted aminopyrrolidine derivatives as compounds of the present invention can be synthesized using chiral pyrrolidine derivatives as starting materials. The following synthetic intermediates were used in the synthesis, using eg so called chiral building blocks. The chiral pyrrolidine derivatives usable as intermediates are not limited to the following compounds.

[Formula 58]

[Journal of Medicinal Chemistry, Vol. 30, No. 10, No. 1171 (1987); WO 94/14794; Tetrahedron, Vol. 61, No. 23, No. 5465 (2005); Tetrahedron Asymmetry, Vol. 15, Issue 20, p. 3249 (2004)]

In a suitable number of steps, these chiral pyrrolidine derivatives can be converted to bicyclic pyrrolidine derivatives which are compounds of the invention. For example, chiral pyrrolidine derivatives can be converted to fused substituted aminopyrrolidine derivatives by introducing suitable substituents into the 3- and 4-positions of the pyrrolidine ring followed by suitable homologation reactions or functional groups Transformation, and cyclization (ring closure) reaction. Examples of cyclization (ring closure) reactions that are suitable synthetic intermediates that are important steps in the transformation reactions include carbon-carbon bond formation reactions or carbon-oxygen (or sulfur) bond formation reactions through carbanion nucleophilic reactions; Ether (or thioether) ring formation reaction of (Mitsunobu) reaction; ring-forming esterification or ring-forming amidation known as lactone or lactam forming reaction; intramolecular condensation ring-closing reactions, such as aldol condensation, Dickmann condensation , ketone-alcohol condensation, Wittig condensation or Reformatsky reaction; deoxycoupling cyclization reactions, such as McMurry reactions; ring-closing metathesis reactions (RCM); Diels-Alder (Diels-Alder) reactions ; radical cyclization reactions; coupled ring closure reactions using metal complexes; and photocyclization reactions.

The inventors of the present invention use chiral pyrrolidine derivatives as important intermediates to carry out the synthesis of fused substituted aminopyrrolidine derivatives, which will use (1S, 5R)-1-amino-3-azabicyclo[ 3.3.0] The synthesis of octane derivatives is specifically described as an example. The inventors of the present invention have selected tert-butoxycarbonyl as the protecting group for the 1-position amine moiety; however, the protecting group for the 1-position amino group may be a protecting group that is not tert-butoxycarbonyl and does not affect ( For example, each reaction step is not inhibited and can be easily deprotected, and the protecting group may be the same as that at the 3-position. In the following cases, the 1-position protecting group is (1R)-1-phenylethyl:

[Formula 59]

In the above schemes, Boc represents tert-butoxycarbonyl.

Step 8 is the allylation step of the 3-position of the pyrrolidine ring (α-position of the ester). Step 8 is usually carried out using allyl halide such as allyl bromide as the allylation reagent in the presence of a base. Examples of the base include potassium carbonate, cesium carbonate, sodium hydride, sodium metal, sodium ethoxide, potassium tert-butoxide, lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide. Examples of the reaction solvent include tetrahydrofuran, acetone, N,N-dimethylformamide, toluene, and mixed solvents thereof. After the reaction is completed, the diastereomers of the allylated compound can be separated and purified by silica gel chromatography and other methods. The inventors of the present invention used tert-butyl ester as the ester at the 3-position of the pyrrolidine ring; however, other ester derivatives may also be used. The above separation of diastereomers is readily performed when a large amount of tert-butyl ester is used.

Step 9 is the step of converting the allyl moiety to a primary alcohol (specifically, 1-hydroxypropyl) by hydroboration-oxidation of the terminal olefin of the allyl moiety. The hydroboration reaction is usually carried out in anhydrous tetrahydrofuran using various reagents: borane complexes (such as borane-tetrahydrofuran complex and borane-dimethyl sulfide complex), monoalkyl Boranes (such as hexylborane), dialkylboranes (such as 9-borabicyclo[3.3.1]nonane (9-BBN), dicyclohexylborane and bis(1,2-dimethylpropane base) borane), chloroborane-dimethyl sulfide complex, dichloroborane-dimethyl sulfide complex, phthalate borane, etc. Usually, the oxidation reaction of the organoborane compound produced by the hydroboration reaction is carried out under alkaline conditions such as an aqueous solution of sodium hydroxide or an aqueous solution containing ethanol using an aqueous hydrogen peroxide solution.

The inventors of the present invention have synthesized a compound in which a 1-hydroxypropyl group is introduced into the 3-position of the pyrrolidine ring in the 2 steps shown in Step 8 and Step 9; however, it is also possible by another synthesis method to synthesize the product. For example, the product can be synthesized by protecting the hydroxyl moiety of commercially available 3-iodopropanol with a suitable protecting group (such as tert-butyldimethylsilyl), and then reacting with a suitable base (such as the base described in step 8) ) in the presence of 3-substituted hydroxypropylation followed by deprotection under suitable conditions. In addition, 3-substituted hydroxypropylation can be carried out after one hydroxyl group of 1,3-propanediol is protected with a suitable protecting group, and then the other hydroxyl group is converted into a halogen atom or a well-known leaving group. In this case, examples of the leaving group include methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy.

Step 10 is the bromination step of the hydroxyl group. It is not suitable to carry out the bromination reaction under the typical strong acid conditions of hydrobromic acid-concentrated sulfuric acid, sodium bromide-sulfuric acid, etc., because there is tert-butyl ester in the molecule. Bromination reactions are suitable reactions using triphenylphosphine-tetrabromomethane in dichloromethane or tetrahydrofuran, reactions using triphenylphosphine dibromide in N,N-dimethylformamide, etc. [see Journal of American Chemical Society, Vol. 125, No. 43, p. 13625 (2003)]. Furthermore, in this bromination reaction, tetrabutylammonium bromide in N,N-dimethylformamide or Vilsmeier's reagent [((chloromethylene)dimethylimmonium chloride] can be used as a reagent. After conversion of the hydroxyl moiety to a suitable leaving group, bromination reagents such as sodium bromide, lithium bromide or calcium bromide in N,N-dimethylformamide or dimethylsulfoxide can be used Bromination reaction. In this case, examples of the leaving group include methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy.

The inventors of the present invention have synthesized a compound in which a 1-bromopropyl group was introduced into the 3-position of the pyrrolidine ring as a compound used in the next step. Examples of compounds that can be used in the next step that are not the product include 1-iodo compounds and compounds into which a leaving group such as methanesulfonyloxy, trifluoromethanesulfonyloxy , benzenesulfonyloxy or p-toluenesulfonyloxy.

Step 11 is the step of generating a carbanion at the 4-position (amide: α-position of pyrrolidone) of the bromine compound pyrrolidine ring synthesized in step 10, using a suitable base, through intramolecular nucleophilic substitution (intramolecular ring closure reaction) ) cause a reaction to form a carbon-carbon double bond. Typical examples of bases include potassium carbonate, cesium carbonate, sodium hydride, sodium metal, sodium ethoxide, potassium tert-butoxide, lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide, bis(trimethylsilyl)amide, Potassium Methylsilyl)amide and Sodium Bis(trimethylsilyl)amide. Examples of the reaction solvent include tetrahydrofuran, acetone, N,N-dimethylformamide, toluene, and mixed solvents thereof. The cyclopentane ring formed by the intramolecular ring closure usually forms a cis-fused ring (cis-3-azabicyclo[3.3.0]octane ring) together with the pyrrolidine ring moiety. This synthetic method can be used to synthesize fused substituted aminopyrrolidine derivatives, such as 3-azabicyclo[4.3.0]nonane derivatives, but can produce cis and trans isomerisms of fused substituted aminopyrrolidine derivatives body mixture. In such cases, the necessary isomers can be isolated by suitable separation and purification procedures such as chromatography on silica gel.

Step 12 is the step of converting tert-butyl ester to carboxylic acid by hydrolysis or deprotection. The inventors of the present invention have chosen tert-butyl esters as esters; however, esters are suitably alkyl esters having 1 to 6 carbon atoms, preferably methyl, ethyl or tert-butyl esters. The tert-butyl ester is hydrolyzed or deprotected in a suitable solvent where the ester is soluble under acidic conditions or in the presence of an acid catalyst. Preferred acids include hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid. In the hydrolysis of methyl or ethyl esters, the ester is reacted with an alkaline solution (such as sodium hydroxide in ethanol or water, potassium hydroxide in ethanol or water, or barium hydroxide in ethanol or water) and then reacted with a solution that does not affect the 3-position. Acidification with a suitable acid for the protecting group, followed by separation and purification.

Step 13 is a step of converting the carboxylic acid at the 1-position of the 3-azabicyclo[3.3.0]octane ring into an amine. This step is usually carried out by a rearrangement reaction from the carboxylic acid to the amine. For example, when the rearrangement reaction is a Curtius rearrangement reaction, in a suitable solvent such as toluene, with a reagent such as sodium azide, trimethylsilyl azide or diphenoxyphosphoryl azide Nitrogen (DPPA) converts carboxylic acid into acyl azide, then heats the reaction solution to form isocyanate, and then converts isocyanate into amine by hydrolysis with hydrochloric acid or the like.

Step 14 is a protection step of the amino group at the 1-position of the 1-amino-3-azabicyclo[3.3.0]octane ring; however, subsequent steps can be performed without this protection. The protecting group for the amino group at the 1-position may be a commonly used amino protecting group, but is preferably a protecting group that can be distinguished from the protecting group at the 3-position in the deprotection step. Specific examples of protecting groups include tert-butoxycarbonyl, acetyl and trifluoroacetyl. The inventors of the present invention chose tert-butoxycarbonyl.

Step 13 and Step 14 can be accomplished in one step by rearrangement reaction using an azide reagent in a suitable solvent. For example, 1-(tert-butoxycarbonyl)amino-3-azabicyclo[ 3.3.0] Octane derivatives.

Step 15 is the reduction step of the carboxyl group of the pyrrolidone (called amide). Step 15 can be carried out using metal hydrides such as lithium aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride or borohydride compounds such as diborane or borane-tetrahydrofuran complexes as reducing agents. Ether solvents typified by toluene or tetrahydrofuran are often used as solvents. The reaction is usually carried out at a temperature of -78°C to 100°C.

Step 16 is the deprotection step of the 1-position of the pyrrolidine ring. Deprotection reactions can be performed without changing other functional groups and configurations. Therefore, since the protecting group at the 1-position of the compound of the present invention is (1R)-1-phenylethyl, the deprotection reaction is carried out under usual deprotection conditions, for example, using a catalyst such as palladium-carbon, Alternatively, the deprotection reaction is carried out by catalytic hydrogenolysis using ammonium formate in a protic polar solvent. When there is a carbon-carbon unsaturated bond as a substituent in the molecule, the carbon-carbon unsaturated bond must be retained while performing deprotection. Therefore, since the 1-protecting group of the compound of the present invention is (1R)-1-phenylethyl, the carbon-carbon unsaturated bond in the molecule is also retained during deprotection, that is, by using, for example, sodium-liquid ammonia ( Birch reducing conditions). After conversion of the 1-position (1R)-1-phenylethyl to benzyloxycarbonyl by the von Braun reaction using benzyl chloroformate, usually in a solvent such as dichloromethane, Groups can be deprotected by the methods described above.

In addition, after the previous synthesis of the corresponding heterocyclic compound (an important synthetic intermediate), the pyrrolidine ring as a fused substituted aminopyrrolidine derivative of the compound of the present invention can be formed by common synthetic methods, etc., see the following scheme:

[Formula 60]

Wherein R ¹³ is an ester group, carbamoyl, nitro or cyano group (which can be converted into an amino group) or an amino group that can have a substituent with 2-7 carbon atoms; PG is an amino protecting group; R ¹⁴ and R ¹⁵ are suitable substituents known to be combined together and then optionally undergo a suitable reaction to form a pyrrolidine ring; R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Y and n are as defined above.

The substituent R ¹³ is preferably an optionally substituted ester group or amino group having 2 to 7 carbon atoms, and is particularly preferably a group that is stable in each reaction step of the pyrrolidine ring-forming reaction listed below.

Here, the substituents R ¹⁴ and R ¹⁵ and the pyrrolidine ring formation method will be described, wherein R ¹⁴ and R ¹⁵ are combined together and then optionally undergo a suitable reaction.

When the substituents R ¹⁴ and R ¹⁵ are each a hydroxymethyl group (-CH ₂ OH), the primary amine can be directly alkylated or the hydroxyl moiety can be converted into a halogen atom or a suitable leaving group and then alkylated, to form a pyrrolidine ring. Preferable examples of the halogen atom include chlorine, bromine and iodine. Examples of leaving groups include methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy.

When the substituents R ¹⁴ and R ¹⁵ are each a carboxyl group, an ester group or an acid halide, the imide derivatives can be synthesized by directly synthesizing the imide derivatives, or by an acid anhydride synthesized by a suitable condensation reaction, and then Reduction of the imide converts the synthetic intermediate to the pyrrolidine derivative. The ester group preferably has 2 to 7 carbon atoms. Using metal hydrides such as lithium aluminum hydride or bis(2-methoxyethoxy) sodium aluminum hydride or borohydride compounds such as diborane or borane-tetrahydrofuran complexes as imide reducing agents, to Reduction of imides. Ether solvents typified by tetrahydrofuran are often used as solvents. The reaction is usually carried out at a temperature of -78°C to 100°C.

When one of the substituents R ¹⁴ and R ¹⁵ is an aminomethyl group (-CH ₂ NH ₂ ), and the other is a carboxyl group or an ester group, an amide derivative (lactam derivative) is synthesized by a suitable condensation reaction, The amide is then reduced to convert the synthetic intermediate to the pyrrolidine derivative. The ester group preferably has 2 to 7 carbon atoms. Amide derivatives (lactam derivatives) are generally synthesized in an alcoholic solvent by heating in the presence or absence of a suitable base. Using metal hydrides such as lithium aluminum hydride or bis(2-methoxyethoxy) sodium aluminum hydride or borohydride compounds such as diborane or borane-tetrahydrofuran complexes as imide reducing agents, reduction amides. Ether solvents typified by tetrahydrofuran are often used as solvents. The reaction is usually carried out at a temperature of -78°C to 100°C. One of the substituents R ¹⁴ and R ¹⁵ of the precursor for the synthesis of intermediate amide derivatives (lactam derivatives) may be nitromethyl (-CH ₂ NO ₂ ), azidomethyl (-CH ₂ N ₃ ) or cyano (—CN) (in this case the other substituent is carboxyl or ester). The precursor can be converted to an amide derivative (lactam derivative) by converting the substituent to an aminomethyl group (—CH ₂ NH ₂ ) in a reduction step followed by a condensation reaction. Use catalytic hydrogen reduction; metal hydrides such as lithium borohydride, lithium aluminum hydride, or sodium bis(2-methoxyethoxy)aluminum hydride; or borohydride compounds such as diborane or borane-tetrahydrofuran complexes material for the reduction step. In addition, when one of the substituents R ¹⁴ and R ¹⁵ is hydroxymethyl (-CH ₂ OH) or halomethyl, and the other is carboxyl or ester, the lactone synthesized by a suitable condensation reaction can be Derivatives are transformed into lactam derivatives.

When one of the substituents R ¹⁴ and R ¹⁵ is aminomethyl (-CH ₂ NH ₂ ) and the other is formyl, a cyclic imine derivative is synthesized by using an appropriate condensation reaction followed by reduction of the imine to (specifically, reductive amination reactions), to convert synthetic intermediates into pyrrolidine derivatives. Synthetic intermediates can be converted to pyrrolidine derivatives by subjecting imines to catalytic hydrogen reduction and appropriate condensation reactions to synthesize amide derivatives (lactam derivatives), followed by reduction of the amide.

When one of the substituents R ¹⁴ and R ¹⁵ is methyl and the other is N-haloaminomethyl (eg -CH ₂ NCl-), a pyrrolidine ring can be formed by free radical reaction (Hofmann-Loeffler- Freitag pyrrolidine synthesis reaction).

Several representative pyrrolidine ring formation methods are exemplified by the following scheme for the synthesis of 3-benzyl-1-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane derivatives, which were prepared using Synthetic intermediates of the representative compound 1-amino-3-azabicyclo[3.3.0]octane derivatives of the present invention:

[Formula 61]

Based on the above description of the discovery of a new synthetic method, those skilled in the art can modify the reactions for the synthesis of fused substituted aminopyrrolidine derivatives in the above exemplified steps, and the above description should not be considered as limiting.

To produce compounds encompassed by the present invention, that is, by introducing 1-(tert-butoxycarbonyl)amino-3-azabicyclo[3.3.0]octane derivatives (which are fused substituted amino Pyrrolidine derivatives) as the 7-position (10-position) substituent of quinolone formic acid parent skeleton (pyridobenzoxazine formic acid parent skeleton), can make the quinolone formic acid parent skeleton compound represented by the following formula and 1-(tertiary Butoxycarbonyl) amino-3-azabicyclo[3.3.0]octane reaction:

[Formula 62]

wherein R ⁸ , R ⁹ , R ¹¹ , X ¹ and A ¹ are as defined above; R ¹⁰¹ represents a hydrogen atom, an alkyl group having 1-6 carbon atoms or a boron substituent (which can form a boron chelate); and X Represents a leaving group.

Preferable examples of the alkyl group having 1 to 6 carbon atoms include methyl, ethyl, isopropyl and tert-butyl. The boron substituent may be dihalogenoboryl or diacyloxyboryl. The dihalogenoboryl group is preferably difluoroboryl (—BF ₂ ). The diacyloxyboryl group is preferably diacetyloxyboryl [—B(OAc) ₂ ]. These boron substituents can be obtained according to known methods.

The preparation of such compounds included in the present invention will be described with the following compound of Example 11 as an example:

[Formula 63]

It can be obtained by dissolving the quinolonecarboxylic acid parent skeleton compound in a suitable solvent, and making the compound with (-)-1-(tert-butoxycarbonyl)amino-3-azabicyclo[3.3.0]octane (which is obtained with The target compound can be obtained by reacting with a compound introduced as a substituent at the 7-position in the presence of a base. The amino group in the compound for introduction as a substituent at the 7-position may be protected by a protecting group. In addition to tert-butoxycarbonyl (Boc group), examples of protecting groups include benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, acetyl, methoxyacetyl, trifluoroacetyl, pivaloyl , formyl, benzoyl, tert-butyl, benzyl, trimethylsilyl and isopropyldimethylsilyl. Examples of bases that can be used include carbonates, bicarbonates or hydroxide salts of alkali metals or alkaline earth metals; trialkylamines such as triethylamine and N,N-diisopropylethylamine; and nitrogen-containing Heterocyclic compounds such as pyridine, 1,8-diazabicycloundecene and N-methylpiperidine. Preference is given to trialkylamines, N-methylpiperidine and triethylamine. There is no specific limitation on the solvent used as long as it does not inhibit the reaction. The solvent is preferably N, N-dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile, dimethylacetamide, tetrahydrofuran or N-methylpyrrolidone, especially preferably dimethylsulfoxide, sulfolane, acetonitrile or di Methylacetamide.

When the quinolone carboxylic acid parent skeleton compound is a boron chelate compound, the boron substituent can be cleaved by hydrolysis, and then the amino protecting group can be deprotected to obtain the target compound. Boron substituents are hydrolyzable under usual conditions. For example, boron substituents can be hydrolyzed by reaction with a base in the presence of an aqueous alcoholic solvent such as methanol or ethanol. The base is preferably triethylamine. The reaction is preferably carried out at a temperature ranging from ice cooling to 90°C. Deprotection is carried out by treating the hydrolyzate with eg concentrated hydrochloric acid under conditions appropriate to the protecting group used. After completion of the reaction, the reaction solution is basified with, for example, sodium hydroxide solution, and then neutralized with a suitable acid (such as hydrochloric acid); subsequently, the precipitated crystals are collected by filtration or extracted with chloroform; and the obtained compound is suitably operated by recrystallization, using, for example, a suitable solvent to obtain the target compound.

In the presence of a suitable solvent and catalyst, optionally in the presence of a ligand, and in the presence of a base, the quinolone compound of the present invention can be prepared by reacting a fused substituted aminopyrrolidine derivative with a quinolone skeleton compound of the following formula, Especially those with a methyl group at the 8-position:

[Formula 64]

This reaction can be performed without a ligand.

The substituent R ¹⁰¹ of the quinolone skeleton compound is a hydrogen atom or an alkyl group with 1-6 carbon atoms. Examples of preferred alkyl groups are methyl, ethyl, isopropyl and tert-butyl. For the leaving group X ¹ , those commonly used in the art are also preferably suitable for this reaction. Preferred examples of such leaving groups are halogen atoms such as bromine atom or iodine atom; substituted sulfonyloxy groups such as trifluoromethanesulfonyloxy. As catalysts, those commonly used in the art are also preferably suitable for the reaction. Preference is given to using Pd catalysts, Cu catalysts or Ni catalysts, more preferably Pd catalysts or Cu catalysts. Catalysts may be suitable for reaction mixtures in the form of tris(dibenzylideneacetone)dipalladium(0), palladium(II) acetate, tetrakis(triphenylphosphine)nickel(0), nickel(II) acetylacetonate ), cuprous iodide (I) or cuprous bromide (I), etc. As for the ligands used in the reaction of the present invention, monodentate ligands or bidentate ligands commonly used in the art are preferably used in the reaction. Examples of such ligands are 1,1-bis(diphenylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or BINAP. As the base, those commonly used in the art are preferably suitable for the reaction. Preference is given to using alkaline earth metal or alkali metal carbonates (for example cesium carbonate, potassium carbonate or sodium carbonate) and alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide.

This reaction refers to the following reaction scheme:

[Formula 65]

In a suitable solvent, in the presence of a catalyst, optionally in the presence of a ligand, and in the presence of a base, the quinolone carboxylic acid skeleton compound is reacted with a condensed substituted aminopyrrolidine compound to obtain the quinolone compound of the present invention. The amino group of the condensed substituted pyrrolidine compound for introducing a substituent at the 7-position may have a protecting group. Examples of such protecting groups are alkoxycarbonyl, such as tert-butoxycarbonyl; aralkoxycarbonyl, such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl; acyl or alkylcarbonyl, such as acetyl, Methoxyacetyl, trifluoroacetyl, pivaloyl or formyl; aralkylcarbonyl such as benzoyl or p-nitrobenzoyl; alkyl such as tert-butyl; aralkyl such as benzyl , p-methoxybenzyl or p-nitrobenzyl; substituted silyl groups such as trimethylsilyl or isopropyldimethylsilyl. Examples of bases for this reaction are carbonates, bicarbonates, phosphates, hydrates or alkoxides of alkali metal atoms or alkaline earth metal atoms; trialkylamines such as triethylamine or N,N-diiso Propylethylamine; nitrogen-containing heterocyclic compounds such as pyridine, 1,8-diazabicycloundecene or N-methylpiperidine. As for the solvent, any solvent that does not inhibit the reaction is preferably suitable for the reaction. Examples of solvents are amides such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methyl-2-pyrrolidone; aryl hydrocarbons such as toluene or xylene; ethers such as tetrahydrofuran , 1,4-dioxane or 1,2-dimethoxyethane; and acetonitrile. More preferred solvents are N,N-dimethylformamide, xylene, 1,4-dioxane or 1,2-dimethoxyethane.

The reactions should proceed as homogeneous and heterogeneous reactions. The reaction is also preferably carried out in a catalytic phase reaction. The reaction is complete within 10 minutes to 7 days. The reaction can be carried out at a temperature ranging from 0°C to 300°C, preferably at a temperature ranging from 30°C to the boiling temperature of the solvent used. The catalyst compound and ligand compound can be mixed together to form the catalyst complex before the other reactive compounds are added, or all the reaction components can be mixed together at once. The catalyst is used in an amount ranging from a catalytic amount to an equimolar amount, preferably a catalytic amount.

In the case of the quinolone backbone compound having an ester moiety, the carboxyl compound is obtained by cleavage of the ester group according to methods known in the art. The quinolones are obtained by cleavage of the protecting group of the amino moiety on the fused substituted aminopyrrolidine moiety according to known methods for the corresponding protecting group. After cleavage of the protecting group, the quinolones are isolated according to methods known in the art (eg, recrystallization from a suitable solvent, etc.).

The compound represented by the following two formulas can be used as the production intermediate of compound (I) of the present invention respectively:

[Formula 66]

In the above formula, R ¹¹ represents the defined R ¹ (hydrogen atom, an alkyl group with 1-6 carbon atoms, a cycloalkyl group with 3-6 carbon atoms or a group derived from amino acid, dipeptide or tripeptide Substituted carbonyl; said alkyl may have substituents selected from the group consisting of hydroxyl, amino, cyano, halogen, alkylthio with 1-6 carbon atoms and alkoxy with 1-6 carbon atoms, And the cycloalkyl group may have one or more substituents selected from: an alkyl group having 1-6 carbon atoms, an amino group, a hydroxyl group and a halogen atom) or an amino protecting group;

R ²¹ represents the already defined R ² (hydrogen atom, an alkyl group having 1-6 carbon atoms or a cycloalkyl group having 3-6 carbon atoms; the alkyl group may have a substituent selected from the group consisting of hydroxyl, amino, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms, and the cycloalkyl group may have one or more substituents selected from the group consisting of: having 1 to 6 carbon atoms Alkyl, amino, hydroxyl and halogen atoms) or amino protecting groups; and

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as already defined.

Here, the amino protecting group represented by R ¹¹ or R ²¹ will be described. The protecting group is not limited as long as it is commonly used in the art. Examples of protecting groups include alkoxycarbonyl such as tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl; and p-nitrobenzyloxycarbonyl; acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl and benzoyl; alkyl or aralkyl groups such as t- Butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl and triphenylmethyl; ethers such as methoxymethyl, tert-butoxymethyl, tetrahydropyranyl and 2,2 , 2-trichloroethoxymethyl; (alkyl- and/or aralkyl-) substituted silyl groups such as trimethylsilyl, isopropyldimethylsilyl, tert-butyl dimethylsilyl, tribenzylsilyl, and tert-butyldiphenylsilyl; and allyl.

[Formula 67]

In the above formula, R ¹⁶ represents an amino protecting group; R ¹¹ , R ²¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as already defined.

The protecting group represented by R ¹⁶ is not limited as long as it is commonly used in the art. Examples of protecting groups include alkoxycarbonyl such as tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; aralkoxycarbonyl such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl; and p-nitrobenzyloxycarbonyl; acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl and benzoyl; alkyl or aralkyl groups such as t- Butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl and triphenylmethyl; ethers such as methoxymethyl, tert-butoxymethyl, tetrahydropyranyl and 2,2 , 2-trichloroethoxymethyl; (alkyl- and/or aralkyl-) substituted silyl groups such as trimethylsilyl, isopropyldimethylsilyl, tert-butyl dimethylsilyl, tribenzylsilyl, and tert-butyldiphenylsilyl; and allyl.

When two or more of R ¹¹ , R ²¹ and R ¹⁶ are protecting groups, any protecting group can be selected according to common knowledge in the art so that the protecting group can be selectively removed.

According to the experimental examples described later, it is known that the 7-position of the fused bicyclic aminopyrrolidine derivative of the present invention is substituted at the 7-position of the quinolone formic acid parent skeleton (or its corresponding position) in the compound obtained as described above (in the example of Example The compound represented by X) has antibacterial activity, specifically, the antibacterial activity against Staphylococcus aureus and Gram-positive bacteria (such as pneumococcus) is stronger than that of levofloxacin or ciprofloxacin commonly used in this field. In this case, it has been confirmed that the site substituted by the amino group in the 7-position substituent is an asymmetric carbon, and the quinolonecarboxylic acid substituted by the 7-position substituent from one enantiomer has higher activity and exhibits Superior properties, pharmacokinetic properties and safety. As a result of the X-ray crystallography of the highly active 7-position substituent or the synthesis of each enantiomer by the chiral pool method and the determination of antibacterial activity, it has been confirmed that the 7-position amino group has the following formula represented by structure:

[Formula 68]

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and Q are as already defined.

The compounds of the invention may be in free form. Alternatively, acid addition salts or salts with carboxyl groups may be formed. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitride, hydrobromide, hydroiodide and phosphate; and organic acid salts such as sulfonate (e.g. sulfonates, benzenesulfonates, p-toluenesulfonates) and carboxylates (e.g. acetates, citrates, maleates, fumarates, lactates). Examples of salts with carboxyl groups include alkali metal salts such as lithium salts, sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts, triethylamine salts, N-methylglucamine salts and Tris-(hydroxymethyl)aminomethane salt. The compounds of the present invention in free form and the acid addition salts of the compounds or salts formed with carboxyl groups may be in the form of hydrates.

The compound (I) of the present invention has strong antibacterial activity, so it can be used as human medicine, animal medicine and fish medicine, agricultural chemicals or food preservatives. For human administration, the compound of the present invention is used in a dose of 50 mg to 1 g, more preferably 100 mg to 500 mg per day for an adult. The dose for animals varies depending on the purpose of administration, the size of the animal to be treated, the type of pathogen infected by the animal and the severity of the disease; the daily dose is usually 1 mg to 200 mg per kg body weight of the animal, more preferably 5 mg to 100 mg. The daily amount is administered once daily, or in 2-4 divided doses. If necessary, the daily dosage can exceed the above dosage.

The compound (I) of the present invention is active against a broad spectrum of microorganisms that cause various infections, and can treat, prevent or alleviate diseases caused by these pathogens. Examples of bacteria or bacteria-like microorganisms against which the compounds of the present invention are effective include Staphylococcus, Streptococcus pyogenes, Hemolytic Streptococcus, Enterococcus, Pneumococcus, Peptostreptococcus, Lymphococcus, Cocci, Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Serratia , Proteus, Pseudomonas aeruginosa, Haemophilus infiuenzae, Acinetobacter, Campylobacter, and Chlamydiatrachomatis.

Examples of diseases caused by these pathogens include folliculitis, furuncle, carbuncle, erysipelas, cellulitis, lymphangitis, paronychia, subcutaneous abscess, hidradenitis, acne conglomerate, atheroma, perirectal abscess, mastitis , superficial secondary infection such as traumatic infection, burn infection or surgical wound infection, pharyngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis (diffuse panbronchiolitis), chronic respiratory disease Secondary infection, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, shigellosis, enteritis, uterine adnexitis, Intrauterine infection, bartholinitis, blepharitis, hordeolum, dacryocystitis, meibomian gland inflammation, corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis, endocarditis , sepsis, meningitis and skin infections.

Examples of mycobacteria to which the compound (I) of the present invention is effective include Mycobacterium tuberculosis (Mycobacterium tuberculosis, M.bobis and M.africanum) and SARS Mycobacterium type (M.cansasii, M.marinum, M.scrofulaceum, M.avium, intracellular M. intracellulare, M. xenopi, M. fortuitum and M. chelonae). Mycobacterial infections caused by these pathogens are broadly classified into tuberculosis, atypical mycobacterial infections, and leprosy. In addition to the lungs, M. tuberculosis infection has been observed in the following sites: thorax, trachea and bronchi, lymph nodes, diffuse systemic distribution, bone and joints, meninges and brain, digestive organs (intestine and liver), skin, breast, eye , middle ear and throat, urethra, male and female reproductive organs. Atypical mycobacterial infections (nontuberculous mycobacterial infections) primarily affect the lungs, but can also occur with regional lymphadenitis, skin and soft tissue infections, osteoarthritis, or systemic diffuse infection.

The compounds of the present invention are also effective against various microorganisms that cause infection in animals, such as Escherichia, Salmonella, Pasteurella, Haemophilus, Baut The genera Bordetella, Staphylococcus and Mycoplasma. Specific examples of animal diseases include avian diseases such as colibacillosis, pullorum, avian paratyphoid, avian cholera, infectious rhinitis, staphylococcal disease, and mycoplasma infection; swine diseases such as colibacillosis, salmonellosis, Pasteurella disease, haemophilus infection, atrophic rhinitis, epidermatitis exudative and mycoplasma infection; cattle disease, such as colibacillosis, salmonellosis, hemorrhagic sepsis, mycoplasma infection, contagious bovine pleuropneumonia and mastitis; dog disease, Examples include E. coli sepsis, Salmonella infection, hemorrhagic sepsis, pyometra, and cystitis; and feline diseases, such as exudative pleurisy, cystitis, chronic rhinitis, Haemophilus infection, kitten diarrhea, and mycoplasma infection.

Antibacterial drugs containing the compound (I) of the present invention can be appropriately selected depending on the method of administration and the preparation method for preparing various commonly used formulations. Examples of antibacterial drug dosage forms containing the compound of the present invention as a main agent include tablets, powders, granules, capsules, solutions, syrups, elixirs and oily or aqueous suspensions. Preparations for injection may contain additives such as stabilizers, preservatives, or solution adjuvants, and may be prepared before use from solid preparations by, for example, storing a solution containing additives in a container and then lyophilizing the solution. made. One dose may be stored in one container, or multiple doses may be stored in one container. Examples of preparations for external use include solutions, suspensions, emulsions, ointments, gels, creams, lotions and sprays. Solid preparations may contain pharmaceutically acceptable additives as well as active compounds. Examples of additives include fillers, binders, disintegrants, solution promoters, wetting agents and lubricants. Liquid preparations may be solutions, suspensions, emulsions, etc., and may contain additives such as suspending agents or emulsifying agents.

Next, Production Examples will be described.

Preparation Example 1 [capsules]:

The compound of embodiment 11 100.0mg

Corn starch 23.0mg

Carboxymethylcellulose calcium 22.5mg

Hydroxymethylcellulose 3.0mg

Magnesium stearate 1.5mg

           

Total 150.0mg

Preparation Example 2 [Solution Formulation]:

The compound of embodiment 11 1-10g

Acetic acid or sodium hydroxide 0.5-2g

Ethyl p-hydroxybenzoate 0.1g

Purified water 87.9-98.4g

             

Total 100g

Preparation Example 3 [Powder to be Mixed with Feed]

The compound of embodiment 17 1-10g

Corn starch 89.5-98.5g

Light anhydrous silicic acid 0.5g

             

Total 100g

Example

The present invention will be specifically described below using reference examples; however, the present invention is not limited to the examples, which should not be regarded as restrictive examples in any sense.

[Reference Example 1]

(S)-3-(tert-Butyldimethylsilyloxy)-2-methylpropanoic acid methyl ester

[Formula 69]

Imidazole (13.3g, 196mmol) and tert-butyldimethylsilyl chloride (14.2g, 94.1mmol) were added to (S)-3-hydroxy-2-methylpropanoic acid methyl ester (11.0g, 93.1mmol ) in dimethylformamide (100ml), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 24 g (quantitative) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.76-3.72 (1H, m), 3.64 (3H, s), 3.63-3.59 (1H, m), 2.65-2.57 (1H, m), 1.10 (3H, d, J=6.84Hz), 0.84(9H,s), 0.01(3H,s), 0.00(3H,s).

[Reference Example 2]

(E)-(R)-5-(tert-butyldimethylsilyloxy)-4-methylpent-2-enoic acid methyl ester

[Formula 70]

At -78°C, diisobutylaluminum hydride (1M in hexane, 86ml) was added to (S)-3-(tert-butyldimethylsilyloxy)-2-methylpropionic acid methyl A solution of the ester (20 g, 86.1 mmol) in dichloromethane (400 ml) was stirred at the same temperature for 2 hours. Saturated sodium potassium tartrate solution was added to the reaction mixture, which was then allowed to warm to room temperature with stirring. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (200ml).

Methyl triphenylphosphonylidene acetate (32 g, 94.7 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was filtered, and then the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 25 g (quantitatively) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 6.94 (1H, dd, J=7.10, 15.90Hz), 5.84 (1H, dd, J=1.20, 15.90Hz), 3.73 (3H, s), 3.57-3.49 (2H, m), 2.53-2.46 (1H, m), 1.05 (3H, d, J=6.80Hz), 0.89 (9H, s), 0.04 (6H, s).

[Reference Example 3]

1-Benzyl-4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3- Methyl formate

[Formula 71]

Add N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethanamine (16.6ml, 65.0mmol) to (E)-(R)-5-(tert-butyldi To a solution of methylsilyloxy)-4-methylpent-2-enoate (14g, 54.2mmol) in dichloromethane (100ml) was added a trace of trifluoroacetic acid. The mixture was stirred for 30 minutes, then saturated aqueous sodium bicarbonate was added. The organic layer was separated and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 14.6 g (69%) of the title compound as a mixture of diastereomers as free Color oil. The diastereomers were used in the next step without separation.

[Reference Example 4]

4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-1,3-dimethyl Acid 1-benzyl ester 3-methyl ester

[Formula 72]

Benzyloxycarbonyl chloride (10.2ml, 71.5mmol) was added to 1-benzyl-4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl methyl]pyrrolidine-3-carboxylate (14.0 g, 35.8 mmol) in dichloromethane (200 mL), and the mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 13.9 g (89%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

[Reference Example 5]

4-[(R)-2-Hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylate 1-benzyl ester 3-methyl ester

[Formula 73]

Under ice-cooling, hydrogen fluoride-pyridine (4ml) was added to 4-[(R)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]-pyrrolidine-1 , in a solution of 1-benzyl 3-methyl 3-dicarboxylate (6.0 g, 7.1 mmol) in pyridine (20 ml), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into ice water, then extracted with ethyl acetate and washed with 1N hydrochloric acid and brine. After drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure to give 4.1 g (93%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

[Reference Example 6]

4-[(R)-2-iodo-1-(methyl)ethyl]-pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester

[Formula 74]

Under ice cooling, triethylamine (2.7ml, 19.1mmol) and methanesulfonyl chloride (1.2ml, 15.3mmol) were added to 4-[(R)-2-hydroxy-1-(methyl)ethyl]pyrrolidine - 1-benzyl 3-methyl 1,3-dicarboxylate (4.1 g, 12.8 mmol) in dichloromethane (100 ml), and the mixture was stirred at room temperature for 30 minutes. After methanol was added to the reaction mixture, the resulting mixture was mixed with a mixture of ethyl acetate and 10% citric acid solution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in acetone (100ml). Sodium iodide (4.1 g, 27.4 mmol) was added and the mixture was heated to reflux for 20 hours. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure. The resulting residue was mixed with a mixture of ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate solution and brine, dried over magnesium sulfate, then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain 5.0 g (84%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.37-7.33 (5H, m), 5.13 (2H, s), 3.83-3.71 (4H, m), 3.58-3.51 (1H, m), 3.27-3.23 ( 1H, m), 3.18-3.09 (2H, m), 2.92-2.83 (1H, m), 2.64-2.55 (1H, m), 1.81-1.75 (1H, m), 1.53-1.48 (1H, m), 1.06-1.01 (3H, m).

[Reference Example 7]

(S)-6-Methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylate 3-benzyl ester 1-methyl ester

[Formula 75]

Under an argon atmosphere at -78°C, a 0.5M solution of potassium hexamethyldisilazide in toluene (28ml, 14.0mmol) was added dropwise to 4-[(R)-2-iodo-1-(methyl) Ethyl]pyrrolidine-1,3-dicarboxylate 1-benzyl 3-methyl ester (5.0 g, 11.5 mmol) in anhydrous tetrahydrofuran (100 ml). After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes. Ammonium chloride solution was added and the mixture was allowed to warm to room temperature. After extraction with ethyl acetate, drying over magnesium sulfate, and filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain 3.2 g (91%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.32 (5H, m), 5.17-5.14 (2H, m), 3.94 (0.5H, dd, J=10.86, 18.92Hz), 3.76-3.69 (5H , m), 3.46(0.5H, d, J=11.72Hz), 3.36(0.5H, dd, J=6.10, 11.47Hz), 3.25(0.5H, dd, J=8.06, 11.96Hz), 3.06(0.5 H, t, J=8.30Hz), 2.73-2.65(1.5H, m), 2.13-2.09(1.5H, m), 1.11(1.5H, d, J=6.10Hz), 0.94(1.5H, brs) .

[Reference Example 8]

(S)-3-Benzyl 6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylate

[Formula 76]

Under ice cooling, 1N sodium hydroxide solution (21ml) was added dropwise to (S)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1- In a mixed solution of methyl ester (3.2 g, 10.4 mmol) in tetrahydrofuran (60 ml) and methanol (20 ml), the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to afford 3.0 g (quantitative) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

[Reference Example 9]

(S)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester Optical isomer A, optical isomer B)

[Formula 77]

Triethylamine (2.9ml, 20.7mmol) and diphenoxyphosphoryl azide (3.4ml, 15.6mmol) were added to (S)-6-methyl-3-azabicyclo[3.2. 0] To a solution of 3-benzyl heptane-1,3-dicarboxylate (3.0 g, 10.4 mmol) in toluene (60 ml) followed by tert-butanol (60 ml). The mixture was heated and stirred at 100°C for 15 hours. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→8:2) to obtain the title compound (3.1 g) of a diastereomeric mixture as a colorless oil. The diastereomers were separated with Chiralpak AD (2cm, hexane:isopropanol=92.5:7.5, flow rate: 30ml/min) to obtain 1.48g (40%) of a colorless oil in the first fraction (optical isomer A ) and 1.38 g (37%) of a second fraction of a colorless oil (optical isomer B).

Optical isomer A:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.14 (2H, s), 4.81-4.76 (1H, m), 3.84 (1H, d, J=10.70Hz), 3.61 -3.53(3H, brm), 2.43-2.31(2H, m), 1.92-1.86(1H, m), 1.75-1.68(1H, m), 1.43(9H, s), 1.14(3H, d, J= 6.80Hz).

Optical isomer B:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.16 (2H, s), 4.87-4.73 (1H, brm), 3.88-3.79 (1H, m), 3.72 (1H, d, J=11.00Hz), 3.43-3.28(2H, brm), 2.89-2.77(1H, brm), 2.67-2.58(1H, m), 2.32(1H, t, J=11.70Hz), 1.76-1.68 (1H, m), 1.44 (9H, s), 0.95-0.92 (3H, m).

Based on NMR comparisons between the more polar isomer and the less polar isomer, optical isomer A was identified as (1R,5S,6S)-1-tert-butoxycarbonylamino-6- Benzyl methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate, optical isomer B identified as (1S,5R,6S)-1-tert-butoxycarbonylamino-6-methyl - Benzyl 3-azabicyclo[3.2.0]heptane-3-carboxylate.

[Reference Example 10]

(1R, 5S, 6S)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane

[Formula 78]

Dissolve benzyl (1R, 5S, 6S)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate (1.4g, 3.9mmol) in In a mixed solvent of methanol (20ml) and tetrahydrofuran (10ml). A small amount of 10% palladium-carbon (50% wet) was added and the mixture was stirred under hydrogen atmosphere for 3 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.89 g (quantitative) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.80 (1H, brs), 3.09 (1H, d, J = 11.20Hz), 3.02 (2H, dd, J = 5.40, 11.20Hz), 2.82 (2H, d , J=11.20Hz), 2.27-2.22 (2H, m), 1.77-1.69 (2H, m), 1.44 (9H, s), 1.17 (3H, d, J=6.60Hz).

[Reference Example 11]

(1S, 5R, 6S)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane

[Formula 79]

Dissolve benzyl (1S, 5R, 6S)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate (1.4g, 3.8mmol) in In a mixed solvent of methanol (20ml) and tetrahydrofuran (10ml). A small amount of 10% palladium-carbon (50% wet) was added and the mixture was stirred under hydrogen atmosphere for 3 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.85 g (quantitative) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.88 (1H, brs), 3.06 (1H, d, J=12.00Hz), 2.96-2.89 (2H, m), 2.71-2.61 (3H, m), 2.39 -2.33 (1H, m), 1.58 (1H, dd, J = 7.40, 12.80 Hz), 1.45 (9H, s), 0.94 (3H, d, J = 6.80 Hz).

[Example 1]

7-{(1R, 5S, 6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]hept-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 80]

(1R, 5S, 6S)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane (870mg, 3.84mmol) and 6,7-difluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (1.25g , 3.46mmol) was dissolved in dimethylsulfoxide (15ml). Triethylamine (0.64ml) was added, and the mixture was stirred at 40°C for 12 hours. After cooling the reaction solution with ice, water was added, and the precipitate was collected by filtration, washed with water and dried. The precipitate was dissolved in ethanol (140ml). Water (30ml) and triethylamine (0.64ml) were added, and the mixture was heated under reflux for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. Then, the reaction solution was washed with chloroform, and under ice-cooling, the aqueous layer was adjusted to pH 12.0 with 10mol/L sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform-methanol (9:1) for 8 Second-rate. The organic layer was dried over anhydrous sodium sulfate, then filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol, and the insoluble matter was removed by filtration. After evaporating the solvent under reduced pressure, the obtained powder was dried under reduced pressure to obtain 562 mg (35%) of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.49 (1H, brs), 7.70 (1H, d, J=13.70Hz), 5.03-4.85 (1H, m), 4.09-4.03 (1H, m), 3.90(1H,d,J=10.50Hz), 3.67(3H,s), 3.48(1H,d,J=10.50Hz), 3.03(1H,d,J=10.50Hz), 2.44(1H,dd,J =12.00, 8.80Hz), 2.15(1H, t, J=5.10Hz), 1.92-1.84(1H, m), 1.69-1.62(1H, m), 1.61-1.49(1H, m), 1.14(3H, d, J = 7.10 Hz).

Anal _. Calcd. for _{C21H23F2N3O4.0.7H2O.0.2EtOH} : _C , _58.25 ; H _, 5.85; F, 8.61; _N , 9.52. Found: C, 58.22; H, 5.84; F, 8.47; N, 9.37.

MS (ESI) m/z: 420 (M+H) ⁺ .

[Example 2]

7-{(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]hept-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 81]

(1S, 5R, 6S)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane (820mg, 3.62mmol) and 6,7-difluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-formic acid-BF ₂ chelate (1.18g , 3.26mmol) was dissolved in dimethylsulfoxide (15ml). Triethylamine (0.61 ml) was added, and the mixture was stirred at 40°C for 12 hours. After cooling the reaction solution with ice, water was added, and the precipitate was collected by filtration, washed with water and dried. The precipitate was dissolved in ethanol (120ml). Water (30ml) and triethylamine (0.61ml) were added, and the mixture was heated under reflux for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. Then, the reaction solution was washed with chloroform. Under ice-cooling, the aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform-methanol (9:1) 6 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol, and the insoluble matter was removed by filtration. After evaporating the solvent under reduced pressure, the resulting powder was dried under reduced pressure to afford 1.1 g (72%) of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.46 (1H, d, J = 2.20Hz), 7.72 (1H, d, J = 13.70Hz), 5.10-4.90 (1H, m), 4.07-4.02 ( 1H, m), 3.75(1H, d, J=11.20Hz), 3.64(3H, s), 3.64-3.59(1H, m), 3.49-3.47(1H, m), 3.09(1H, d, J= 10.00Hz), 2.68-2.60(1H, m), 2.51(1H, t, J=7.30Hz), 2.20(1H, t, 10.5Hz), 1.85(1H, dd, J=8.50, 12.70Hz), 1.63 -1.42 (2H, m), 0.96 (3H, d, J = 7.30 Hz).

_{Anal .} Calcd. for _{C21H23F2N3O4-0.7H2O} : C, _58.38 ; _H , 5.69; F, 8.79; _N , 9.73. Found: C, 58.24; H, 5.69; F, 8.59; N, 9.52.

MS (ESI) m/z: 420 (M+H) ⁺ .

[Example 3]

10-{(1S,5R,6S)-1-amino-6-methyl-3-azabicyclo[3.2.0]hept-3-yl}-9-fluoro-2,3-di Hydrogen-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

[Formula 82]

Dissolve (1S,5R,6S)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane (546.3 mg, 2.41 mmol) in dimethylmethylene Sulfone (12ml). Add 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxa Oxazine-6-carboxylic acid-BF ₂ chelate (794.1 mg, 2.41 mmol) and triethylamine (1221 mg, 12.07 mmol), the mixture was stirred for 5 days. Then, 90% aqueous ethanol (135 ml) and triethylamine (15 ml) were added to the reaction mixture, which was stirred at 80°C for 4.5 hours. The solvent was evaporated under reduced pressure and 10% citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to short silica gel column chromatography (3% methanol/chloroform). The resulting crude product was dissolved in concentrated hydrochloric acid and washed with dichloromethane. At 0°C, the aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting solid was washed with ethanol and dried under reduced pressure to give the title compound (695 mg) as a light yellow solid.

mp: 122-124°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.31 (1H, s), 7.46 (1H, d, J = 13.67Hz), 4.55 (1H, d, J = 6.84Hz), 4.46 (1H, d, J=11.47Hz), 4.30(1H,d,J=11.47Hz), 3.71(1H,d,J=10.74Hz), 3.45(1H,d,J=9.77Hz), 3.27(1H,t,J= 8.79Hz), 3.09(1H, d, J=9.77Hz), 2.58-2.56(1H, m), 2.37(1H, t, J=7.81Hz), 2.12(1H, t, J=11.47Hz), 1.78 (1H, dd, J = 12.33, 8.42Hz), 1.48 (3H, d, J = 6.59Hz), 0.94 (3H, d, J = 7.08Hz).

Anal _. Calcd. for _{C20H22FN3O4 - H2O} : C, 59.25; H, 5.97; N, 10.36; _F , 4.69. Found: C, 59.41; H, 5.65; N, 10.36; F, 4.97.

MS (EI) m/z: 388 (M+H) ⁺ .

IR (ATR) v: 2956, 2929, 2866, 1716, 1612, 1579, 1523, 1450, 1385, 1335, 1298, 1255 cm ^-1 .

[Reference Example 12]

(R)-3-(tert-Butyldimethylsilyloxy)-2-methylpropanoic acid methyl ester

[Formula 83]

Add imidazole (6.44g, 42.8mmol) and tert-butyldimethylsilyl chloride (6.05g, 88.8mmol) to methyl (R)-3-hydroxy-2-methylpropanoate (5.0g, 42.33 mmol) in dimethylformamide (50 ml), the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with hexane twice. The extract was dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to afford 9.3 g (95%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 3.76-3.72 (1H, m), 3.64 (3H, s), 3.63-3.59 (1H, m), 2.65-2.57 (1H, m), 1.10 (3H, d, J=6.84Hz), 0.84(9H,s), 0.01(3H,s), 0.00(3H,s).

[Reference Example 13]

(E)-(S)-5-(tert-butyldimethylsilyloxy)-4-methylpent-2-enoic acid methyl ester

[Formula 84]

Diisobutylaluminum hydride (1M in hexane, 17.2ml) was added to (R)-3-(tert-butyldimethylsilyloxy)-2-methylpropanoic acid at -78°C To a solution of methyl ester (4.0 g, 17.2 mmol) in dichloromethane (100 ml), the mixture was stirred at the same temperature for 4 hours. Saturated sodium potassium tartrate solution was added to the reaction mixture, which was stirred and warmed to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure to give aldehyde (3.5 g) as a colorless oil. The resulting aldehyde was dissolved in dichloromethane (50ml). Under ice-cooling, methyl triphenylphosphonoacetate (7.08 g, 20.75 mmol) was added, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.8 g (85%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 6.94 (1H, dd, J=7.10, 15.90Hz), 5.84 (1H, dd, J=1.20, 15.90Hz), 3.73 (3H, s), 3.57-3.49 (2H, m), 2.53-2.46 (1H, m), 1.05 (3H, d, J=6.80Hz), 0.89 (9H, s), 0.04 (6H, s).

[Reference Example 14]

1-Benzyl-4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-3- Methyl formate

[Formula 85]

Add N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2.97ml, 11.6mmol) to (E)-(S)-5-(tert-butyldi To a solution of methylsilyloxy)-4-methylpent-2-enoate (2.5g, 9.67mmol) in dichloromethane (20ml) was added a trace of trifluoroacetic acid. The mixture was stirred for 30 minutes, then saturated aqueous sodium bicarbonate was added. The organic layer was separated and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.0 g (78%) of the title compound of a mixture of diastereomers as free Color oil. The diastereomers were used in the next step without separation.

[Reference Example 15]

4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-1,3-dimethyl Acid 1-benzyl ester 3-methyl ester

[Formula 86]

Benzyloxycarbonyl chloride (3.25ml, 22.8mmol) was added to 1-benzyl-4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl methyl]pyrrolidine-3-carboxylate (2.97g, 7.58mmol) in dichloromethane (20ml) and the mixture was stirred for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture. The organic layer was separated, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 3.1 g (96%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

[Reference Example 16]

4-[(S)-2-Hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylate 1-benzyl ester 3-methyl ester

[Formula 87]

Under ice-cooling, hydrogen fluoride-pyridine (2 ml) was added to 4-[(S)-2-(tert-butyldimethylsilyloxy)-1-(methyl)ethyl]pyrrolidine-1, In a solution of 1-benzyl 3-dicarboxylate 3-methyl ester (6.0 g, 7.1 mmol) in pyridine (20 ml), the mixture was stirred at room temperature for 13 hours. Another 2 ml of hydrogen fluoride-pyridine was added, and the mixture was stirred for 23 hours. The reaction mixture was poured into ice water, then extracted with ethyl acetate and washed with 1N hydrochloric acid and brine. After drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure to give 4.5 g (quantitative) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.31 (5H, m), 5.13 (2H, brs), 3.87-3.75 (2H, brm), 3.72 (3H, s), 3.52-3.47 (3H, m), 3.27-3.11(1H, m), 2.98-2.90(1H, m), 2.69-2.58(1H, m), 1.82-1.66(2H, m), 0.95(3H, d, J=19.80Hz) .

[Reference Example 17]

1-Benzyl 4-[(S)-2-iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylate 3-methyl ester

[Formula 88]

Under ice-cooling, triethylamine (3.4ml, 24mmol) and methanesulfonyl chloride (1.5ml, 19.2mmol) were added to 4-[(S)-2-hydroxy-1-(methyl)ethyl]pyrrolidine- 1-Benzyl 3-methyl 1,3-dicarboxylate (5.1 g, 16 mmol) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 30 minutes. After methanol was added to the reaction mixture, the resulting mixture was mixed with a mixture of ethyl acetate and 10% citric acid solution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in acetone (100ml). Sodium iodide (4.8 g, 32 mmol) was added and the mixture was heated to reflux for 20 hours. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure. The resulting residue was mixed with a mixture of ethyl acetate and water. The organic layer was washed with saturated sodium thiosulfate solution and brine, dried over magnesium sulfate, then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain 6.5 g (94%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.37-7.35 (5H, m), 5.13 (2H, s), 3.83-3.71 (4H, m), 3.58-3.51 (1H, m), 3.27-3.23 ( 1H, m), 3.18-3.09 (2H, m), 2.92-2.83 (1H, m), 2.64-2.55 (1H, m), 1.59-1.48 (2H, m), 1.02 (3H, d, J=6.60 Hz).

[Reference Example 18]

(R)-6-Methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylate 3-benzyl ester 1-methyl ester

[Formula 89]

Under an argon atmosphere at -78°C, a 0.5M solution of potassium hexamethyldisilazide in toluene (33ml, 16.5mmol) was added dropwise to 4-[(S)-2-iodo-1-(methyl) Ethyl]pyrrolidine-1,3-dicarboxylate 1-benzyl 3-methyl ester (6.4g, 14.8mmol) in anhydrous tetrahydrofuran (100ml). After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes. Ammonium chloride solution was added and the mixture was allowed to warm to room temperature. After extraction with ethyl acetate, drying over magnesium sulfate and filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to obtain 3.5 g (78%) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.29 (5H, m), 5.18 (2H, brs), 3.97-3.89 (1H, m), 3.77-3.69 (4H, m), 3.46 (1H, d, J = 11.70Hz), 3.25 (1H, dd, J = 12.10, 7.90Hz), 3.08-3.03 (1H, m), 2.60-2.75 (2H, m), 1.51-1.57 (1H, m), 0.94 (3H, brs).

[Reference Example 19]

(R)-3-Benzyl 6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylate

[Formula 90]

Under ice cooling, 1N sodium hydroxide solution (23ml) was added dropwise to (R)-6-methyl-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylic acid 3-benzyl ester 1- In a mixed solution of methyl ester (3.5 g, 11.5 mmol) in tetrahydrofuran (60 ml) and methanol (20 ml), the mixture was stirred for 30 minutes. The reaction solution was neutralized with 1N hydrochloric acid, followed by extraction with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give 3.4 g (quantitative) of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were used in the next step without separation.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.30 (5H, m), 5.19 (2H, brs), 4.00-3.91 (1H, m), 3.81-3.70 (1H, m), 3.50 (1H, d, J = 11.70 Hz), 3.27 (1H, dd, J = 11.70, 7.80 Hz), 3.11 (1H, t, J = 7.70 Hz), 2.80-2.66 (2H, m), 0.95 (3H, s).

[Reference Example 20]

Benzyl (R)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate (Optical Isomer C, Optical Isomer D)

[Formula 91]

Triethylamine (3.2ml, 22.8mmol) and diphenoxyphosphoryl azide (3.7ml, 17.1mmol) were added to (R)-6-methyl-3-azabicyclo[3.2. 0] To a solution of 3-benzyl heptane-1,3-dicarboxylate (3.3g, 11.4mmol) in toluene (70ml) followed by tert-butanol (70ml). The mixture was heated and stirred at 100°C for 15 hours. The reaction mixture was cooled, then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→8:2) to obtain 3.5 g of the title compound as a mixture of diastereomers as a colorless oil. The diastereomers were separated by Chiralpak AD (2cm, hexane:isopropanol=92.5:7.5, flow rate: 30ml/min) to obtain 1.72g (42%) of a colorless oil in the first fraction (optical isomer C ) and 1.68 g (41%) of a second fraction of a colorless oil (optical isomer D).

Optical isomer C:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.30 (5H, m), 5.16 (2H, s), 4.87-4.73 (1H, brm), 3.88-3.79 (1H, m), 3.72 (1H, d, J = 11.00Hz), 3.43-3.28 (2H, bm), 2.89-2.77 (1H, brm), 2.67-2.58 (1H, m), 2.32 (1H, t, J = 11.70Hz), 1.76-1.68 (1H, m), 1.44 (9H, s), 0.95-0.92 (3H, m).

Optical isomer D:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.14 (2H, s), 4.81-4.76 (1H, m), 3.84 (1H, d, J=10.70Hz), 3.61 -3.53(3H, brm), 2.43-2.31(2H, m), 1.92-1.86(1H, m), 1.75-1.68(1H, m), 1.43(9H, s), 1.14(3H, d, J= 6.80Hz).

According to the NOE test results, optical isomer C was identified as (1R, 5S, 6R)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid Benzyl ester, while optical isomer D was identified as benzyl (1S,5R,6R)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate ester.

[Reference Example 21]

(1R, 5S, 6R)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane

[Formula 92]

Dissolve benzyl (1R,5S,6R)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate (180 mg, 0.59 mmol) in methanol (5ml). A small amount of 10% palladium-carbon (50% wet) was added and the mixture was stirred under hydrogen atmosphere for 1 hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 114 mg (85%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.88 (1H, brs), 3.06 (1H, d, J=12.00Hz), 2.96-2.89 (2H, m), 2.71-2.61 (3H, m), 2.39 -2.33 (1H, m), 1.58 (1H, dd, J = 12.80, 7.40 Hz), 1.45 (9H, s), 0.94 (3H, d, J = 6.80 Hz).

[Reference Example 22]

(1S, 5R, 6R)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane

[Formula 93]

Dissolve benzyl (1S, 5R, 6R)-1-tert-butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylate (1.1 g, 3.1 mmol) in In a mixed solvent of methanol (20ml) and tetrahydrofuran (10ml). A small amount of 10% palladium-carbon (50% wet) was added and the mixture was stirred under hydrogen atmosphere for 3 hours. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to afford 0.70 g (quantitative) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.80 (1H, brs), 3.09 (1H, d, J = 11.20Hz), 3.02 (2H, dd, J = 11.20, 5.40Hz), 2.82 (2H, d , J=11.20Hz), 2.27-2.22 (2H, m), 1.77-1.69 (2H, m), 1.44 (9H, s), 1.17 (3H, d, J=6.60Hz).

[Example 4]

7-{(1R, 5S, 6R)-1-amino-6-methyl-3-azabicyclo[3.2.0]hept-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 94]

(1R, 5S, 6R)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane (114mg, 0.50mmol) and 6,7-difluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (155mg, 0.43mmol) was dissolved in dimethylsulfoxide (2ml). Triethylamine (0.084ml) was added, and the mixture was stirred at 40°C for 12 hours. After cooling the reaction solution with ice, water was added, and the precipitate was collected by filtration, washed with water and dried. The precipitate was dissolved in ethanol (20ml). Water (5ml) and triethylamine (0.084ml) were added, and the mixture was heated under reflux for 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with 10% citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Concentrated hydrochloric acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. Then, the reaction solution was washed with chloroform. Under ice cooling, the aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and extracted 8 times with chloroform-methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol and the insoluble matter was removed by filtration. After evaporating the solvent under reduced pressure, the obtained powder was dried under reduced pressure to obtain 70 mg (39%) of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.50 (1H, s), 7.70 (1H, d, J=13.67Hz), 5.02-4.84 (1H, m), 4.07-4.03 (1H, m), 3.74(1H, d, J=10.25Hz), 3.62(3H, s), 3.60-3.56(2H, m), 2.94(1H, d, J=10.25Hz), 2.63-2.55(1H, m), 2.51 -2.47(1H, m), 2.24-2.18(1H, m), 1.85(1H, dd, J=12.57, 7.93Hz), 1.69-1.48(2H, m), 0.87(3H, d, J=6.84Hz ).

Anal _. Calcd. for _{C21H23F2N3O4.0.4H2O.0.3EtOH} : _C , _58.90 ; H _, 5.86; F _, 8.63; N, 9.54. Found: C, 58.84; H, 5.78; F, 8.66; N, 9.51.

MS (ESI) m/z: 420 (M+H) ⁺ .

[Example 5]

7-{(1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo[3.2.0]hept-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 95]

(1S, 5R, 6R)-1-(tert-butoxycarbonylamino)-6-methyl-3-azabicyclo[3.2.0]heptane (705mg, 3.12mmol) and 6,7-difluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-formic acid-BF ₂ chelate (1.07g , 2.96mmol) was dissolved in dimethylsulfoxide (12ml). Triethylamine (0.52ml) was added, and the mixture was stirred at 40°C for 12 hours. After cooling the reaction solution with ice, water was added, and the precipitate was collected by filtration, washed with water and dried. The precipitate was dissolved in ethanol (120ml). Water (30ml) and triethylamine (0.52ml) were added, and the mixture was heated under reflux for 3 hours. The reaction mixture was dissolved in ethyl acetate and washed with 10% citric acid solution, water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. Then, the reaction solution was washed with chloroform. Under ice cooling, the aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and extracted 8 times with chloroform-methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol and the insoluble matter was removed by filtration. After evaporating the solvent under reduced pressure, the obtained powder was dried under reduced pressure to obtain 740 mg (57%) of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, d, J = 1.71Hz), 7.70 (1H, d, J = 13.67Hz), 5.07-4.88 (1H, m), 4.08-4.03 ( 1H, m), 3.73-3.63 (2H, m), 3.67 (3H, s), 3.55-3.51 (1H, m), 3.18 (1H, d, J=10.50Hz), 2.40 (1H, dd, J= 12.21, 8.79Hz), 2.13(1H, t, J=5.13Hz), 1.95-1.89(1H, m), 1.16(3H, d, J=7.08Hz), 1.66-1.57(2H, m), 1.56- 1.44 (1H, m).

_Anal. Calcd. for _C21H23F2N3O4 ·HCl· _1.3H2O ·0.6EtOH: C, _{52.60 ;} H, 6.00; Cl, 6.99; _F , 7.50; N, 8.29. Found: C, 52.35; H, 5.74; Cl, 6.84; F, 7.54; N, 8.01.

MS (ESI); m/z: 420 (M+H) ⁺ .

[Reference Example 23]

(3R)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (polar lower isomer)

(3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (polar higher isomer)

[Formula 96]

tert-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (30 g, 104 mmol) and allyl bromide (62.71 g, 518 mmol) were dissolved in dimethyl In formamide (300ml), the original atmosphere was replaced with argon. Under ice-cooling, sodium hydride (55% oil dispersion, 11.3 g, 259 mmol) was added, and the mixture was stirred at room temperature for 5 hours. A 10% tartaric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Then, the residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=100:0→80:20→65:35) to obtain 15.8 g (46%) of a colorless oil in the first fraction (more polar lower isomer) and 15.1 g (44%) of a second fraction of colorless oil (more polar isomer). The resulting more polar isomer crystallized upon standing at room temperature.

Based on the X-ray crystallographic structure of the product described in Reference Example 24, the absolute configuration at the 3-position of each isomer was determined after conversion of the more polar isomer into the product.

Less polar isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.52-5.42 (2H, m), 4.95 (1H, dd, J=10.30, 1.00Hz), 4.78 (1H, dd, J=17.10, 1.20Hz), 3.60(1H, d, J=10.30Hz), 2.86(1H, d, J=17.10Hz), 2.80(1H, d, J=10.30Hz), 2.35(1H, d, J=17.10Hz), 2.27 (1H, dd, J=13.70, 6.80Hz), 2.16 (1H, dd, J=13.70, 7.80Hz), 1.52 (3H, d, J=7.30Hz), 1.44 (9H, s).

More polar isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.72-5.62 (1H, m), 5.49 (1H, q, J=7.20Hz), 5.15 (1H, s), 5.13 -5.10(1H, m), 3.28(1H, d, J=10.30Hz), 3.16(1H, d, J=10.30Hz), 2.88(1H, d, J=17.10Hz), 2.48-2.35(3H, m), 1.51 (3H, d, J = 7.10 Hz), 1.35 (9H, s).

[Reference Example 24]

(3S)-3-(3-Hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl Esters (derived from the more polar isomers)

[Formula 97]

(3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (more polar isomer) ( 51.5g, 0.156mol) was dissolved in tetrahydrofuran (780ml). Then, under nitrogen flow, in an ice-salt bath with an internal temperature of 0°C while stirring while cooling, a 0.5M 9-BBN solution in tetrahydrofuran (345ml, 0.173mol) was added dropwise with a dropping funnel. After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The mixture was cooled again in an ice-salt bath, and at an internal temperature of 2°C, a 0.5M solution of 9-BBN in tetrahydrofuran (156ml, 78mmol) was added dropwise with a dropping funnel. After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The mixture was cooled again in an ice-salt bath, and at an internal temperature of 2°C, a 0.5M 9-BBN solution in tetrahydrofuran (120ml, 60mmol) was added dropwise with a dropping funnel. After the dropwise addition was completed, the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The mixture was cooled again in an ice-salt bath, and 780 ml of 1N sodium hydroxide solution was added dropwise at an internal temperature of 0°C over 15 minutes (internal temperature: 2°C or lower). The mixture was stirred for 10 minutes, and then 78 ml of a 30% hydrogen peroxide solution was added dropwise over 30 minutes at an internal temperature of 4°C or lower. After vigorous stirring at the same temperature for 30 minutes, 1.6 L of diethyl ether was added. After adding 1.6 L of saturated sodium bicarbonate solution, the layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed sequentially with brine, 10% citric acid solution, 10% sodium thiosulfate solution, brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was subjected to flash silica gel column chromatography and eluted with a mixed solvent of methanol-chloroform (1:50, v/v). Fractions containing the target material were combined, concentrated and dried under reduced pressure to afford 40.61 g (74.9%) of the title compound as a colorless oil. In addition, part of the title compound was purified by recrystallization from diethyl ether to give needle-like crystals which were used for X-ray crystallography. As a result, the absolute configuration at the 3-position of the product was determined to be the (3S)-configuration.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.48 (1H, q, J = 7.3Hz), 3.62 (2H, t, J = 6.2Hz), 3.34 (1H, d , J=10.3Hz), 3.14(1H, d, J=10.3Hz), 2.95(1H, d, J=17.1Hz), 2.33(1H, d, J=16.8Hz), 1.88-1.67(3H, m ), 1.51 (3H, d, J = 7.1 Hz), 1.54-1.47 (1H, m), 1.33 (9H, s).

[Table 1]

X-ray crystallography conditions:

Crystal size 0.36 mm × 0.18 mm × 0.08 mm

Radiation CuKα

Tube current 50 kV

Tube voltage 80 mA

Diffractometer AFC7R

Temperature 25°C

Formula C20H29NO4

Formula 347.45

Orthogonal crystal system

Space group P2 ₁ 2 ₁ 2

Z value 4

Cell parameters

α=90.0000°β=90.0000°γ=90.0000°

d _{Calculated value} 1.11 g/ ^cm3

Measured number of reflections 1828 (unique)

μ 6.19cm ^-1

Phase determination direct method (software; SIR92)

Phase Refined Full Matrix Least Squares

R1 5.3% ＝∑||Fo|-|Fc||/∑|Fo|for I＞ 2.0 σdata

R 7.0% = ∑(Fo ² -Fc ² )/∑Fo ²

Rw 14.0％ ＝[∑w(Fo ² -Fc ² ) ² /∑w(Fo ² ) ² ] ^1/2

Data were collected under the assay conditions shown in the table above, then the initial phase was determined by the direct method and the phase was refined by the full matrix least squares method. For refinement, an anisotropy temperature factor is used for non-hydrogen atoms and the position of the hydrogen atoms is determined by calculating the fitted coordinates. As a result of the analysis, the relative configuration of the compound is shown in the ORTEP diagram of FIG. 1 . Based on the asymmetric carbon a having a known absolute configuration, the absolute configuration of the asymmetric carbon b is determined. The results are shown in Figure 2.

[Reference Example 25]

(3S)-5-Oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 98]

At -74°C, (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.29g, 10.0mmol ) into a solution of methanol (100ml) into ozone. When the reaction solution turned blue, stop feeding ozone, and then feed nitrogen into the solution at the same temperature. Sodium borohydride (568 mg) was added at the same temperature, and the mixture was stirred for 1.5 hours while heating to -40°C. The reaction solution was poured into 10% citric acid solution (50 ml), and the mixture was stirred well. The methanol component was distilled off, and the aqueous layer was extracted with ethyl acetate (200ml, 100ml). The organic layer was washed with brine (50ml×2), then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to a slurry. Hexane was added to the resulting residue, and the resulting slurry was stirred. The solid was collected by filtration and dried to give 1.70 g of the title compound as a white solid. The filtrate was concentrated, hexane was added to the resulting residue, and the resulting slurry was stirred. The solid was collected by filtration to afford 0.66 g of the title compound as a white solid. The same operation was repeated to obtain 0.35 g of the title compound (total yield: 2.7 l g, 82%, white solid).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.71 (1H, s), 7.35-7.24 (5H, m), 5.50 (1H, q, J = 7.3Hz), 3.41 (1H, d, J = 10.5Hz ), 3.20 (1H, d, J = 10.5Hz), 2.98 (1H, d, J = 17.1Hz), 2.92 (1H, d, J = 17.8Hz), 2.87 (1H, d, J = 17.8Hz), 2.37 (1H, d, J=17.1 Hz), 1.51 (3H, d, J=7.3 Hz), 1.31 (9H, s).

MS (ESI) m/z: 332 (M+H) ⁺ .

[Reference Example 26]

(3S)-3-(2-Hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 99]

Sodium borohydride (465 mg) was added to (3S)-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrolidine at -40°C - In methanol solution of tert-butyl 3-carboxylate (2.71g, 8.19mmol). After heating to room temperature, 10% citric acid solution was added to the reaction solution, and the mixture was stirred. The reaction solution was poured into a mixture of ethyl acetate (50 ml) and 10% citric acid solution (10 ml), followed by extraction with ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100ml), and the organic layers were combined and washed with brine (50ml×2). The obtained organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→0:1→ethyl acetate-methanol=10:1) to obtain 2.20 g (81%) of the title compound, It is a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.24 (5H, m), 5.48 (1H, q, J=7.1Hz), 3.73-3.64 (2H, m), 3.38 (1H, d, J= 10.2Hz), 3.23(1H, d, J=10.2Hz), 2.97(1H, d, J=17.0Hz), 2.41(1H, d, J=17.0Hz), 2.05(1H, dt, J=14.0, 6.8 Hz), 1.91 (1H, dt, J = 14.0, 6.6 Hz), 1.51 (3H, d, J = 7.1 Hz), 1.32 (9H, s).

MS (ESI) m/z: 334 (M+H) ⁺ .

[Reference Example 27]

(3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl Base]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 100]

Triethylamine (3.0ml, 21.8mmol) was added to (3S)-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3 - A solution of tert-butyl formate (2.42g, 7.25mmol) in dichloromethane (70ml) and the mixture was cooled to 0°C. (tert-butyldimethylsilyl)trifluoromethanesulfonate (2.50ml, 10.9mmol) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. After adding ice cubes and stirring, the reaction solution was poured into a mixture of ethyl acetate (50ml) and saturated sodium bicarbonate (50ml), followed by extraction with ethyl acetate (200ml, 100ml). The organic layers were combined and washed with brine (50ml). After drying over anhydrous sodium sulfate and filtering, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1) to obtain 2.84 g (88%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.22 (5H, m), 5.45 (1H, q, J=7.1Hz), 3.62-3.57 (2H, m), 3.38 (1H, d, J= 10.3Hz), 3.26(1H, d, J=10.3Hz), 2.93(1H, d, J=17.0Hz), 2.42(1H, d, J=17.0Hz), 1.98(1H, dt, J=13.7, 6.8 Hz), 1.88 (1H, dt, J = 13.7, 6.7 Hz), 1.50 (3H, d, J = 7.1 Hz), 1.31 (9H, s).

[Reference Example 28]

(3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-fluoro-5-oxo-1-[(1R)-1-benzene tert-butyl ethyl]pyrrolidine-3-carboxylate

[Formula 101]

Under a nitrogen atmosphere, 1.8 M lithium diisopropylamide in tetrahydrofuran (4.10 ml) was added dropwise to (3S)-3-[2-(tert-butyldimethyl Silyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester in tetrahydrofuran. After stirring at the same temperature for 15 minutes, a solution of N-fluorobenzenesulfonimide (2.63 g, 8.33 mmol) in tetrahydrofuran (18 ml) was added dropwise over 15 minutes. After stirring at the same temperature for 30 minutes, saturated ammonium chloride solution (20 ml) was added, and the mixture was heated to 0°C. The reaction solution was poured into a mixture of ethyl acetate (100ml) and 1mol/ml hydrochloric acid (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed successively with saturated sodium bicarbonate solution (50ml) and brine (50ml×2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane was added to the resulting residue to prepare a slurry and the solids were removed by filtration. The filtrate was concentrated and the resulting solid was removed by filtration. Further concentration of the filtrate afforded 3.44 g of the crude title compound as a pale yellow oil. The resulting crude product was used in the next reaction without further purification.

[Reference Example 29]

(3S)-4-fluoro-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 102]

Under a nitrogen atmosphere at 0°C, acetic acid (0.66ml, 11.54mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran (8.3ml, 8.3mmol) were sequentially added to the crude (3S)-3-[2- (tert-butyldimethylsilyloxy)ethyl]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester ( 3.44g) in tetrahydrofuran solution. After stirring at room temperature for 20 hours, the reaction solution was poured into a mixture of ethyl acetate (100ml) and saturated sodium bicarbonate solution (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml×2), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 2.06 g (91%, two steps) of the title compound as colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.48 (1H, q, J=7.1Hz), 5.21 (1H, d, J=51.7Hz), 3.78-3.69 (2H , m), 3.38(1H, dd, J=1.1, 10.5Hz), 3.30(1H, d, J=10.5Hz), 2.10(1H, m), 2.01(1H, m), 1.56(3H, d, J = 7.1 Hz), 1.32 (9H, s).

[Reference Example 30]

(3S)-3-(2-Bromoethyl)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 103]

Under nitrogen atmosphere, carbon tetrabromide (1.88g, 5.68mmol) and triphenylphosphine (1.49g, 5.68mmol) were sequentially added to (3S)-4-fluoro-3-(2-hydroxyethyl Dichloromethane (20ml) solution of tert-butyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (1.66g, 4.74mmol). After warming to room temperature, the reaction solution was stirred for 1 hour and concentrated to about 5 ml. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1) to obtain 2.17 g (91%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.48 (1H, q, J = 7.1Hz), 5.22 (1H, d, J = 51.5Hz), 3.39 (1H, ddd , J=5.5, 10.7, 11.0Hz), 3.30-3.23(3H, m), 2.42(1H, dddd, J=1.2, 5.5, 11.0, 14.2Hz), 2.32(1H, dddd, J=2.4, 5.5, 10.7, 14.2 Hz), 1.57 (3H, d, J = 7.1 Hz), 1.33 (9H, s).

[Reference Example 31]

(1S, 5R)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-methanol tert-butyl acid

[Formula 104]

Under a nitrogen atmosphere, at -72 ° C, within 10 minutes, a 1.0 M tetrahydrofuran solution (5.02 ml) of lithium hexamethyldisilazide was added dropwise to (3S)-3-(2-bromoethyl)- In a solution of tert-butyl 4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (2.04g, 4.92mmol) in tetrahydrofuran (40ml). The mixture was stirred at the same temperature for 15 minutes and then at 0°C for 30 minutes. The reaction was quenched with 10% citric acid solution (2ml) and poured into a mixture of ethyl acetate (100ml) and 10% citric acid solution (20ml). After extraction with ethyl acetate (150ml), the organic layer was washed with brine (20ml×2), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 1.41 g (86%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.57 (1H, q, J = 7.3Hz), 3.53 (1H, d, J = 10.7Hz), 3.09 (1H, dd , J=4.9, 10.7Hz), 2.76-2.51 (3H, m), 1.57 (3H, d, J=7.3Hz), 1.45 (9H, s), 1.42 (1H, m).

MS (ESI) m/z: 334 (M+H) ⁺ .

[Reference Example 32]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-nitrogen Heterobicyclo[3.2.0]heptane

[Formula 105]

Trifluoroacetic acid (10ml) was added to (1S,5R)-1-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0 ] Heptane-1-carboxylic acid tert-butyl ester (1.06g, 3.18mmol) in dichloromethane (10ml). The mixture was stirred for 4 hours, then the solvent was concentrated under reduced pressure. Toluene (40ml) was added to the residue and trifluoroacetic acid was removed by evaporation. The residue was dried under reduced pressure to afford crude formic acid as a pale yellow solid.

Triethylamine (0.89ml) and diphenoxyphosphoryl azide (0.75ml) were added successively to a solution of crude formic acid obtained above in toluene (10ml) and tert-butanol (10ml). The mixture was stirred at room temperature for 20 minutes, at 40°C for 1 hour, and at 90°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→3:2) to obtain 811 mg (73%) of the title compound as a white amorphous substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.59 (1H, q, J = 7.3Hz), 5.36 (1H, br), 3.68 (1H, br), 2.96 (1H , brd, J=10.0Hz), 2.66-2.45(2H, m), 2.39(1H, br), 1.72(1H, dt, J=12.9, 9.0Hz), 1.56(3H, d, J=7.3Hz) , 1.40 (9H, s).

MS (ESI) m/z: 349 (M+H) ⁺ .

[Reference Example 33]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo [3.2.0] Heptane

[Formula 106]

At 0°C, a 1.16M solution of borane-tetrahydrofuran complex in tetrahydrofuran (6.0ml) was added dropwise to (1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro -4-Oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (811mg, 2.33mmol) in tetrahydrofuran (6.0ml). The mixture was warmed to room temperature, stirred for 5 hours, then cooled to -10°C. A mixture of ethanol (9.0ml)-water (1.0ml) was carefully added dropwise. After triethylamine (3.0 ml) was added dropwise, the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, and the precipitated white solid was removed by filtration through celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to obtain 530 mg (68%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.18 (5H, m), 5.19 (1H, br), 3.37 (1H, q, J=6.8Hz), 3.27 (1H, dd, J=1.7, 9.0Hz), 3.13(1H, brd, J=8.3Hz), 2.49-2.38(2H, m), 2.23(1H, m), 2.13-2.08(2H, m), 2.00(1H, m), 1.39( 9H, brs), 1.36 (3H, d, J = 6.8 Hz).

[Reference Example 34]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.2.0]heptane

[Formula 107]

10% palladium-carbon catalyst (50% wet, 50 mg) was added to (1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl ]-3-azabicyclo[3.2.0]heptane (530 mg, 1.58 mmol) in ethanol, and the resulting mixture was stirred at 50° C. for 5 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 321 mg of crude amine as a white solid.

¹ H-NMR (400MHz, CD ₃ OD) δ: 3.07-3.00 (2H, m), 2.87-2.80 (2H, m), 2.35 (1H, m), 2.03-1.95 (2H, m), 1.67 (1H , dt, J = 12.0, 9.0 Hz), 1.34 (9H, s), 1.00 (1H, dd, J = 2.1, 6.2 Hz).

[Example 6]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.2.0]hept-3-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 108]

6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-formic acid-BF ₂ Chelate (577mg, 1.60mmol) and triethylamine (0.699ml, 5.02mmol) were sequentially added to (1R, 5R)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo [3.2.0] In a solution of heptane (crude product; 321 mg) in dimethyl sulfoxide (5.0 ml). The mixture was heated at 40°C with stirring for 24 hours. Triethylamine (0.35 ml) was added, and the resulting mixture was further stirred at the same temperature for 17 hours. Then, 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid was added - BF ₂ chelate (58mg) and triethylamine (0.125ml). In addition, 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4 -Oxoquinoline-3-carboxylic acid-BF ₂ chelate (480mg, 240mg) and triethylamine (0.389ml, 0.195ml). After the last addition of reagents, the mixture was stirred for 5.5 hours. Then, a mixture of ethanol:water=4:1 (30ml) and triethylamine (4.5ml) was added to the reaction solution, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150ml) and washed successively with 10% citric acid solution (30ml), water (30ml×2) and brine (30ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue (890 mg) was dissolved in concentrated hydrochloric acid (4.0 ml), and the resulting solution was stirred at room temperature for 10 minutes. The reaction solution was diluted with 6M hydrochloric acid and washed with chloroform (5ml×15). The aqueous layer was adjusted to pH 13.2 with saturated sodium hydroxide solution under ice cooling, then adjusted to pH 7.4 with hydrochloric acid, followed by extraction with chloroform (80ml×3). The organic layer was dried over anhydrous sodium sulfate, and filtered to remove the drying agent. Then, the filtrate was concentrated under reduced pressure. The residue was fully dried under vacuum, redissolved in a mixed solvent of chloroform:methanol=10:1, and filtered through a membrane filter. The filtrate was concentrated under reduced pressure to obtain a tan solid. The resulting solid was purified by recrystallization from ethanol-ammonia to give 193 mg (33%) of the title compound as pale yellow needles.

mp: 235°C (decomposition).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, d, J = 1.2Hz), 7.73 (1H, d, J = 13.4Hz), 4.96 (1H, m), 4.13 (1H, m) , 4.07(1H, m), 3.72(3H, s), 3.60(1H, brd, J=10.4Hz), 3.52(1H, m), 3.42(1H, brd, J=10.4Hz), 2.51(1H, m), 2.32 (1H, m), 1.99-1.92 (2H, m), 1.70-1.52 (2H, m).

Anal _. Calcd. _{for C20H20F3N3O4} : C, 56.74; H, 4.76; _F , 13.46; _N , 9.92. Found values: C, 56.68; H, 4.71; F, 13.15; N, 9.86.

HRMS (FAB ₎ ; m _/ z calcd _{for C20H21F3N3O4} (M+H) ⁺ : _424.1484 . Found value: 424.1475.

IR(ATR) v: 2938, 2842, 1720, 1616, 1544, 1511, 1450, 1436, 1365, 1324, 1276, 1222, 1180, 1159, 1135, 1052, 1010, ^{931 cm -1} .

[Reference Example 35]

(3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-5-oxo-1-[(1R)-1- Phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 109]

Under a nitrogen atmosphere, 1.8 M lithium diisopropylamide in tetrahydrofuran (3.10 ml) was added dropwise to (3S)-3-[2-(tert-butyldimethyl Silyloxy)ethyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.24g, 5.00mmol) in tetrahydrofuran (20ml) in solution. After stirring at the same temperature for 10 minutes, methyl iodide (0.34ml, 5.50mmol) was added. The mixture was stirred at the same temperature for 15 minutes and then heated to -10°C over 10 minutes. Then 10% aqueous citric acid (5ml) was added. The reaction solution was poured into a mixture of ethyl acetate (100ml) and 10% citric acid solution (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml×2), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting dark brown residue was used in the next reaction without further purification.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.46 (0.5H, q, J=7.1Hz), 5.45 (0.5H, q, J=7.1Hz), 3.73-3.54 (2H, m), 3.37(0.5H, d, J=10.5Hz), 3.36-3.31(1H, m), 3.28(0.5H, d, J=10.2Hz), 2.75(0.5H, q, J= 7.3Hz), 2.40(0.5H, q, J=7.3Hz), 2.03(0.5H, m), 1.92(0.5H, ddd, J=5.4, 7.2, 13.8Hz), 1.83(0.5H, m), 1.71(0.5H, m), 1.51(1.5H, d, J=7.1Hz), 1.50(1.5H, d, J=7.1Hz), 1.35(4.5H, s), 1.34(4.5H, s), 1.21(1.5H, d, J=7.3Hz), 1.12(1.5H, d, J=7.3Hz), 0.88(2×4.5H, s), 0.03(2×1.5H, s), 0.02(1.5H , s), 0.01(1.5H, s).

[Reference Example 36]

(3S)-3-(2-Hydroxyethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert Butyl ester

[Formula 110]

The above crude (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-5-oxo-1-[(1R)-1-benzene tert-butyl ethyl]pyrrolidine-3-carboxylate was dissolved in tetrahydrofuran (10 ml). Then, under a nitrogen atmosphere, acetic acid (0.572ml, 10.0mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran (10.0ml, 10.0mmol) were added sequentially. After stirring at room temperature for 12 hours, the reaction solution was poured into a mixture of ethyl acetate (100ml) and brine (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→1:2) to obtain 1.56 g (90%, two steps) of the title compound as a mixture of diastereomers as a colorless oil .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.25 (5H, m), 5.46 (0.5H, q, J=7.1Hz), 5.45 (0.5H, q, J=7.1Hz), 3.73-3.62 (2H, m), 3.35(0.5H, d, J=10.5Hz), 3.33(0.5H, d, J=10.5Hz), 3.26(0.5H, d, J=10.5Hz), 3.25(0.5H, d, J = 10.5Hz), 2.78 (0.5H, q, J = 7.3Hz), 2.42 (0.5H, q, J = 7.3Hz), 2.13 (0.5H, dt, J = 14.2, 6.6Hz), 2.00 (0.5H, dt, J = 14.2, 6.8Hz), 1.84 (0.5H, dt, J = 14.2, 6.4Hz), 1.71 (0.5H, dt, J = 14.2, 6.4Hz), 1.52 (1.5H, d , J=7.1Hz), 1.50(1.5H, d, J=7.1Hz), 1.37(4.5H, s), 1.35(4.5H, s), 1.22(1.5H, d, J=7.3Hz), 1.14 (1.5H, d, J=7.3Hz).

[Reference Example 37]

(3S)-3-(2-Bromoethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert Butyl ester

[Formula 111]

Under nitrogen atmosphere, carbon tetrabromide (1.64g, 4.95mmol) and triphenylphosphine (1.30g, 4.95mmol) were sequentially added to (3S)-3-(2-hydroxyethyl)-4 -Methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.56g, 4.50mmol) in dichloromethane (20ml). After warming to room temperature, the reaction solution was stirred for 10 minutes and concentrated to about 5 ml. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=4:1→2:1→1.5:1) to obtain 1.30 g (70%) of the title compound as a mixture of diastereomers as white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.47 (0.5H, q, J=7.1Hz), 5.46 (0.5H, q, J=7.1Hz), 3.35-3.19 (3H, m), 3.14(0.5H, d, J=10.5Hz), 3.13(0.5H, d, J=10.5Hz), 2.80(0.5H, q, J=7.4Hz), 2.48-2.39(1H , m), 2.30(0.5H, ddd, J=6.2, 10.4, 13.9Hz), 2.19-2.02(1H, m), 1.54(1.5H, d, J=7.1Hz), 1.52(1.5H, d, J=7.1 Hz), 1.37 (4.5H, s), 1.36 (4.5H, s), 1.22 (1.5H, d, J=7.4Hz), 1.14 (1.5H, d, J=7.4Hz).

MS (ESI) m/z: 410 (M+H) ⁺ .

[Reference Example 38]

(1S,5S)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1- tert-butyl formate

[Formula 112]

Under a nitrogen atmosphere, a 1.0M solution of lithium hexamethyldisilazide in tetrahydrofuran (3.8ml, 3.80mmol) was added dropwise to (3S)-3-(2-bromoethyl) at -72°C within 7 minutes. In a solution of tert-butyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (1.30g, 3.17mmol) in tetrahydrofuran (20ml) . The mixture was stirred at the same temperature for 30 minutes. After heating to -10°C and stirring for 1.5 hours, a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.0 ml, 4.0 mmol) was added within 2 minutes, and the mixture was stirred at 0°C for 20 hours. A 10% citric acid solution (20 ml) was added at the same temperature. The reaction solution was poured into a mixture of ethyl acetate (100 ml) and 10% citric acid solution (10 ml). After extraction with ethyl acetate (150ml), the organic layer was washed with brine (30ml), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to obtain 0.845 g (81%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.56 (1H, q, J = 7.1Hz), 3.42 (1H, d, J = 10.2Hz), 3.13 (1H, d , J=10.2Hz), 2.65(1H, ddd, J=4.7, 10.3, 11.9Hz), 2.25(1H, ddd, J=4.7, 9.5, 11.9Hz), 2.09(1H, m), 1.86(1H, dt, J = 11.9, 9.5 Hz), 1.57 (3H, d, J = 7.1 Hz), 0.71 (9H, s), 1.25 (3H, s).

MS (ESI) m/z: 330 (M+H) ⁺ .

[Reference Example 39]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3- Azabicyclo[3.2.0]heptane

[Formula 113]

Trifluoroacetic acid (5ml) was added to (1S,5S)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0] A solution of tert-butyl heptane-1-carboxylate (0.845g, 2.56mmol) in dichloromethane (10ml). The mixture was stirred for 15 hours, and then the reaction solution was concentrated under reduced pressure. Toluene (3 x 40ml) was added to the residue and trifluoroacetic acid was removed by evaporation. The residue was dried under reduced pressure to give crude formic acid as a white solid.

Triethylamine (0.786ml) and diphenoxyphosphoryl azide (0.608ml) were added successively to a solution of crude formic acid obtained above in toluene (10ml) and tert-butanol (10ml). The mixture was stirred at room temperature for 1 hour and at 80°C for 10 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→3:2) to obtain 548 mg (62%, two steps) of the title compound as a colorless viscous Oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.55 (1H, q, J = 7.1 Hz), 4.81 (1H, br), 3.60 (1H, br), 3.02 (1H , d, J=11.3Hz), 2.30-2.10(3H, m), 2.02(1H, m), 1.56(3H, d, J=7.1Hz), 1.38(9H, s), 1.27(3H, s) .

MS (ESI) m/z: 345 (M+H) ⁺ .

[Reference Example 40]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methyl-3-[(1R)-1-phenylethyl]-3-azabis cyclo[3.2.0]heptane

[Formula 114]

At 0°C, a 1.09M solution of borane/tetrahydrofuran complex in tetrahydrofuran (3.6ml, 3.98mmol) was added dropwise to (1S,5S)-1-(tert-butoxycarbonylamino)- 5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (548mg, 1.59mmol) in tetrahydrofuran (10ml) . After heating to room temperature and stirring for 3 hours, a 1.09 M solution of borane/tetrahydrofuran complex in tetrahydrofuran (3.6 ml, 3.98 mmol) was added at the same temperature. The mixture was stirred at room temperature for 15 hours, then cooled to 0 °C. A mixture of ethanol (9.0ml)-water (1.0ml) was carefully added dropwise. After triethylamine (3.0 ml) was added dropwise, the mixture was heated under reflux for 1 hour. The reaction solution was concentrated, and the precipitated white solid was filtered through celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→5:1) to obtain 184 mg (35%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.17 (5H, m), 4.58 (1H, br), 3.28 (1H, q, J=6.6Hz), 2.95 (1H, d, J=8.5Hz ), 2.91(1H, brd, J=9.0Hz), 2.14-2.05(4H, m), 1.68(1H, m), 1.38(9H, brs), 1.34(3H, d, J=6.6Hz), 1.14 (3H, s).

[Reference Example 41]

(1S,5S)-1-(tert-butoxycarbonylamino)-5-methyl-3-azabicyclo[3.2.0]heptane

[Formula 115]

10% palladium-carbon catalyst (50% wet, 200 mg) was added to (1S,5S)-1-(tert-butoxycarbonylamino)-5-methyl-3-[(1R)-1-phenylethyl ]-3-azabicyclo[3.2.0]heptane (184mg, 0.057mmol) in ethanol, and the mixture was stirred at 40°C for 5 hours under a hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to afford the crude amine as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.69 (1H, br), 3.27 (1H, d, J = 11.5Hz), 2.92 (1H, br), 2.82 (1H, d, J = 11.2Hz), 2.62(1H, brd, J=11.2Hz), 2.13(1H, brm), 1.98(1H, ddd, J=5.6, 9.8, 12.7Hz), 1.71(1H, m), 1.59(1H, m), 1.44 (9H, s), 1.16 (3H, s).

[Example 7]

7-[(1R, 5S)-1-amino-5-methyl-3-azabicyclo[3.2.0]hept-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 116]

6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-formic acid-BF ₂ Chelate (231mg, 0.668mmol) and triethylamine (0.279ml, 2.01mmol) were sequentially added to the above crude (1S, 5S)-1-(tert-butoxycarbonylamino)-5-methyl-3 - Azabicyclo[3.2.0]heptane in dimethyl sulfoxide (2.0 ml). The mixture was heated and stirred at 40°C for 5 hours. Then, a mixture of ethanol:water=4:1 (7.5ml) and triethylamine (1.0ml) was added to the reaction solution, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100ml), and washed successively with 10% citric acid solution (20ml), water (20ml×2) and brine (20ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC (0.1% formic acid solution-acetonitrile system) to give a light yellow solid. The obtained pale yellow solid was dissolved in concentrated hydrochloric acid (1.0 ml), and the solution was stirred at room temperature for 10 minutes. The reaction solution was diluted with 6M hydrochloric acid (8 ml) and washed with chloroform (5 ml). The aqueous layer was adjusted to pH 12.4 with saturated sodium hydroxide solution under ice cooling, then adjusted to pH 7.3 with hydrochloric acid, then diluted with water (10 ml), and extracted with chloroform (50 ml×3). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was fully dried in vacuum, then dissolved in a mixed solvent of chloroform:methanol=10:1, and filtered through a membrane filter. The filtrate was concentrated under reduced pressure to afford 60 mg (26%) of the title compound as a pale yellow solid.

mp: 123-125°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.46 (1H, d, J = 1.7Hz), 7.70 (1H, d, J = 13.7Hz), 4.97 (1H, m), 4.05 (1H, m) , 3.74(1H, d, J=11.5Hz), 3.68(3H, s), 3.65(1H, m), 3.20(1H, brd, J=9.8Hz), 3.11(1H, brd, J=10.3Hz) , 2.11 (1H, m), 1.95 (1H, m), 1.83 (1H, m), 1.72-1.46 (3H, m), 1.14 (3H, s).

Anal _. Calcd _. for _{C21H23F2N3O4 - H2O} -0.25EtOH: C, 57.52; H, 5.95; F, _8.46 ; N, 9.36. Found: C, 57.80; H, 5.77; F, 8.41; N, 9.40.

_{HRMS (FAB); m/z calcd for C21H24F2N3O4 ( M} +H) ⁺ : _420.1735 . Found value: 420.1739.

IR(ATR) v: 2931, 2842, 1727, 1616, 1540, 1508, 1436, 1346, 1315, 1270, 1226, 1187, 1133, 1097, 1051 cm ^-1 .

[Reference Example 42]

(4R)-4-allyl-4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 117]

Lithium borohydride (4.96g, 0.228mol) was suspended in tetrahydrofuran (500ml). Within 10 minutes, (3R)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (50.0 g, 0.152mol) in tetrahydrofuran (100ml)-ethanol (17.7ml) was added to the suspension. The mixture was heated to 40°C, stirred for 12 hours, then heated to reflux for 20 hours. After cooling to 0°C, saturated ammonium chloride solution (100ml) was carefully added. After distilling off the THF component under reduced pressure, the reaction solution was poured into a mixture of ethyl acetate (100ml) and saturated ammonium chloride solution (100ml), followed by extraction with ethyl acetate (1000ml, 750ml). The organic layers were combined and washed with brine (200ml). After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain 29.9 g (76%) of the title compound as a colorless viscous oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.59-5.47 (2H, m), 4.97 (1H, m), 4.90 (1H, m), 3.50 (2H, d, J = 5.1Hz), 3.23 (1H, d, J = 10.1Hz), 2.71 (1H, d, J = 10.1Hz), 2.37 (1H, d, J = 16.8Hz), 2.26 (1H, d, J = 16.8 Hz), 2.08 (2H, d, J=7.3 Hz), 1.84 (1H, m), 1.51 (3H, d, J=7.1 Hz).

MS (ESI) m/z: 260 (M+H) ⁺ .

[Reference Example 43]

(4R)-4-allyl-4-benzyloxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 118]

Under nitrogen atmosphere, benzyl bromide (17.1ml, 0.144mol) and sodium hydride (55% dissolved in liquid paraffin, 6.27g, 0.144mol) were sequentially added to (4R)-4-allyl- 4-Hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (31.1g, 0.120mol) in tetrahydrofuran (300ml)-dimethylformamide (75ml) solution. The mixture was stirred at the same temperature for 30 minutes. Methanol (5ml) was added carefully and stirred until gas evolution ceased. Then, the reaction was quenched with saturated ammonium chloride solution (50ml). The reaction solution was poured into a mixture of ethyl acetate (1000ml) and water (150ml), followed by extraction with ethyl acetate (1500ml). The organic layer was washed successively with water (200ml) and brine (200ml×2), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to obtain 41.3 g (99%) of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.23 (10H, m), 5.52-5.42 (2H, m), 4.93 (1H, m), 4.84 (1H, m), 4.51 (1H, d, J = 12.2Hz), 4.47 (1H, d, J = 12.2Hz), 3.27 (2H, s), 3.21 (1H, d, J = 10.0Hz), 2.69 (1H, d, J = 10.0Hz), 2.37 (1H,d,J=16.9Hz), 2.26(1H,d,J=16.9Hz), 2.11(1H,m), 2.05(1H,m), 1.46(3H,d,J=7.3Hz).

[Reference Example 44]

(4R)-4-Benzyloxymethyl-4-(2-hydroxyethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 119]

At -70°C, to (4R)-4-allyl-4-benzyloxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (4.00g, 11.45mmol ) into a solution of dichloromethane (100ml) and stirred at the same temperature for 15 minutes. When the reaction solution turned dark blue, stop feeding ozone, and then feed nitrogen gas into the reaction solution until the solution became colorless. Sodium borohydride (434 mg, 11.45 mmol) and methanol (40 ml) were added at the same temperature, and the mixture was warmed to room temperature within 3 hours. Sodium borohydride (325 mg, 8.58 mmol) was added and the mixture was stirred at room temperature for a further 24 hours. Saturated ammonium chloride solution was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (200ml) and water (200ml), followed by extraction with ethyl acetate (500ml). The organic layer was washed with brine (200ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→1:9→0:1) to obtain 3.22 g (79%) of the title compound as a colorless viscous oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.23 (10H, m), 5.46 (1H, q, J = 7.1Hz), 4.55 (1H, d, J = 11.8Hz), 4.48 (1H, d , J=11.8Hz), 3.54-3.45(2H, brm), 3.36(2H, s), 3.24(1H, d, J=10.2Hz), 2.72(1H, d, J=10.2Hz), 2.38(1H , d, J=17.0 Hz), 2.28 (1H, d, J=17.0 Hz), 2.15 (1H, br), 1.69-1.58 (2H, m), 1.44 (3H, d, J=7.1 Hz).

[Reference Example 45]

(4S)-4-Benzyloxymethyl-4-(2-bromoethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 120]

Under nitrogen atmosphere, carbon tetrabromide (3.17g, 9.56mmol) and triphenylphosphine (2.51g, 9.56mmol) were sequentially added to (4R)-4-benzyloxymethyl-4-(2-hydroxyethyl yl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (3.22 g, 9.10 mmol) in dichloromethane (20 ml), and the mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→1:2) to obtain 3.18 g (84%) of the title compound as light yellow Oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.25 (10H, m), 5.46 (1H, q, J = 7.1Hz), 4.52 (1H, d, J = 12.2Hz), 4.46 (1H, d , J=12.2Hz), 3.28(2H, s), 3.25(1H, d, J=10.1Hz), 3.17-3.04(2H, m), 2.67(1H, d, J=10.1Hz), 2.37(1H , d, J=17.1Hz), 2.26 (1H, d, J=17.1Hz), 2.05 (1H, ddd, J=5.9, 10.4, 14.0Hz), 1.96 (1H, ddd, J=6.1, 10.6, 14.0 Hz), 1.44 (3H, d, J = 7.1 Hz).

[Reference Example 46]

(1S,5R)-5-Benzyloxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0] Methyl heptane-1-carboxylate

[Formula 121]

Under a nitrogen atmosphere, a 1.0M solution of lithium hexamethyldisilazide in tetrahydrofuran (14.5ml, 14.5mmol) was added to (4S)-4-benzyloxymethyl-4-(2-bromo Ethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.75g, 6.60mmol) and methyl chloroformate (0.54ml, 6.93mmol) in tetrahydrofuran (20ml) solution . The mixture was stirred for 12 hours while gradually warming to room temperature. The reaction solution was cooled to 0°C. Saturated ammonium chloride solution (5 ml) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (100ml) and water (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to obtain 2.12 g (82%) of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.24 (10H, m), 5.59 (1H, q, J = 7.1Hz), 4.47 (1H, d, J = 12.0Hz), 4.43 (1H, d , J=12.0Hz), 3.63(3H, s), 3.53(1H, d, J=9.3Hz), 3.49(1H, d, J=9.3Hz), 3.37(1H, d, J=10.0Hz), 2.78 (1H, ddd, J=9.3, 9.5, 12.2Hz), 2.73 (1H, d, J=10.0Hz), 2.22 (1H, ddd, J=3.4, 9.3, 12.2Hz), 1.91 (1H, ddd, J = 3.4, 10.5, 12.2 Hz), 1.63 (1H, ddd, J = 9.5, 10.5, 12.2 Hz), 1.58 (3H, d, J = 7.1 Hz).

MS (ESI) m/z: 394 (M+H) ⁺ .

[Reference Example 47]

(1S,5R)-5-Hydroxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane -1-methyl carboxylate

[Formula 122]

10% palladium-carbon catalyst (50% wet, 200 mg) was added to (1S,5R)-5-benzyloxymethyl-2-oxo-3-[(1R)-1-phenylethyl]- In a solution of methyl 3-azabicyclo[3.2.0]heptane-1-carboxylate (1.82g, 4.62mmol) in ethanol (20ml)-tetrahydrofuran (20ml), the mixture was stirred at 40°C for 2.5 hours under a hydrogen atmosphere . After removing the catalyst by filtration, the filtrate was concentrated to obtain the title compound as colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.60 (1H, q, J = 7.1Hz), 3.79 (1H, dd, J = 4.2, 11.8Hz), 3.78 (3H , s), 3.58 (1H, dd, J = 7.1, 11.8Hz), 3.56 (1H, d, J = 10.0Hz), 2.73-2.65 (2H, m), 2.57 (1H, dd, J = 4.2, 7.1 Hz), 2.30 (1H, m), 1.83 (1H, m), 1.62 (1H, m), 1.59 (3H, d, J = 7.1 Hz).

MS (ESI) m/z: 304 (M+H) ⁺ .

[Reference Example 48]

(1S,5R)-5-fluoromethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane -1-methyl carboxylate

[Formula 123]

Bis(2-methoxyethyl)aminosulfur trifluoride (1.98ml, 10.7mmol) was added to (1S,5R)-5-hydroxymethyl-2-oxo at room temperature under nitrogen atmosphere -3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane-1-carboxylic acid methyl ester (1.30g, 4.30mmol) in dichloromethane solution. The mixture was heated to 50°C and stirred for 12 hours. Then, saturated sodium bicarbonate solution (10 ml) was added, and the mixture was stirred for 10 minutes. The reaction solution was poured into a mixture of ethyl acetate (50ml) and water (30ml), followed by extraction with ethyl acetate (200ml). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1.5:1) to obtain 1.26 g (96%) of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.29 (5H, m), 5.63 (1H, q, J = 7.2Hz), 4.51 (1H, dd, J = 9.8, 47.1Hz), 4.47 (1H , dd, J=9.8, 47.0Hz), 3.76(3H, s), 3.41(1H, d, J=10.0Hz), 2.78(1H, m), 2.76(1H, d, J=10.0Hz), 2.27 (1H, ddd, J = 3.6, 9.3, 12.5Hz), 1.93 (1H, ddd, J = 3.6, 10.5, 12.4Hz), 1.68 (1H, m), 1.62 (3H, d, J = 7.2Hz).

MS (ESI) m/z: 306 (M+H) ⁺ .

[Reference Example 49]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-fluoromethyl-2-oxo-3-[(1R)-1-phenylethyl Base]-3-azabicyclo[3.2.0]heptane

[Formula 124]

Add 1M sodium hydroxide solution to (1S,5R)-5-fluoromethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0] Heptane-methyl-1-carboxylate (1.26g, 4.13mmol) in tetrahydrofuran (10ml)-methanol (5.0ml). The mixture was stirred for 12 hours. The reaction solution was adjusted to pH 2 or lower with 6M hydrochloric acid, and the tetrahydrofuran and methanol components were removed by filtration under reduced pressure. The residue was poured into a mixture of ethyl acetate and 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure to afford 1.17 g (97%) of crude formic acid as a white solid.

Under a nitrogen atmosphere, the crude formic acid (1.02g, 3.51mmol) was dissolved in a mixture of toluene (20ml), tert-butanol (20ml) and triethylamine (0.98ml, 7.03mmol), and diphenoxy Phosphoryl azide (0.833ml, 3.87mmol). The mixture was stirred at 40°C for 1 hour and then at 80°C for 12 hours. The reaction solution was poured into a mixture of ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml), followed by extraction with ethyl acetate (150 ml). The organic layer was washed with brine (30ml), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to obtain 746 mg (59%) of the title compound as colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.29 (5H, m), 5.60 (1H, q, J = 7.1Hz), 4.95 (1H, br), 4.61 (1H, dd, J = 9.6, 47.3Hz), 4.47(1H, dd, J=9.6, 47.3Hz), 2.15(1H, d, J=9.5Hz), 2.70(1H, d, J=9.5Hz), 2.36(1H, m), 2.17 -2.08 (2H, m), 1.60 (3H, d, J=7.1 Hz), 1.42 (9H, s).

MS (ESI) m/z: 363 (M+H) ⁺ .

[Reference Example 50]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-fluoromethyl-3-[(1R)-1-phenylethyl]-3-aza Bicyclo[3.2.0]heptane

[Formula 125]

Under a nitrogen atmosphere, 65% Red-Al ^TM in toluene (1.76ml, 5.85mmol) was added dropwise to (1S,5S)-1-(tert-butoxycarbonylamino) within 10 minutes at -15°C )-5-fluoromethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (707mg, 1.95mmol) in toluene . The mixture was warmed to room temperature, stirred for 1.5 hours, and cooled to 0 °C. A 25% sodium potassium tartrate tetrahydrate solution (10 ml) was carefully added while maintaining the internal temperature of the reaction solution at 10°C or lower. The reaction solution was poured into a mixture of ethyl acetate (10ml) and brine (10ml), followed by extraction with ethyl acetate (150ml). The organic layer was washed with brine (30ml) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→5:1→2:1) to obtain 567 mg (83%) of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.18 (5H, m), 4.89 (1H, br), 4.63 (1H, dd, J=9.8, 47.9Hz), 4.53 (1H, J=9.8, 47.6Hz), 3.33(1H, q, J=6.4Hz), 2.95(2H, d, J=8.8Hz), 2.40(1H, d, J=8.8Hz), 2.18-2.14(3H, m), 1.93 -1.87 (2H, m), 1.37 (9H, s), 1.36 (3H, d, J=6.4Hz).

MS (ESI) m/z: 349 (M+H) ⁺ .

[Example 8]

7-[(1S, 5S)-1-amino-5-fluoromethyl-3-bicyclo[3.2.0]hept-3-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl-1-yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 126]

10% palladium-carbon catalyst (M, about 50% wet, 50 mg) was added to (1S,5S)-1-(tert-butoxycarbonylamino)-5-fluoromethyl-3-[(1R)-1 - In a solution of -phenylethyl]-3-azabicyclo[3.2.0]heptane (567mg, 1.63mmol) in ethanol (10ml), the mixture was stirred at 50°C for 2.5 hours under hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give crude amine (364 mg) as colorless crystals.

The crude amine was dissolved in dimethylsulfoxide (4.0ml), and triethylamine (0.62ml, 4.45mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclocyclo Propyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (642 mg, 1.78 mmol). The mixture was stirred with heating at 40°C for 24 hours. Then, a mixture of ethanol:water=3:1 (20.0ml) and triethylamine (3.0ml) was added to the reaction solution, and the mixture was heated under reflux for 1.5 hours. The reaction solution was poured into a mixture of ethyl acetate (20ml) and 10% citric acid solution (10ml), followed by extraction with ethyl acetate (50ml×3). The organic layers were combined and washed with brine (50ml). Then, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative HPLC (0.1% formic acid solution-acetonitrile system) to give a pale yellow solid. The obtained pale yellow solid was dissolved in concentrated hydrochloric acid (1.5 ml), and the resulting solution was stirred at room temperature for 10 minutes. The reaction solution was diluted with 6M hydrochloric acid (20ml) and washed with chloroform (7ml). The aqueous layer was adjusted to pH 12.4 with saturated sodium hydroxide solution under ice cooling, then adjusted to pH 7.3 with hydrochloric acid, and extracted with chloroform (50ml×2). The aqueous layer was adjusted to pH 7.4 again, and extracted with chloroform (50ml×2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The residue was thoroughly dried in vacuo, then dissolved in chloroform. The solution was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethanol and reprecipitated from hexane. The resulting solid was collected by filtration and dried to give 219 mg (31%) of the title compound as a pale yellow solid.

mp: 186-188°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 4.34 (1H, d, J = 7.9Hz), 4.96 (1H, m), 4.70 (1H, dd, J = 10.0, 47.4 Hz), 4.64(1H, dd, J=10.0, 47.1Hz), 4.02(1H, m), 3.67-3.61(5H, m), 3.33(1H, brd, J=10.5Hz), 3.22(1H, brd , J=9.8Hz), 2.11 (1H, m), 2.00-1.88 (2H, m), 1.73 (1H, m), 1.60 (1H, m), 1.47 (1H, m).

_Anal. Calcd _. for _{C21H22F3N3O4.0.25H2O.0.25EtOH} : _C , _56.95 ; H, 5.33; _F , 12.57; N, 9.27. Found: C, 56.94; H, 5.11; F, 12.74; N, 9.23.

_{HRMS (FAB); m/z calcd for C21H23F3N3O4 ( M +} H) ⁺ : 438.16406. Measured value: 438.16743.

IR (ATR) v: 3386, 2935, 1716, 1616, 1540, 1508, 1442, 1436, 1351, 1319, 1274, 1228, 1184, 1122, 1051 cm ^-1 .

[Reference Example 51]

(4R)-4-allyl-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 127]

Under nitrogen atmosphere, methyl iodide (1.87ml, 30.1mmol) and sodium hydride (55% dissolved in liquid paraffin, 1.31g, 30.1mol) were sequentially added to (4R)-4-allyl- In a solution of 4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (7.09g, 27.3mmol) in tetrahydrofuran (80ml)-dimethylformamide (20ml). The mixture was warmed to room temperature and stirred for 1 hour. Methanol (2ml) was added carefully and stirred until gas evolution ceased. Then, the reaction was quenched with saturated ammonium chloride solution (10 ml). The reaction solution was poured into a mixture of ethyl acetate (100ml) and water (100ml), followed by extraction with ethyl acetate (800ml). The organic layer was washed successively with water (200ml) and brine (200ml×2), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1→1:1) to obtain 7.42 g (99%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.24 (5H, m), 5.54-5.43 (2H, m), 4.94 (1H, m), 4.84 (1H, m), 3.33 (3H, s) , 3.20(2H, s), 3.19(1H, d, J=10.0Hz), 2.69(1H, d, J=10.0Hz), 2.36(1H, d, J=17.1Hz), 2.24(1H, d, J = 17.1 Hz), 2.05-2.03 (2H, m), 1.50 (3H, d, J = 7.3 Hz).

[Reference Example 52]

(4R)-4-(2-Hydroxyethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 128]

At -70°C, to (4R)-4-allyl-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (3.28g, 12.0mmol ) into methanol (20ml)-dichloromethane (20ml) solution, and stirred at the same temperature for 30 minutes. When the reaction solution turned dark blue, stop feeding ozone, and then feed nitrogen gas into the reaction solution until the solution became colorless. Sodium borohydride (454 mg, 12.0 mmol) was added at the same temperature, and the mixture was warmed to room temperature within 2 hours. After heating, sodium borohydride (227 mg, 6.0 mmol) was added, and the mixture was stirred for 24 hours. Then, sodium borohydride (113 mg, 3.0 mmol) was added again, and the mixture was stirred for 0.5 hours. Saturated ammonium chloride solution (10 ml) was added, and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (50ml) and water (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:0→10:1) to obtain 2.85 g (86%) of the title compound as a colorless viscous oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.49 (1H, q, J=7.1Hz), 3.55-3.44 (2H, m), 3.37 (3H, s), 3.30 (1H, d, J = 9.5Hz), 3.28 (1H, d, J = 9.5Hz), 3.22 (1H, d, J = 10.0Hz), 2.72 (1H, d, J = 10.0Hz), 2.38 (1H , d, J=16.8 Hz), 2.26 (1H, d, J=16.8 Hz), 1.64 (2H, t, J=6.0 Hz), 1.50 (3H, d, J=7.1 Hz).

[Reference Example 53]

(4S)-4-(2-Bromoethyl)-4-methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

[Formula 129]

Under nitrogen atmosphere, carbon tetrabromide (3.58g, 10.8mmol) and triphenylphosphine (2.83g, 10.8mmol) were sequentially added to (4R)-4-(2-hydroxyethyl)-4 at 0°C -Methoxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.85g, 10.3mmol) in dichloromethane (30ml) and the mixture was stirred for 10 minutes. The mixture was warmed to room temperature and stirred for 24 hours, then the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane→hexane:ethyl acetate=2:1→1:1→1:2) to obtain 2.07 g (59%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.49 (1H, q, J = 7.3Hz), 3.32 (3H, s), 3.24 (1H, d, J = 10.3Hz ), 3.23(2H, s), 3.20-3.07(2H, m), 2.67(1H, d, J=10.3Hz), 2.38(1H, d, J=16.8Hz), 2.25(1H, d, J=16.8Hz), 2.25(1H, d, J= 16.8Hz), 2.03-1.90 (2H, m), 1.50 (3H, d, J=7.3Hz).

[Reference Example 54]

(1S,5R)-5-methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0] Methyl heptane-1-carboxylate

[Formula 130]

Under a nitrogen atmosphere at -70°C, a 1.0M solution of lithium hexamethyldisilazide in tetrahydrofuran (13.4ml, 13.4mmol) was added to (4S)-4-(2-bromoethyl)-4-methyl Oxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (2.07g, 6.08mmol) and methyl chloroformate (0.493ml, 6.38mmol) in tetrahydrofuran (20ml) middle. The mixture was stirred for 14 hours while gradually warming to room temperature. The reaction solution was cooled to 0°C. A 10% citric acid solution (20ml) was added and the mixture was stirred for 10 minutes. Then, the reaction solution was poured into a mixture of ethyl acetate (100ml) and water (50ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with brine (50ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→2:1) to obtain 1.53 g (79%) of the title compound as a light brown oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.60 (1H, q, J = 7.1), 3.72 (3H, s), 3.43 (1H, d, J = 9.5Hz) , 3.40(1H, d, J=9.5Hz), 3.36(1H, d, J=9.8Hz), 3.28(3H, s), 2.75(1H, dt, J=12.2, 10.5Hz), 2.72(1H, d, J=9.5Hz), 2.21 (1H, ddd, J=3.4, 9.3, 12.2Hz), 1.86 (1H, ddd, J=3.4, 10.5, 12.2Hz), 1.62 (1H, dt, J=12.2, 9.3 Hz), 1.58 (3H, d, J = 7.1 Hz).

MS (ESI) m/z: 318 (M+H) ⁺ .

[Reference Example 55]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl Base]-3-azabicyclo[3.2.0]heptane

[Formula 131]

1M sodium hydroxide solution (5.0ml) was added to (1S,5R)-5-methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-aza A solution of methyl bicyclo[3.2.0]heptane-1-carboxylate (1.53g, 4.82mmol) in tetrahydrofuran (10ml)-methanol (5.0ml). The mixture was stirred for 9 hours. The reaction solution was adjusted to pH 2 or lower with 6M hydrochloric acid, and the tetrahydrofuran and methanol components were removed by filtration under reduced pressure. The residue was poured into a mixture of ethyl acetate (30ml) and 1M hydrochloric acid (30ml), followed by extraction with ethyl acetate (150ml). The organic layer was washed with saturated sodium chloride solution (30 ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure to obtain crude formic acid as a pale yellow oil.

Under a nitrogen atmosphere, the crude formic acid was dissolved in a mixture of tert-butanol (30ml) and triethylamine (1.34ml, 9.64mmol) and diphenoxyphosphoryl azide (1.14ml, 5.30mmol) was added. The mixture was stirred at 40°C for 2 hours and then at 80°C for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to obtain 595 mg (33%, two steps) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.23 (5H, m), 2.25 (1H, q, J = 7.1H), 4.87 (1H, brs), 3.55 (1H, d, J = 9.2Hz ), 3.42(1H, brd, J=9.2Hz), 3.35(1H, d, J=9.6Hz), 3.33(3H, s), 2.71(1H, d, J=9.6Hz), 2.33(1H, m ), 2.12-2.00 (2H, m), 1.60 (3H, d, J = 7.1 Hz), 1.43 (9H, s).

[Reference Example 56]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methoxymethyl-3-[(1R)-1-phenylethyl]-3- Azabicyclo[3.2.0]heptane

[Formula 132]

Under nitrogen atmosphere, 65% Red-Al ^TM solution in toluene (1.43ml, 4.75mmol) was added dropwise to (1S,5S)-1-(tert-butoxycarbonylamino) within 2 minutes at 0°C -5-methoxymethyl-2-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (593mg, 1.58mmol) in toluene middle. The mixture was warmed to room temperature, stirred for 2 hours and cooled to 0 °C. A 20% potassium sodium tartrate tetrahydrate solution (10 ml) was carefully added while maintaining the internal temperature of the reaction solution at 10°C or lower. The reaction solution was poured into a mixture of ethyl acetate (10ml) and brine (10ml), followed by extraction with ethyl acetate (100ml). The organic layer was washed with brine (20ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to obtain 244 mg (43%) of the title compound as colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.17 (5H, m), 5.56 (1H, brs), 3.58 (1H, d, J=10.0Hz), 3.43 (1H, d, J=10.0Hz ), 3.37(3H, s), 3.28(1H, q, J=6.5Hz), 3.10(1H, br), 2.86(1H, d, J=8.7Hz), 2.34(1H, d, J=8.7Hz ), 2.23-2.01 (3H, brm), 1.84 (2H, brt, J = 8.1 Hz), 1.35 (9H, brs), 1.34 (3H, d, J = 6.5 Hz).

MS (ESI) m/z: 361 (M+H) ⁺ .

[Example 9]

7-[(1S,5S)-1-amino-5-methoxymethyl-3-azabicyclo[3.2.0]hept-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl-1-yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 133]

10% palladium-carbon catalyst (50% wet, 50 mg) was added to (1S,5S)-1-(tert-butoxycarbonylamino)-5-methoxymethyl-3-[(1R)-1- In a solution of phenylethyl]-3-azabicyclo[3.2.0]heptane (242mg, 0.67mmol) in ethanol (20ml), the mixture was stirred at 50°C for 7 hours under hydrogen atmosphere. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure to give the crude amine (164 mg) as a colorless viscous oil.

The crude amine (164mg) was dissolved in dimethyl sulfoxide (2.0ml), and triethylamine (0.178ml, 1.28mmol) and 6,7-difluoro-1-[(1R,2S)-2 were added sequentially -Fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid-BF ₂ chelate (254 mg, 0.704 mmol). The mixture was stirred with heating at 40°C for 23 hours. Then, a mixture of ethanol:water=5:1 (6.0ml) and triethylamine (1.0ml) was added to the reaction solution, and the mixture was heated under reflux for 2 hours. After ethanol and triethylamine components in the reaction solution were evaporated under reduced pressure, the residue was poured into a mixture of ethyl acetate (20ml) and 10% citric acid solution (10ml), followed by extraction with ethyl acetate (80ml). The organic layer was washed with brine (20ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The obtained residue was purified by reverse-phase preparative HPLC (0.1% formic acid solution-acetonitrile system) to obtain a light yellow amorphous substance. The obtained pale yellow amorphous was dissolved in concentrated hydrochloric acid (2.0 ml), and the solution was stirred at room temperature for 10 minutes. The reaction solution was diluted with 6M hydrochloric acid (15ml) and washed with chloroform (10ml). The aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution under ice cooling, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform (50ml×2, 30ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The residue was thoroughly dried in vacuo, then dissolved in chloroform. The solution was filtered through a membrane filter, and the filtrate was concentrated under reduced pressure. The resulting residue was crystallized from hexane, and the crystals were collected by filtration and dried to give 184 mg (61%) of the title compound as a pale yellow solid.

mp: 86-88°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, d, J = 1.5Hz), 7.69 (1H, d, J = 13.4Hz), 4.95 (1H, m), 4.02 (1H, m) , 3.70-3.58(7H, m), 3.39(3H, s), 3.23(1H, d, J=10.5Hz), 3.19(1H, d, J=10.3Hz), 2.09(1H, m), 1.99- 1.87(2H,m), 1.74(1H,m), 1.61(1H,m), 1.48(1H,m).

_Anal. Calcd. for _{C22H25F2N3O5.0.25H2O.0.25EtOH :} C, _58.06 ; _H , 5.85; F, 8.16; _N , 9.03. Found: C, 57.92; H, 5.86; F, 8.16; N, 9.09.

HRMS _{(FAB); m/z calcd for C22H26F2N3O5 ( M +} H) ⁺ : _450.18405 . Measured value: 450.18358.

IR(ATR) v: 2931, 2827, 1724, 1616, 1546, 1504, 1434, 1392, 1348, 1313, 1274, 1228, 1184, 1101, ^{1051 cm -1} .

[Reference Example 57]

(3R)-3-[1-(Hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine

[Formula 134]

Lithium borohydride (1.174 g, 53.90 mmol) was added to ethyl 1-[(3R)-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-3-yl]cyclopropanecarboxylate Esters [see Journal of Medicinal Chemistry, Volume 46, Issue 6, Page 1005 (2003)] (2.03g, 6.74mmol) in tetrahydrofuran (20ml) solution. The mixture was heated and stirred on a 70°C oil bath for 30 hours. After cooling to room temperature, the reaction solution was poured into ice-cooled 10% citric acid solution (80ml), followed by extraction with ethyl acetate (200ml). The organic layer was washed with water (80ml) and brine (80ml), dried over anhydrous sodium sulfate, then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2→1:1→2:1→1:0→chloroform:methanol=9:1) to obtain 1.30 g (74%) of the title The compound is a colorless transparent colloidal solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.26-7.35 (5H, m), 5.48 (1H, q, J=6.9Hz), 3.45 (2H, s), 3.04-3.12 (1H, m), 2.37 -2.50 (2H, m), 2.19 (1H, dd, J = 16.0, 8.9 Hz), 1.51 (2H, d, J = 7.1 Hz), 0.43 (4H, s).

MS (ESI) m/z: 260 (M+H) ⁺ .

[Reference Example 58]

(3R)-3-[1-(tert-butyldiphenylsilyloxymethyl)cycloprop-1-yl]-5-oxo-1-[(1S)-1- Phenylethyl]pyrrolidine

[Formula 135]

tert-Butyldiphenylsilyl chloride (2.83ml, 10.88mmol) was added to (3R)-3-[1-(hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[ (1S)-1-phenylethyl]pyrrolidine (2.35g, 9.06mmol) and imidazole (925mg, 13.59mmol) in N,N-dimethylformamide (30ml) solution, the mixture was stirred at room temperature 20 hours. The reaction solution was diluted with ethyl acetate (150ml), washed with water (50ml×2) and brine (50ml×2), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19→1:9→1:4→1:1) to obtain 3.88 g (86%) of the title compound as a colorless transparent gum solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.56-7.59 (4H, m), 7.26-7.46 (11H, m), 5.48 (1H, q, J=7.0Hz), 3.46 (1H, d, J= 10.7Hz), 3.39(1H, d, J=10.7Hz), 3.10(2H, td, J=18.4, 9.6Hz), 2.51(1H, m), 2.32(1H, dd, J=16.5, 8.9Hz) , 2.14 (1H, dd, J = 16.5, 10.4Hz), 1.46 (3H, d, J = 7.1Hz), 1.01 (9H, s), 0.33-0.39 (4H, m).

MS (ESI) m/z: 498 (M+H) ⁺ .

[Reference Example 59]

(3R)-3-[1-(tert-butyldiphenylsilyloxymethyl)cycloprop-1-yl]-5-oxo-1-[(1S)-1- Phenylethyl]pyrrolidin-4-ylcarboxylate ethyl ester

[Formula 136]

At 0°C, ethyl chloroformate (0.059ml, 0.617mmol) and lithium hexamethyldisilazide in tetrahydrofuran (1.0M, 0.57ml, 0.570mmol) were added dropwise to (3R) within 2 minutes. -3-[1-(tert-butyldiphenylsilyloxymethyl)cycloprop-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine ( 258mg, 0.518mmol) in tetrahydrofuran (2ml) solution. The mixture was stirred at 0°C for 30 minutes and at room temperature for 30 minutes, and then a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0M, 0.57ml, 0.570mmol) was added. The mixture was stirred at room temperature for 2.5 hours, and then ice-cooled. The reaction was quenched with 10% citric acid solution (20ml). The resulting mixture was extracted with ethyl acetate (50ml). The organic layer was washed with water (20ml) and brine (20ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to obtain 227 mg (77%) of the title compound as a colorless transparent gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.54-7.64 (4H, m), 7.26-7.45 (11H, m), 5.46 (1H, q, J=6.9Hz), 4.23 (1H, ddd, J= 14.3, 7.1, 1.8Hz), 3.29-3.52 (4H, m), 3.12 (1H, t, J = 9.0Hz), 2.65 (1H, dd, J = 18.6, 8.5Hz), 1.48 (2H, d, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.02 (9H, s), 0.33 (4H, m).

MS (ESI) m/z: 570 (M+H) ⁺ .

[Reference Example 60]

(3R)-3-[1-(Hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-yl ethyl formate

[Formula 137]

At 0°C, hydrogen fluoride-pyridine complex (10ml) was added dropwise to (3R)-3-[1-(tert-butyldiphenylsilyloxymethyl)cyclopropane-1- In a solution of ethyl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylate (2.81 g, 4.93 mmol) in pyridine (20 ml). The mixture was stirred at room temperature for 2.5 hours, then poured into ice water (150ml) and extracted with ethyl acetate (300ml). The resulting organic layer was washed with 10% citric acid solution (100ml), water (100ml) and brine (100ml), and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2→1:1→2:1) to obtain 1.378 g (84%) of the title compound as a pale yellow gum shaped solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.26-7.36 (5H, m), 5.46 (1H, q, J = 7.1 Hz), 4.25 (2H, q, J = 7.2 Hz), 3.49 (2H, dd , J=23.2, 10.5Hz), 3.36(1H, d, J=11.7Hz), 3.09(2H, dt, J=20.8, 8.9Hz), 2.67(1H, q, J=8.5Hz), 1.54(3H , d, J=7.1 Hz), 1.31 (3H, t, J=7.1 Hz), 0.35-0.50 (4H, m).

MS (ESI) m/z: 332 (M+H) ⁺ .

[Reference Example 61]

(3R)-3-[1-(iodomethyl)cycloprop-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-yl ethyl formate

[Formula 138]

At room temperature, imidazole (708 mg, 10.40 mmol), triphenylphosphine (2.727 g, 10.40 mmol) and iodine (2.111 g, 8.32 mmol) were sequentially added to the (3R)-3-[1-(hydroxymethyl) ring Propan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylate (1.378g, 4.16mmol) in dichloromethane (50ml) middle. The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure. Then, the residue was dissolved in ethyl acetate (200ml) and washed with water (50ml x 2) and brine (50ml). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to obtain 1.606 g (88%) of the title compound as a pale yellow gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.26-7.39 (5H, m), 5.47 (1H, q, J=7.2Hz), 4.28 (2H, q, J=7.2Hz), 3.19-3.23 (2H , m), 3.03-3.12 (3H, m), 2.94 (1H, m), 1.54 (3H, d, J=7.1Hz), 1.33 (3H, t, J=7.1Hz), 0.80-0.87 (2H, m), 0.63 (2H, m).

MS (ESI) m/z: 442 (M+H) ⁺ .

[Reference Example 62]

(1S,5S)-2-Oxo-3-[(1S)-1-phenylethyl]-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane Ethyl-1-ylformate

[Formula 139]

Under salt ice cooling, a toluene solution of potassium hexamethyldisilazide (0.5M, 8.94ml, 4.47mmol) was added dropwise to the (3R)-3-[1-(iodomethyl) ring within 5 minutes. Propan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylate ethyl ester (1.517g, 3.44mmol) in toluene (30ml). The mixture was stirred at the same temperature for 1 hour and 20 minutes, and then at room temperature for 5.5 hours. The reaction solution was ice-cooled, and the reactant was quenched with 10% citric acid solution (20 ml), followed by extraction with ethyl acetate (200 ml). The organic layer was washed with water (50ml x 2) and brine (50ml). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to obtain 717 mg (67%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.27-7.38 (5H, m), 5.61 (1H, q, J=7.1Hz), 4.14-4.28 (2H, m), 3.02-3.07 (3H, m) , 2.91(1H, dt, J=9.8, 3.8Hz), 2.29(1H, d, J=12.2Hz), 1.61(3H, d, J=7.1Hz), 1.28(3H, t, J=7.2Hz) , 0.62(2H, m), 0.44(2H, m).

MS (ESI) m/z: 314 (M+H) ⁺ .

[Reference Example 63]

(1R,5S)-3-[(1S)-1-phenylethyl]-6-spirocyclopropane-2-thio-3-azabicyclo[3.2.0]heptane Ethyl Alkyl-1-ylcarboxylate

[Formula 140]

Add Lawesson's reagent (1.146 g, 2.83 mmol) to (1S,5S)-2-oxo-3-[(1S)-1-phenylethyl]-6-spiro In a solution of ethyl propane-3-azabicyclo[3.2.0]heptan-1-ylcarboxylate (592mg, 1.89mmol) in toluene (20ml). The mixture was heated and stirred on a 90°C oil bath under a nitrogen atmosphere for 6.5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19→1:9→1:4) to obtain 0.57 g (92%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.30-7.36 (5H, m), 6.40 (1H, q, J=7.1Hz), 4.11-4.32 (2H, m), 3.33 (1H, dd, J= 12.0, 6.8Hz), 3.22 (2H, t, J = 11.7Hz), 3.09 (1H, d, J = 6.3Hz), 2.37 (1H, d, J = 12.2Hz), 1.68 (3H, d, J = 7.1 Hz), 1.28 (3H, t, J = 7.2 Hz), 0.58 (1H, m), 0.42 (2H, m).

MS (ESI) m/z: 330 (M+H) ⁺ .

[Reference Example 64]

(1S, 5S)-3-[(1S)-1-phenylethyl]-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane-1-ylmethyl ethyl acetate

[Formula 141]

Add Raney nickel (4ml) to (1R,5S)-3-[(1S)-1-phenylethyl]-6-spirocyclopropane-2-thio-3-azabicyclo[3.2.0 ]heptan-1-ylcarboxylate (0.57g, 1.73mmol) in ethanol (40ml). The mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. After filtering through celite, the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered through a short plug of silica gel. The filtrate was evaporated under reduced pressure to give 503 mg (97%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.22-7.44 (5H, m), 4.20 (2H, q, J = 7.0Hz), 3.30 (1H, m), 3.24 (1H, d, J = 8.8Hz ), 2.72 (1H, d, J = 5.1Hz), 2.59 (1H, d, J = 11.5Hz), 2.52 (1H, d, J = 9.8Hz), 2.45 (1H, d, J = 8.8Hz), 2.26 (1H, d, J = 11.5Hz), 1.95 (1H, dd, J = 9.3, 5.6Hz), 1.39 (3H, d, J = 6.3Hz), 1.29 (3H, t, J = 7.1Hz), 0.51 (1H, m), 0.31-0.40 (3H, m).

MS (ESI); m/z: 300 (M+H) ⁺ .

[Reference Example 65]

(1S,5S)-3-Benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane-1-ylcarboxylate ester

[Formula 142]

Benzyl chloroformate (0.72ml, 5.04mmol) was added to (1S,5S)-3-[(1S)-1-phenylethyl]-6-spirocyclopropane-3-azabicyclo[3.2.0 ]heptan-1-ylcarboxylate (503mg, 1.68mmol) in dichloromethane (10ml). The mixture was stirred at room temperature under nitrogen atmosphere for 16 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to obtain 505 mg (91%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.27-7.40 (5H, m), 5.18 (2H, m), 4.21 (2H, q, J=7.2Hz), 3.92 (1H, dd, J=36.6, 12.0Hz), 3.64(2H, dd, J=23.3, 11.6Hz), 3.27(1H, m), 3.02(1H, d, J=6.1Hz), 2.73(1H, m), 2.02(1H, t, J = 10.4 Hz), 1.29 (3H, t, J = 7.1 Hz), 0.47-0.58 (3H, m), 0.32 (1H, m).

MS (ESI); m/z: 330 (M+H) ⁺ .

[Reference Example 66]

(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-spirocyclopropane-3-azabicyclo [3.2.0] Heptane

[Formula 143]

Add 1N sodium hydroxide solution (4.60ml, 4.60mmol) to (1S,5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane at room temperature Ethyl-1-ylcarboxylate (500mg, 1.52mmol) in ethanol/tetrahydrofuran (4.6ml/2.3ml) solution. The mixture was stirred at the same temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was acidified with 1N hydrochloric acid, followed by extraction with ethyl acetate (100ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure to give crude (1S,5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane-1-ylcarboxylic acid (501 mg) as free Color transparent gel-like solid.

Diphenoxyphosphoryl azide (0.393ml, 1.82mmol) was added to the obtained crude (1S,5S)-3-benzyloxycarbonyl-6-spirocyclopropane-3-azabicyclo[ 3.2.0] Heptan-1-ylcarboxylic acid (501 mg) and triethylamine (0.381 ml, 2.73 mmol) in toluene (7.5 ml). The mixture was stirred at room temperature under a nitrogen atmosphere for 5 minutes, then on a 90°C oil bath for 40 minutes. Then, tert-butanol (15 ml) was added to the reaction solution, and the mixture was heated and stirred on an oil bath at 120°C for 6 hours. After evaporating the reaction solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to obtain 347 mg (two steps, 61%) of the title compound as Colorless transparent gel-like solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.28-7.39 (5H, m), 5.16 (2H, m), 4.90 (1H, m), 3.95 (1H, t, J=11.6Hz), 3.41-3.58 (3H, m), 2.80(1H, m), 2.34(1H, t, J=10.3Hz), 2.20(1H, d, J=12.0Hz), 1.45(9H, s), 0.46-0.56(3H, m), 0.28(1H, m).

MS (ESI) m/z: 317 (M-tBu+H) ⁺ .

[Example 10]

7-[(1S,5R)-1-amino-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane-3- Base] -1-[(1R, 2S)-2-fluorocyclopropyl]-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-methyl acid

[Formula 144]

10% palladium-carbon catalyst (about 50% wet, 103 mg) was added to (1S,5R)-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-spirocyclopropane-3-nitrogen In a solution of heterobicyclo[3.2.0]heptane (342mg, 0.918mmol) in methanol (30ml), the mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain crude (1S, 5R)-1-(tert-butoxycarbonylamino)-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane (230mg ), a colorless transparent gel-like solid.

The resulting crude (1S,5R)-1-(tert-butoxycarbonylamino)-6-spirocyclopropane-3-azabicyclo[3.2.0]heptane (230 mg ), 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid- A mixture of _BF2 chelate (331mg, 0.918mmol), triethylamine (0.384ml, 2.76mmol) and dimethylsulfoxide (3ml) was stirred for 17 hours. Then, ethanol (20ml), water (5ml) and triethylamine (2.5ml) were added to the reaction solution, and the resulting mixture was heated under reflux on an oil bath at 110°C for 3 hours. After evaporating the solvent under reduced pressure, 10% citric acid solution (50 ml) was added to the residue, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with water (50ml×2) and brine (50ml) and dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in concentrated hydrochloric acid (20ml). The resulting acidic solution was transferred into a separatory funnel, and then washed with chloroform (20ml×8). The aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution under ice cooling, then adjusted to pH 7.4 with hydrochloric acid, and extracted with a mixed solvent of chloroform:methanol=9:1 (200ml×2). The organic layers were combined and dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from ethanol and dried under reduced pressure to afford 125 mg (32%) of the title compound as a pale pink powder.

mp: 182-203°C (decomposition).

[α] _D ^23.5 = -14.4° (c = 0.104, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, d, J = 1.2Hz), 7.71 (1H, d, J = 13.9Hz), 4.98 (1H, dm, J = 47.4Hz), 4.03 -4.08(1H, m), 3.70-3.73(1H, m), 3.70(3H, s), 3.61(1H, d, J=10.7Hz), 3.37(1H, m), 3.23(1H, d, J = 10.0Hz), 2.42 (1H, d, J = 5.9Hz), 2.29 (1H, d, J = 12.2Hz), 2.16 (1H, d, J = 12.5Hz), 1.44-1.66 (2H, m), 0.48-0.57 (3H, m), 0.29-0.33 (1H, m).

_Anal. Calcd. for _{C22H23F2N3O4.0.75H2O.0.25HCl} : C, _58.19 ; H, 5.49; N, 9.25; _{F , 8.37} ; Cl, 1.95. Found: C, 57.93; H, 5.41; N, 9.15; F, 8.43; Cl, 2.44.

MS (FAB) m/z: 432 (M+H) ⁺ .

HRMS ₍ FAB) _{Calcd for C22H23F2N3O4} +H: _432.1735 . Found value: 432.1714.

IR(ATR) v: 2871, 2763, 2721, 2575, 2517, 1720, 1612, 1568, 1535, 1493, 1456, 1365, 1350, 1321, 1267, 1205, 1157 ^{cm -1} .

[Reference Example 67]

(1R ^* , 5R ^* )-3-Benzyl-3-azabicyclo[3.3.0]octane-1-ylcarboxylate

[Formula 145]

A catalytic amount of trifluoroacetic acid was added to methyl 1-cyclopentene-1-carboxylate (2.52 g, 20.0 mmol) and N-benzyl-N-(methoxymethyl)-N-trifluoroacetic acid at room temperature In a solution of methylsilylmethylamine (5.00 g, 21.1 mmol) in dichloromethane (40 ml), the mixture was heated and stirred at room temperature for 15.5 hours. The reaction solution was diluted with dichloromethane (100ml) and washed with saturated sodium bicarbonate solution (80ml). The washed aqueous layer was extracted with dichloromethane (50ml). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→90:10→80:20) to obtain 4.28 g (83%) of the title compound as a colorless transparent oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33-7.21 (5H, m), 3.67 (3H, s), 3.58 (1H, d, J=13.2Hz), 3.52 (1H, d, J=13.2Hz ), 2.92(1H, d, J=9.3Hz), 2.88(1H, m), 2.67(1H, t, J=8.2Hz), 2.44(1H, d, J=9.3Hz), 2.31(1H, dd , J=8.8, 4.4Hz), 2.06-1.60 (5H, m), 1.54-1.47 (1H, m).

MS (ESI); m/z: 260 (M+H) ⁺ .

[Reference Example 68]

(1R ^* , 5R ^* )-3-Benzyloxycarbonyl-3-azabicyclo[3.3.0]octane-1-ylcarboxylate

[Formula 146]

Benzyl chloroformate (3.53ml, 24.6mmol) was added to methyl (1R ^* ,5R ^* )-3-benzyl-3-azabicyclo[3.3.0]octane-1-ylcarboxylate at room temperature (4.27g, 16.46mmol) in dichloromethane (50ml) and the mixture was stirred on an oil bath at 40°C for 23 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→80:20→67:33) to obtain 2.24 g (45%) of the title compound as a colorless transparent oil things.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.12 (2H, s), 3.97 (1H, d, J=11.7Hz), 3.71-3.64 (4H, m), 3.45 -3.28(2H,m), 2.94-2.87(1H,m), 2.23-2.15(1H,m), 2.03-1.94(1H,m), 1.85-1.71(3H,m), 1.52(1H,m) .

MS (ESI) m/z: 304 (M+H) ⁺ .

[Reference Example 69]

(1R ^* , 5R ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane alkyl

[Formula 147]

Add 1N sodium hydroxide solution (22.0ml, 22.0mmol) to (1R ^* ,5R ^* )-3-benzyloxycarbonyl-3-azabicyclo[3.3.0]octan-1-yl at room temperature To a solution of methyl formate (2.21g, 7.29mmol) in methanol (22ml)-tetrahydrofuran (44ml), the mixture was stirred at room temperature for 2 hours. After the solvent was concentrated under reduced pressure, the residue was acidified with 3N hydrochloric acid, and extracted with ethyl acetate (200ml). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure to obtain crude formic acid. The resulting crude formic acid was used in the next reaction without further purification.

Diphenoxyphosphoryl azide (2.03ml, 9.42mmol) was added to a solution of crude formic acid and triethylamine (2.02ml, 14.5mmol) obtained above in toluene (40ml) under ice-cooling. The mixture was heated and stirred at room temperature for 30 minutes, then heated and stirred on a 90° C. oil bath for 3.5 hours. The reaction solution was diluted with ethyl acetate (200ml) and washed successively with saturated sodium bicarbonate solution (80ml), water (80ml) and brine (80ml). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure to obtain crude isocyanate. The resulting crude isocyanate was dissolved in 1,4-dioxane (20 ml), and 6N hydrochloric acid (20 ml) was added. Then, the mixture was heated and stirred on a 50°C oil bath for 0.5 hours. The reaction solution was diluted with water and ethanol, concentrated under reduced pressure, and then azeotropically distilled with ethanol (twice). The residue was dissolved in dichloromethane (40ml), and triethylamine (5.05ml, 36.3mmol) and di-tert-butyl dicarbonate (3.17g, 14.5mmol) were added successively at room temperature. The reaction solution was stirred at room temperature for 5 hours, then diluted with ethyl acetate (200ml) and washed with water (80ml) and brine (80ml). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→80:20→67:33) to obtain 1.32 g (3.66 mmol, 51%) of the title compound as a colorless transparent gummy solid .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.27 (5H, m), 5.12 (2H, s), 4.75 (1H, brs), 3.74-3.59 (3H, m), 3.31-3.23 (1H, m), 2.74-2.48 (1H, m), 2.04-1.88 (3H, m), 1.80-1.71 (2H, m), 1.43 (10H, m).

MS (ESI) m/z: 305 (M-tBu+H) ⁺ .

[Reference Example 70]

(+)-(1R ^* , 5S ^* )-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0] Octane and (-)-(1R ^* , 5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo [3.3.0] Octane

[Formula 148]

The racemate (1R ^* , 5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (1.32g, 3.66 mmol) is optically resolved by an optical column (CHIRALCEL OJ, 20mm diameter × 250mm, hexane: isopropanol=90:10, flow rate=20ml/min, 50mg per resolution), to obtain (+)-(1R ^* ,5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (586 mg, 1.626 mmol, RT=5.5 min, [α] _D ^25.1 =+19.3°(c=0.145, chloroform)) and (-)-(1R ^* , 5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-azabicyclo [3.3.0] Octane (590 mg, 1.637 mmol, retention time = 6.9 min, [α] _D ^25.1 = -20.0° (c = 0.155, chloroform).

[Example 11]

7-{(1R ^* , 5S ^* )-1-amino-3-azabicyclo[3.3.0]octane-3-yl}-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [7-position substituent derived from (+)-optical isomers]

[Formula 149]

Add 10% palladium-carbon catalyst (ca. 50% wet, 115 mg) to (+)-(1R ^* ,5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-nitrogen Heterobicyclo[3.3.0]octane (575mg, 1.595mmol) in methanol (20ml) was dissolved, and the resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to obtain crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (388 mg) as a colorless transparent gummy solid.

The crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (388 mg) obtained above, 6,7-difluoro-1-[(1R,2S)-2 -Fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (576mg, 1.595mmol) and triethylamine (0.667ml, 4.79 mmol) was dissolved in dimethyl sulfoxide (4 ml), and the resulting solution was heated and stirred on an oil bath at 35-40° C. for 16 hours. A mixed solution of ethanol:water=4:1 (50ml) and triethylamine (5ml) was added to the reaction solution, and the mixture was heated under reflux on an oil bath at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200ml) and washed with 10% citric acid solution (80ml), water (50ml x 2) and brine (50ml). The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in concentrated hydrochloric acid (10 ml) under ice-cooling. After stirring at room temperature for 20 minutes, the reaction solution was washed with chloroform (30ml×3). The aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution under ice cooling, and then adjusted to pH 7.4 with hydrochloric acid. Then, the solvent was evaporated under reduced pressure. The residue was suspended in methanol and filtered. Then, the filtrate was concentrated under reduced pressure (twice), suspended in a mixed solvent of chloroform:methanol=9:1, and then filtered. The mother liquor was concentrated under reduced pressure to remove sodium chloride. The resulting residue was purified by PTLC (preparative TLC; lower solvent chloroform:methanol:water=7:3:1) and further by recrystallization from ethanol-ammonia water to obtain 111 mg (17%) of the title compound as a light yellow powder .

mp: 169-172°C.

[α] _D ^25.1 = +103.5° (c = 0.228, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 7.68 (1H, d, J = 13.9Hz), 5.05-4.80 (1H, m), 4.04 (1H, m), 3.77 ( 1H, t, J=9.0Hz), 3.63(3H, s), 3.52(2H, s), 3.35(1H, dd, J=9.8, 4.9Hz), 2.30(1H, m), 2.04(1H, m ), 1.89-1.47 (7H, m).

_{Anal .} Calcd. for _{C21H23F2N3O4.0.25EtOH.0.75H2O} : C, _58.10 ; H, 5.90; _{F ,} 8.55; N, 9.45. Found: C, 57.87; H, 5.51; F, 8.60; N, 9.11.

MS (EI); m/z: 419 (M ⁺ ).

IR (ATR) v: 2952, 2873, 2831, 2177, 1712, 1614, 1577, 1535, 1498, 1460, 1389, 1360, 1323, 1271, 1205 cm ^-1 .

[Example 12]

7-[(1R ^* , 5S ^* )-1-amino-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro Cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid [7-position substituent derived from (-)- Optical isomers]

[Formula 150]

Add 10% palladium-carbon catalyst (about 50% wet, 114 mg) to (-)-(1R ^* ,5S ^* )-3-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-3-nitrogen Heterobicyclo[3.3.0]octane (569mg, 1.579mmol) was dissolved in methanol (30ml), and the resulting mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (373 mg) as a colorless transparent gummy solid.

Crude 1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane (373mg), 6,7-difluoro-1-[(1R,2S)-2 -Fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline- ₃ -carboxylic acid-BF chelate (570mg, 1.579mmol) and triethylamine (0.660ml, 4.74mmol) was dissolved in dimethylsulfoxide (4ml), and the resulting solution was heated and stirred on an oil bath at 35-40°C for 16 hours. A mixed solvent of ethanol:water=4:1 (50ml) and triethylamine (5ml) was added to the reaction solution, and the mixture was heated to reflux on an oil bath at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200ml) and washed with 10% citric acid solution (80ml), water (50ml x 2) and brine (50ml). The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in concentrated hydrochloric acid (10 ml) under ice-cooling. After stirring at room temperature for 20 minutes, the reaction solution was washed with chloroform (30ml×3). The aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution under ice cooling, and then adjusted to pH 7.4 with hydrochloric acid. Then, the solvent was evaporated under reduced pressure. The residue was suspended in methanol:aqueous ammonia=20:1 and filtered. Then, the filtrate was concentrated under reduced pressure (twice), suspended in a mixed solvent of chloroform:methanol=9:1 and filtered. The mother liquor was concentrated under reduced pressure to remove sodium chloride. The resulting residue was purified by PTLC (lower solvent chloroform:methanol:water=7:3:1) and crystallized from ethanol-diethyl ether to obtain 32 mg (5%) of the title compound as a tan powder.

mp: 171-174°C.

[α] _D ^25.1 = +52.1° (c = 0.073, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 7.65 (1H, d, J=13.9Hz), 5.02-4.82 (1H, m), 4.00 (1H, m), 3.86- 3.80 (1H, m), 3.62-3.55 (4H, m), 3.36-3.31 (1H, m), 3.15-3.10 (1H, m), 2.24 (1H, m), 2.05-1.30 (8H, m).

Anal _{. Calcd} . for _{C21H23F2N3O4.0.5EtOH} - _1.25H2O : C, _56.83 ; H, 6.18; F _, 8.17; N, 9.04. Found: C, 56.41; H, 5.68; F, 8.76; N, 8.64.

MS (EI); m/z: 419 (M ⁺ ).

IR(ATR) v: 2948, 2871, 2576, 2162, 1712, 1616, 1566, 1495, 1456, 1390, 1363, 1319, 1269 cm ^-1 .

[Reference Example 71]

(3S)-3-[3-(tert-butyldimethylsilyloxy)-1-propyl]-5-oxo-1-[(1R)-1-phenyl Ethyl]pyrrolidine-3-carboxylate tert-butyl ester

[Formula 151]

(3S)-3-(3-Hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (46g) and Imidazole (11.9g) was dissolved in dimethylformamide (600ml). After adding tert-butyldimethylsilyl chloride (23.2 g) under ice-cooling, the mixture was stirred at room temperature for 59.5 hours. The reaction solution was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→2:1) to obtain 29.7 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.22 (5H, m), 5.48 (1H, q, J = 7.11Hz), 3.58 (2H, t, J = 6.13Hz), 3.34 (1H, d , J=10.05Hz), 3.12(1H, d, J=10.05Hz), 2.94(1H, d, J=16.91Hz), 2.31(1H, d, J=17.16Hz), 1.86-1.74(1H, m ), 1.72-1.62(1H, m), 1.51(3H, d, J=7.11Hz), 1.49-1.24(2H, m), 1.33(9H, s), 0.88(9H, s), 0.03(6H, s).

[Reference Example 72]

(3S)-3-[3-(tert-butyldimethylsilyloxy)-1-propyl]-4-fluoro-5-oxo -1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 152]

(3S)-3-[3-(tert-butyldimethylsilyloxy)-1-propyl]-5-oxo-1-[(1R)-1-phenylethyl]pyrrole tert-Butyl alkane-3-carboxylate (30 g) was dissolved in tetrahydrofuran (280 ml), and the original atmosphere was replaced with argon. Then, lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran) (78.0 ml) was added dropwise at -15°C, and the mixture was stirred at -5°C for 30 minutes. After cooling to -15°C again, a solution of N-fluorobenzenesulfonimide (26.6 g) in tetrahydrofuran (220 ml) was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction solution was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2) to obtain 8.15 g of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.53-5.44 (1H, m), 5.18 (1H, d, J=51.72Hz), 3.64-3.52 (2H, m) , 3.32-3.19(2H, m), 1.92-1.65(2H, m), 1.55(3H, d, J=4.66Hz), 1.33(9H, s), 0.88(9H, s), 0.03(6H, s ).

MS (FAB) m/z: 480 (M+H) ⁺ .

IR (ATR) v: 3421, 2977, 2935, 2877, 1698, 1454, 1369, 1309, 1249, 1153, 1058, 1035, 1006, ^{842 cm -1} .

[Reference Example 73]

(3S)-4-fluoro-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 153]

(3S)-3-[3-(tert-butyldimethylsilyloxy)-1-propyl]-4-fluoro-5-oxo-1-[(1R)-1-phenyl Ethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (8.15 g) was dissolved in tetrahydrofuran (25.0 ml). Acetic acid (22.0 ml) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (25.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 21.5 hrs. The reaction solution was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→8:2→1:1) to obtain 5.77 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.22 (5H, m), 5.48 (1H, q, J = 7.03Hz), 5.20 (1H, d, J = 51.48Hz), 3.69-3.59 (2H , m), 3.31-3.21 (2H, m), 1.95-1.72 (2H, m), 1.68-1.43 (2H, m), 1.56 (3H, d, J=7.11 Hz), 1.33 (9H, s).

[Reference Example 74]

(3S)-3-(3-Benzenesulfonyloxy-1-propyl)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrole tert-butyl alkane-3-carboxylate

[Formula 154]

(3S)-4-fluoro-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl (12.20g) was dissolved in dichloromethane (400ml). Benzenesulfonyl chloride (9.06ml), triethylamine (10.7ml) and 4-dimethylaminopyridine (2.04g) were added under ice-cooling, and the mixture was stirred at room temperature for 12.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was stirred for 30 minutes, followed by extraction with dichloromethane. The organic layer was washed successively with 10% citric acid solution and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=8:2→1:1) to obtain 11.7 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.94-7.87 (2H, m), 7.71-7.63 (1H, m), 7.60-7.53 (2H, m), 7.37-7.23 (5H, m), 5.46 ( 1H, q, J=7.11Hz), 5.15(1H, d, J=51.48Hz), 4.10-3.98(2H, m), 3.26-3.15(2H, m), 1.88-1.50(4H, m), 1.55 (3H,s), 1.30(9H,s).

[Reference Example 75]

(1S,5R)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-yl tert-butyl formate

[Formula 155]

(3S)-3-(3-Benzenesulfonyloxy-1-propyl)-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- Tert-butyl formate (10.9 g) was dissolved in tetrahydrofuran (350 ml), and the original atmosphere was replaced with argon. Then, potassium hexamethyldisilazide (0.5 M in toluene) (86.5 ml) was added dropwise at -15°C, and the mixture was stirred at 0°C for 1.5 hours. After cooling to -10°C, saturated aqueous ammonium chloride solution (100 ml) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→7:1) to obtain 4.36 g of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.25 (5H, m), 5.58-5.49 (1H, m), 3.63 (1H, d, J = 10.3Hz), 2.91 (1H, dd, J = 10.3, 3.2Hz), 2.67-2.56(1H, m), 2.50-2.38(1H, m), 2.26-2.09(1H, m), 2.06-1.94(1H, m), 1.74-1.66(1H, m) , 1.54 (3H, d, J = 7.1 Hz), 1.50-1.40 (1H, m), 1.34 (9H, s).

[Reference Example 76]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-nitrogen Heterobicyclo[3.3.0]octane

[Formula 156]

(1S, 5R)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-ylcarboxylate The ester (4.36g, 12.5mmol) was dissolved in dichloromethane (70ml). Trifluoroacetic acid (70 ml) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After evaporating the solvent under reduced pressure, the residue was azeotropically distilled with toluene to obtain formic acid (3.70 g).

The resulting formic acid was dissolved in toluene. Triethylamine (3.51ml, 25.2mmol) and diphenoxyphosphoryl azide (2.98ml, 13.8mmol) were added, and the mixture was heated to reflux for 5 hours. The solvent was evaporated under reduced pressure. Then, 1,4-dioxane (110 ml) and 6N hydrochloric acid (110 ml) were added to the residue, and the resulting mixture was stirred at 60°C for 2.5 hours. After extraction with water and ethyl acetate, the aqueous layer was basified with saturated sodium hydroxide solution and extracted twice with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (11.05 g) was added to the residue, and the resulting mixture was stirred at 75°C for 6 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to obtain 3.69 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.23 (5H, m), 5.50 (1H, q, J=7.1Hz), 5.22 (1H, brs), 3.34 (2H, s), 2.49-2.37 (1H, m), 2.32-2.03 (3H, m), 2.02-1.90 (1H, m), 1.51 (3H, d, J=7.1Hz), 1.55-1.48 (1H, m), 1.35 (9H, s ).

[Reference Example 77]

(1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo [3.3.0] Octane

[Formula 157]

(1R, 5R)-1-(tert-butoxycarbonylamino)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3. 0] Octane (3.69g, 10.2mmol) was dissolved in tetrahydrofuran (200ml). A 1.20M solution of borane-tetrahydrofuran complex in tetrahydrofuran (42.4 ml, 50.9 mmol) was added dropwise under ice-cooling, and the mixture was stirred for 2 hours while gradually warming to room temperature. The solvent was evaporated under reduced pressure. Under ice-cooling, 90% aqueous ethanol (100ml) and triethylamine (100ml) were added to the residue, and the mixture was heated to reflux for 2 hours. After evaporating the solvent under reduced pressure, the residue was extracted with saturated aqueous sodium bicarbonate and dichloromethane. Then, the target substance was extracted from the water with dichloromethane. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=95:5→90:10) to obtain 3.33 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.18 (5H, m), 5.38 (1H, brs), 3.22 (1H, q, J=6.37Hz), 2.92-2.57 (4H, m), 2.12 -1.86 (4H, m), 1.80-1.67 (1H, m), 1.63-1.52 (3H, m), 1.42 (9H, s), 1.32 (3H, d, J=6.37Hz).

[Reference Example 78]

(1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane

[Formula 158]

(1R, 5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane ( 700mg, 2.0mmol) was dissolved in ethanol (30ml). 10% palladium-carbon (50% wet) (1.01 g) was added, and the resulting mixture was stirred at 50° C. for 15 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was treated by silica gel column chromatography (dichloromethane:methanol=98:2→95:5) to obtain 446 mg of the title compound as a pale yellow solid.

[α] _D ²³ -15° (c=0.100, MeOH).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.29 (1H, brs), 3.47-3.18 (2H, m), 2.93-2.79 (2H, m), 2.15-1.71 (6H, m), 1.45 (9H, s).

[Example 13]

10-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-9-fluoro-2,3-dihydro -3-(S)-Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

[Formula 159]

Triethylamine (0.222ml, 1.59mmol) and 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3 -de][1,4]Benzoxazine-6-carboxylic acid-BF ₂ chelate (209 mg, 0.64 mmol) was added to (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro - In a solution of 3-azabicyclo[3.3.0]octane (129mg, 0.53mmol) in dimethyl sulfoxide (4.0ml). The resulting mixture was stirred at 40°C for 18.5 hours. Triethylamine (0.111 ml, 0.80 mmol) was further added to the reaction solution, and the resulting mixture was stirred at 40°C for 6.5 hours. Ethanol (6.0ml), water (2.0ml) and triethylamine (2.0ml) were added to the reaction solution, and the mixture was heated under reflux for 1.5 hours. After evaporating the solvent under reduced pressure, the residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1→98:2) to obtain an oily substance (261 mg). The obtained oil (261 mg) was dissolved in concentrated hydrochloric acid (2.4 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 3 hours. The reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. 10% methanol-chloroform was added to the residue. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from ethanol-ammonia to give 145 mg of the title compound as a pale yellow solid.

mp: 285-293°C (decomposition).

[α] _D ²⁴ -40.3° (c=0.100, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, d, J = 1.23Hz), 7.70 (1H, d, J = 13.7Hz), 5.07-4.85 (1H, m), 4.10-4.02 ( 1H, m), 3.93-3.78 (2H, m), 3.70-3.53 (2H, m), 3.66 (3H, s), 2.21-2.04 (2H, m), 2.01-1.83 (2H, m), 1.83- 1.46 (4H, m).

MS (FAB) m/z: 406 (M+H) ⁺ .

Anal _. Calcd. _{for C20H21F2N3O4} : C, 59.25; H, 5.22; F, 9.37 _{; N} , 10.37. Found: C, 59.22; H, 5.16; F, 9.16; N, 10.27.

IR(ATR)v: 3365, 2931, 2861, 1706, 1619, 1521, 1461, 1442, 1415, 1396, 1278, 1230, 1141, 1130, 1093, 1047, 983, 964, 900, 879 ^{, 863, 800cm - 1} .

[Example 14]

7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-8-cyano-6-fluoro -1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 160]

Triethylamine (0.272ml, 1.95mmol) and 8-cyano-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-6,7-difluoro-1,4 -Ethyl dihydro-4-oxoquinoline-3-carboxylate (240 mg, 0.71 mmol) was added to (1R, 5R)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo [3.3.0] In a solution of octane (148 mg, 0.61 mmol) in acetonitrile (10 ml), the mixture was stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure, the residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1→3:7) to obtain ethyl ester substituted with a substituent at the 7-position (231 mg). The resulting ethyl ester (231 mg) was dissolved in tetrahydrofuran (3.0 ml) and ethanol (6.0 ml). 1N Sodium hydroxide solution (0.82 ml) was added, and the mixture was stirred at room temperature for 3.5 hrs. After evaporating the solvent under reduced pressure, the residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. Concentrated hydrochloric acid (2.0 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. Then, the reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. 10% methanol-chloroform was added to the residue, and the insoluble matter was removed by filtration. Then, the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from ethanol-ammonia to give 128 mg of the title compound as a pale yellow solid.

mp: 268-280°C (decomposition).

[α] _D ²⁴ -1.8° (c=0.100, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.40 (1H, d, J = 1.96Hz), 7.96 (1H, d, J = 14.46Hz), 5.29-5.05 (1H, m), 4.28-4.00 ( 3H, m), 3.94-3.80 (2H, m), 2.23-2.10 (2H, m), 2.04-1.56 (6H, m).

MS (FAB); m/z: 433 (M+H) ⁺ .

_{Anal .} Calcd. _{for C21H19F3N4O3} : C, 58.33; H, 4.43; _F , 13.18; N, 12.96. Found: C, 58.24; H, 4.36; F, 13.10; N, 12.84.

IR(ATR)v: 3359, 3039, 2213, 1720, 1623, 1552, 1477, 1452, 1405, 1375, 1311, 1259, 1226, 1172, 1137, 1112, 1074, 1054, 991, 931, 887 ^{, 806cm - 1} .

[Example 15]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocycloprop-1-yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 161]

Triethylamine (3.30ml, 23.7mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methoxy-4- Oxoquinoline-3-carboxylic acid-BF ₂ chelate (2.93g, 8.12mmol) was added to (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[ 3.3.0] In a solution of octane (1.32g, 5.40mmol) in dimethylsulfoxide (30ml). The resulting mixture was stirred at 40°C for 19 hours. Then triethylamine (1.70ml, 12.3mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methoxy-4 -Oxoquinoline-3-carboxylic acid-BF ₂ chelate (1.00 g, 2.77 mmol) was added to the reaction solution, and the resulting mixture was stirred at 40° C. for 16 hours. Ethanol (45ml), water (15ml) and triethylamine (15ml) were added to the reaction solution, and the mixture was heated under reflux for 1.5 hours. After evaporation of the solvent under reduced pressure, the resulting residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed 3 times with water and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The obtained oil (3.30 g) was dissolved in concentrated hydrochloric acid (20 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Chloroform was added to the residue. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford 769 mg of the title compound as a pale yellow solid.

mp: 191-195°C (decomposition).

[α] _D ²⁴ +97° (c=0.100, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, d, J = 1.23Hz), 7.70 (1H, d, J = 13.73Hz), 5.07-4.85 (1H, m), 4.10-4.02 ( 1H, m), 3.93-3.78 (2H, m), 3.70-3.53 (2H, m), 3.66 (3H, s), 2.21-2.04 (2H, m), 2.01-1.83 (2H, m), 1.83- 1.46 (4H, m).

MS (FAB); m/z: 438 (M+H) ⁺ .

Anal _{. Calcd .} for _{C21H22F3N3O4.0.75H2O :} C, 55.94; H, 5.25; F, _12.64 ; N, 9.32. Found: C, 56.03; H, 5.51; F, 12.79; N, 9.66.

IR (ATR) v: 2958, 2871, 1724, 1621, 1513, 1452, 1319, 1056, 929, 804 cm ^-1 .

[Example 16]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-1-[(1R,2S)-2-fluorocyclo Propane]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 162]

Triethylamine (0.447ml, 3.21mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methyl-4- Oxoquinoline-3-carboxylic acid (450 mg, 1.61 mmol) was added to (1R, 5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane ( 260mg, 1.07mmol) in dimethylsulfoxide (6.0ml), and the resulting mixture was stirred at 70-80°C for 18.5 hours. Triethylamine (0.224ml, 1.61mmol) was added to the reaction solution again, and the resulting mixture was stirred at 70-80°C for 6 days. Triethylamine (0.447ml, 3.21mmol) was added again, and the resulting mixture was stirred at 70-80°C for 10 days. The reaction solution was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=98:2) to obtain an oily substance (369 mg). The obtained oil (369 mg) was dissolved in concentrated hydrochloric acid (3.0 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 1 hr. The reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained residue was purified by PTLC (using the developing layer of chloroform:methanol:water=7:3:1 in the lower layer). The resulting fractions were then concentrated under reduced pressure to give a residue which was solidified with isopropanol to give 21 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.50 (1H, d, J = 2.94Hz), 8.06 (1H, d, J = 8.58Hz), 7.13 (1H, d, J = 8.82Hz), 5.13 -4.90(1H, m), 4.18-4.10(1H, m), 3.89-3.77(1H, m), 3.45-3.25(3H, m), 2.58(3H, s), 2.20-1.98(3H, m) , 1.93-1.82 (1H, m), 1.81-1.57 (3H, m), 1.37-1.22 (1H, m).

MS (FAB); m/z: 404 (M+H) ⁺ .

Anal _. Calcd. _{for C21H23F2N3O3} · _0.5H2O · 0.25 IPA _: C, _61.11 ; H, 6.13; N, 9.83. Found: C, 61.11; H, 5.72; N, 9.74.

IR (ATR) v: 2956, 2873, 2823, 1708, 1610, 1508, 1432, 1355, 1313, 1255, 1133, 929 ^{cm -1} .

[Example 17]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropane]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 163]

Triethylamine (0.215ml, 1.54mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methyl-4-oxo Quinoline- ₃ -carboxylic acid-BF chelate (530 mg, 1.53 mmol) was added to (1R, 5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3. 0] Octane (250mg, 1.02mmol) in DMSO (5.0ml). The mixture was stirred at room temperature for 7 days. Then triethylamine (0.215ml, 1.54mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methyl-4- Oxoquinoline-3-carboxylic acid-BF ₂ chelate (530 mg, 1.53 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 7 days. Then triethylamine (0.215ml, 1.54mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methyl-4- Oxoquinoline-3-carboxylic acid-BF ₂ chelate (530 mg, 1.53 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 10 days. Ethanol (6.0 ml), water (2.0 ml) and triethylamine (2.0 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 1 hr. After evaporating the solvent under reduced pressure, the residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane:methanol=98:2), and the obtained fraction was concentrated under reduced pressure. Then, the residue was dissolved in concentrated hydrochloric acid (3.5 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 1 hr. The reaction solution was washed 5 times with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained residue was purified by PTLC (using the developing layer of chloroform:methanol:water=7:3:1 in the lower layer). The resulting residue was solidified with isopropanol to give 7.1 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.50 (1H, s), 7.77 (1H, d, J=13.73Hz), 5.80-4.80 (1H, m), 4.22-4.10 (1H, m), 3.99-3.85(1H, m), 3.68-3.47(2H, m), 3.43-3.34(1H, m), 2.68(3H, s), 2.21-1.98(3H, m), 1.97-1.56(4H, m ), 1.42-1.23 (1H, m).

MS (FAB); m/z: 422 (M+H) ⁺ .

Anal _. Calcd. for _{C21H22F3N3O3-0.5H2O} - _0.25 IPA _: C, _58.65 ; H, _5.66 ; F, 12.80; N, 9.43. Found: C, 58.63; H, 5.35; F, 12.35; N, 9.22.

IR(ATR)v: 2971, 2856, 1722, 1614, 1450, 1432, 1322, 1132, 1097, 987, 954, 929, 887, 856, 804 ^{cm -1} .

[Example 18]

7-[(1R,5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-1-(6-amino-3,5-di Fluoropyridin-2-yl)-1,4-dihydro-8-chloro-6-fluoro-4-oxoquinoline-3-carboxylic acid

[Formula 164]

N-methylpyrrolidine (0.246ml, 2.37mmol) and 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid (306mg, 0.79mmol) was added to (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3. 0] octane (193 mg, 0.79 mmol) in acetonitrile (10.0 ml) and the mixture was heated to reflux for 10 hours. Again 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (92mg, 0.24mmol) was added to the reaction solution, and the resulting mixture was heated to reflux for 4.5 hours. After evaporating the solvent under reduced pressure, the residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The obtained oil (409 mg) was dissolved in concentrated hydrochloric acid (3.0 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 2.5 hours. The reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Chloroform was added to the residue, and insoluble materials were removed by filtration. Then, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by recrystallization from ethanol to obtain 47 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 8.79 (1H, s), 8.07-7.90 (2H, m), 6.75 (2H, d, J=8.58Hz), 3.87-3.65 (2H, m) , 3.50-3.25 (2H, m), 2.09-1.96 (2H, m), 1.88-1.53 (4H, m).

MS (FAB); m/z: 512 (M+H) ⁺ .

_{Anal. Calcd .} for _{C22H18ClF4N5O3-0.5H2O :} C, _50.73 ; H, 3.68; Cl, 6.81; F, 14.59; N, 13.45. Found: C, 50.75; H, 3.58; Cl, 6.52; F, 14.31; N, 13.09.

IR(ATR)v: 3480, 3345, 3070, 2954, 2865, 1724, 1606, 1484, 1438, 1386, 1307, 1112 ^{cm -1} .

[Reference Example 79]

3-(Oxiran-2-ylmethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 165]

Dissolve tert-butyl (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (4.9 g, 14.9 mmol) in dichloro In methane, mCPBA (10.3 g, 59.5 mmol) was added. The mixture was stirred at room temperature for 15 hours, then heated to reflux for 3 hours. After evaporation of the solvent under reduced pressure, the residue was mixed with a mixture of ethyl acetate and saturated sodium thiosulfate solution. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4:1→1:1) to obtain 4.33 g (84%) of the title compound as a colorless oily mixture of diastereomers. The diastereomers were used in the next step without separation and purification.

[Reference Example 80]

(1S,5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1- tert-butyl carbamate

[Formula 166]

3-(oxirane-2-ylmethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.2g, 12.16mmol ) was dissolved in tetrahydrofuran (50ml). Under an argon atmosphere, a 1M solution of lithium hexamethyldisilazide in tetrahydrofuran (18 ml, 1.5 equivalents) was added at -78°C, and the resulting mixture was gradually heated. When the reaction temperature reached about room temperature, the reaction was quenched with ammonium chloride solution, then extracted with ethyl acetate. The extract was dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1→1:1→1:2) to obtain 1.07 g (26%) of the title compound with a single isomer as Colorless oil. Collected 1.0 g (24%) of starting material. 1.20 g (29%) of a 4-membered ring closure compound were obtained as a by-product as a mixture of diastereomers.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.48 (1H, q, J=7.08Hz), 4.36-4.30 (1H, m), 3.35-3.30 (2H, m) , 3.12 (1H, d, J = 10.25Hz), 2.44-2.38 (2H, m), 2.29 (1H, dt, J = 13.83, 4.94Hz), 2.16-2.09 (1H, m), 1.84 (1H, dd , J=13.79, 5.25Hz), 1.50 (3H, d, J=7.08Hz), 1.37 (9H, s).

[Reference Example 81]

(1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-yl tert-butyl formate

[Formula 167]

(1S, 5S)-7-Hydroxy-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-ylcarboxylate The ester (1.0 g, 2.89 mmol) was dissolved in dichloromethane (15 mL). Bis(2-methoxyethyl)aminosulfur trifluoride (BAST) (0.59 ml) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hr. The reaction solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1→4:1→1:1) to obtain 711 mg (71%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.50 (1H, q, J=7.1Hz), 5.24 (1H, dt, J=52.2, 3.2Hz), 3.48 (1H , d, J=10.0Hz), 3.26-3.21(2H, m), 2.61-2.37(2H, m), 2.21-2.04(2H, m), 1.48(3H, d, J=7.1Hz), 1.36( 9H, s).

[Reference Example 82]

(1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-yl formic acid

[Formula 168]

(1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-ylcarboxylate The ester (705mg, 2.03mmol) was dissolved in dichloromethane (4ml). Trifluoroacetic acid (4 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the resulting mixture was again concentrated under reduced pressure to obtain 595 mg (quantitative) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.14 (5H, m), 5.48 (1H, q, J = 7.08Hz), 5.32-5.19 (1H, m), 3.61 (1H, d, J = 10.74Hz), 3.43 (1H, d, J = 10.01Hz), 3.33 (1H, d, J = 10.50Hz), 2.64-2.05 (4H, m), 1.49 (3H, d, J = 7.08Hz).

[Reference Example 83]

(1R,5S)-1-amino-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane alkyl

[Formula 169]

Toluene (10 ml) and triethylamine (565 μl, 4.05 mmol) were added to (1R,5R)-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-nitrogen Heterobicyclo[3.3.0]octan-1-ylcarboxylic acid (590mg, 2.03mmol). Then, diphenoxyphosphoryl azide (567 µl) was added, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was heated under reflux for 1 hour and mixed with a mixture of ethyl acetate-saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was dissolved in dioxane (10ml). 6N Hydrochloric acid (10 ml) was added, and the resulting mixture was heated and stirred at 70°C for 2 hours. After washing with ether, the aqueous layer was basified with 10M sodium hydroxide solution, and extracted 5 times with toluene. The extract was dried over magnesium sulfate and filtered, then the solvent was evaporated under reduced pressure to give 476 mg (90%) of the title compound as a colorless oil. The product was used in the next step without purification.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.16 (5H, m), 5.53 (1H, q, J = 7.00Hz), 5.20 (1H, dt, J = 52.70, 4.40Hz), 3.49 (1H , d, J = 10.30Hz), 2.86 (1H, d, J = 10.30Hz), 2.66 (1H, d, J = 10.00Hz), 2.52-2.19 (3H, m), 1.93 (1H, ddd, J = 39.50, 15.00, 4.10 Hz), 1.52 (2H, brs), 1.47 (3H, d, J = 7.10 Hz).

[Reference Example 84]

(1R, 5S)-1-(tert-butoxycarbonylamino)-7-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo [3.3.0] Octane

[Formula 170]

(1R,5S)-1-amino-7-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (537mg, 2.05mmol) was dissolved in toluene (20ml). Under argon atmosphere, Red-Al ^™ (65% in toluene) (2.53ml, 8.12mmol) was added and the resulting mixture was stirred at 80°C for 1 hour. A 5M sodium hydroxide solution was added to the reaction solution, followed by extraction with toluene. The extract was dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in toluene (20ml). Di-tert-butyl dicarbonate (475 mg, 2.18 mmol) was added, and the resulting mixture was stirred at 50°C for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→8:2→7:3) to obtain 450 mg (71%) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.20 (5H, m), 5.20 (1H, d, J = 54.00Hz), 4.90 (1H, brs), 3.22 (1H, q, J = 6.50Hz ), 2.92(1H, d, J=7.60Hz), 2.58(1H, d, J=9.80Hz), 2.48-2.20(4H, m), 1.79(1H, t, J=16.80Hz), 1.43(9H , s), 1.33 (3H, d, J = 6.60 Hz).

[Reference Example 85]

(1R,5S)-1-(tert-butoxycarbonylamino)-7-fluoro-3-bicyclo[3.3.0]octane

[Formula 171]

(1R, 5S)-1-(tert-butoxycarbonylamino)-7-fluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane ( 450mg, 1.29mmol) was dissolved in methanol (15ml). A catalytic amount of 10% palladium-carbon catalyst (50% wet) was added and the resulting mixture was stirred at 40° C. for 12 hours under an atmosphere of hydrogen. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 316 mg (quantitative) of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.24 (1H, d, J = 53.71Hz), 5.07 (1H, s), 3.48-3.42 (1H, m), 3.23 (2H, dd, J = 14.77, 12.33Hz), 2.93-2.87 (1H, m), 2.76 (1H, brs), 2.44-2.16 (3H, m), 1.95-1.86 (1H, m), 1.44 (9H, s).

[Example 19]

7-{(1R,5S)-1-amino-7-fluoro-3-azabicyclo[3.3.0]octane-3-yl}-6- -1-[(R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 172]

(1R,5S)-1-(tert-butoxycarbonylamino)-7-fluoro-3-azabicyclo[3.3.0]octane (296mg, 1.21mmol) and 6,7-difluoro-1- [(1R,2S)-2-Fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (437mg, 1.21mmol) Dissolve in dimethylsulfoxide (6ml). Triethylamine (203 μl, 1.45 mmol) was added, and the resulting mixture was stirred at 40° C. for 1 day. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to give a yellow powder, which was dissolved in ethanol (35ml)-water (9ml). Triethylamine (202 µl) was added, and the mixture was heated to reflux for 4 hours. After evaporation of the solvent under reduced pressure, the residue was mixed with a mixture of ethyl acetate and 10% citric acid solution. The organic layer was dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. Then, concentrated hydrochloric acid (9 ml) was added to the residue, and the mixture was stirred at room temperature for 2 hr. The reaction solution was diluted with concentrated hydrochloric acid, then transferred to a separatory funnel, and washed 3 times with chloroform. Then, the hydrochloric acid layer was adjusted to pH 12 with 12M sodium hydroxide solution under ice cooling. The layer was adjusted to pH 7.4 with 1M hydrochloric acid and 0.01M hydrochloric acid, and extracted with chloroform-methanol (9:1). Then, the aqueous layer was adjusted to pH 7.4 again, and an extraction operation was performed. After repeating this operation 5 times, the organic layer was dried over magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. Ethanol was added to the residue, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to afford 220 mg (42%) of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 7.66 (1H, d, J=13.70Hz), 5.45-5.31 (1H, brm), 5.04-4.86 (1H, brm), 4.06-4.01(1H, m), 3.87(1H, t, J=8.90Hz), 3.73-3.51(6H, m), 2.52-2.25(3H, m), 2.15-1.89(2H, m), 1.64- 1.47 (2H, m).

_Anal. Calcd. for _C21H22F3N3O4 · _1.0H2O ·0.4EtOH: C, 55.26; H, _5.62 ; _F , 12.03; _N , 8.87. Found: C, 55.05; H, 5.35; F, 12.32; N, 8.76.

MS (ESI) m/z: 438 (M+H) ⁺ .

[Reference Example 86]

(3S)-3-(2-Methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-methan tert-butyl acid

[Formula 173]

Carbon tetrachloride (550ml), acetonitrile (550ml) and water (550ml) were dissolved in (3S)-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1 -Phenylethyl]pyrrolidine-3-formic acid tert-butyl ester (38.2g, 0.110mol), add ruthenium(III) chloride hydrate (456mg, 2.20mmol) and high iodide (sodium periodide) successively ( 94.1 g, 0.440 mol). The resulting mixture was stirred in a 15°C water bath with a constant temperature circulator for 2.5 hours while maintaining the internal temperature at 20-25°C. The reaction solution was cooled in an ice bath, and 1N hydrochloric acid solution (2.2 L) was added when the internal temperature was 10°C or lower, followed by extraction with 2 L of chloroform. The aqueous layer was extracted with chloroform (1 L x 3). Then, the organic layers were combined, washed with brine (2 L×2), and dried over anhydrous sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting crude product was dissolved in N,N-dimethylformamide (370ml). At room temperature, sodium bicarbonate (37.9 g, 0.451 mol) and methyl iodide (70.7 g, 0.498 mol) were added with stirring, and the mixture was stirred for 3 days. The reaction solution was poured into ice water (1.8 L), followed by extraction with ethyl acetate (1.8 L, 0.5 L). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1), and the fraction containing the target substance was concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate, washed with 10% sodium thiosulfate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting solid was dried to obtain 35.0 g of the title compound as a pale tan solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.25 (5H, m), 5.48 (1H, q, J = 7.1Hz), 3.68 (3H, s), 3.33 (1H, d, J = 10.3Hz ), 3.13(1H, d, J=10.3Hz), 2.93(1H, d, J=16.8Hz), 2.34-2.20(3H, m), 2.13-1.94(2H, m), 1.51(3H, d, J = 7.1 Hz), 1.32 (9H, s).

[Reference Example 87]

{(1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1-yl} tert-butyl formate

[Formula 174]

(3S)-3-(2-Methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester ( 35.0 g, 93.2 mmol) was dissolved in tetrahydrofuran (1 L). Under nitrogen atmosphere, 2M lithium diisopropylamide/heptane/tetrahydrofuran/ethylbenzene solution (100ml, 200mmol) was added dropwise over 30 minutes at an internal temperature of -69°C. After stirring at the same temperature for 1 hour, the reaction solution was poured into 1N hydrochloric acid solution (2L) in an ice bath, followed by extraction with ethyl acetate (2L, 1L). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to obtain 22.2 g of the title compound as light red crystals. The filtrate was further concentrated to obtain 2.88 g of the title compound as pale red crystals. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 2.09 g of the title compound as colorless crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.50 (1H, q, J = 7.1Hz), 3.38 (1H, d, J = 10.5Hz), 3.23 (1H, d , J=10.5Hz), 2.55-2.35 (3H, m), 2.05-1.94 (1H, m), 1.53 (3H, d, J=7.1Hz), 1.38 (9H, s).

[Reference Example 88]

{(1S,5R,6R)-6-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane -1-yl}formic acid tert-butyl ester;

{(1S,5R,6S)-6-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane -1-yl}formic acid tert-butyl ester

[Formula 175]

{(1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1-yl} tert-Butyl formate (1.30 g, 3.88 mmol) was dissolved in tetrahydrofuran (40 mL). At 0°C, sodium borohydride (185 mg, 4.92 mmol) was added, and the mixture was stirred for 1 hour. A saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (20ml). Under nitrogen atmosphere, [bis(2-methoxymethyl)amino]sulfur trifluoride (1.73 g, 7.82 mmol) was added and the mixture was stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (30% ethyl acetate/hexane) to obtain 797 mg of the title (6R)-fluoro isomer (colorless oil) and 170 mg of the title ( 6S)-fluoroisomer (colorless oil).

(6R)-Fluoro isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.46 (1H, q, J = 7.08Hz), 5.28 (1H, d, J = 51.76Hz), 3.48 (1H, d , J=22.71Hz), 3.41(1H, d, J=10.50Hz), 3.08(1H, d, J=10.50Hz), 2.57-2.49(1H, m), 2.21-2.12(1H, m), 1.83 -1.58 (2H, m), 1.50 (3H, d, J=7.08Hz), 1.35 (9H, s).

MS (EI); m/z: 348 (M+H) ⁺ .

(6S)-Fluoroisomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.26 (5H, m), 5.49-5.40 (2H, m), 3.51 (1H, d, J = 10.24Hz), 3.41 (1H, d, J = 29.76Hz), 3.21(1H, d, J=10.00Hz), 2.46-2.44(1H, m), 2.23-2.20(1H, m), 2.03-1.93(1H, m), 1.88-1.82(1H, m ), 1.52 (3H, d, J=6.83Hz), 1.32 (9H, s).

MS (EI); m/z: 348 (M+H) ⁺ .

[Reference Example 89]

{(1S,5S,6R)-3-Benzyloxycarbonyl-6-fluoro-3-azabicyclo[3,3,0]octane-1-yl}carboxylic acid tert-butyl ester

[Formula 176]

{(1S, 5R, 6R)-6-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1 tert-butyl-yl}carboxylate (420mg, 1.21mmol) was dissolved in tetrahydrofuran (20ml), and 1M borane-tetrahydrofuran complex (3.63ml, 3.63mmol) was added dropwise under nitrogen atmosphere. After 5 hours, 1M borane-tetrahydrofuran complex (3.63ml, 3.63mmol) was added, and after 15 hours, further 1M borane-tetrahydrofuran complex (3.63ml, 3.63mmol) was added. After stirring for 3 hours, ethanol (18ml), water (2ml) and triethylamine (2ml) were added, and the resulting mixture was stirred at 80°C for 2 hours. The reaction solution was evaporated under reduced pressure, and saturated ammonium chloride solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (3ml). Benzyloxycarbonyl chloride (1.03 g, 6.04 mmol) was added and the mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 367 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.26 (5H, m), 5.12 (2H, s), 4.85 (1H, d, J = 52.44Hz), 3.86 (1H, d, J = 11.71Hz ), 3.77-3.73(1H, m), 3.40-3.35(2H, m), 3.16-3.10(1H, m), 2.46-2.42(1H, m), 2.03-1.82(3H, m), 1.45(9H , s).

MS (EI) m/z: 386 (M+Na) ⁺ .

[Reference Example 90]

{(1S,5S,6S)-3-Benzyloxycarbonyl-6-fluoro-3-azabicyclo[3,3,0]octane-1-yl}carboxylic acid tert-butyl ester

[Formula 177]

{(1S, 5R, 6S)-6-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1 tert-butyl-yl}carboxylate (402mg, 1.16mmol) was dissolved in tetrahydrofuran (20ml), and 1M borane-tetrahydrofuran complex (5.79ml, 5.79mmol) was added dropwise under nitrogen atmosphere. After 2 hours, 1M borane-tetrahydrofuran complex (3.47ml, 3.47mmol) was added; after 14 hours, further 1M borane-tetrahydrofuran complex (3.47ml, 3.47mmol) was added. After stirring for 2.5 hours, ethanol (18ml), water (2ml) and triethylamine (2ml) were added, and the resulting mixture was stirred at 80°C for 2 hours. The reaction solution was evaporated under reduced pressure, and saturated ammonium chloride solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in dichloromethane (2.8ml). Benzyloxycarbonyl chloride (1.03 g, 6.04 mmol) was added, and the resulting mixture was stirred at 40°C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to obtain 359 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.29 (5H, m), 5.13 (2H, s), 5.06 (1H, d, J=49.84Hz), 3.99 (1H, dd, J=20.12, 11.59Hz), 3.79(1H, d, J=11.95Hz), 3.58-3.55(1H, m), 3.38(1H, dd, J=46.71, 11.34Hz), 3.00(1H, brd, J=25.37Hz) , 2.26-1.94 (4H, m), 1.43 (9.0H, s).

MS (EI) m/z: 386 (M+Na) ⁺ .

[Reference Example 91]

{(1S, 5R, 6R)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl}methanol benzyl ester

[Formula 178]

Tert-butyl {(1S,5S,6R)-3-benzyloxycarbonyl-6-fluoro-3-azabicyclo[3,3,0]octan-1-yl}carboxylate (362mg, 1.00mmol) Dissolve in dichloromethane (10ml). Trifluoroacetic acid (2.5ml) was added, and the mixture was stirred for 15 hours. The solvent was evaporated under reduced pressure. 1N Sodium hydroxide solution was added to the obtained residue, and the obtained mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in toluene (10 ml). Triethylamine (202 mg, 1.99 mmol) and diphenoxyphosphoryl azide (339 mg, 1.20 mmol) were added under nitrogen atmosphere, and the resulting mixture was stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure. Then, dioxane (20ml) and 6N hydrochloric acid (20ml) were added, and the resulting mixture was stirred at 40°C for 3 hours. After concentration under reduced pressure and azeotropic distillation with ethanol, 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (1087 mg, 4.98 mmol) was added to the resulting residue, and the resulting mixture was stirred at 50°C for 2 hr. The reaction solution was purified by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 125 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.11 (2H, s), 4.95-4.80 (2H, m), 3.88-3.63 (3H, m), 3.28-3.24 ( 1H, m), 2.83-2.75 (1H, m), 2.12-1.98 (4H, m), 1.44 (9H, s).

MS (EI) m/z: 401 (M+Na) ⁺ .

[Reference Example 92]

{(1S, 5R, 6S)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl}methanol benzyl ester

[Formula 179]

Tert-butyl {(1S,5S,6S)-3-benzyloxycarbonyl-6-fluoro-3-azabicyclo[3,3,0]octan-1-yl}carboxylate (354mg, 0.97mmol) Dissolve in dichloromethane (10ml). Trifluoroacetic acid (3ml) was added and the mixture was stirred for 21 hours. The solvent was evaporated under reduced pressure. 1N Sodium hydroxide solution was added to the obtained residue, and the obtained mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene (8 ml). Under nitrogen atmosphere, triethylamine (197 mg, 1.95 mmol) and diphenoxyphosphoryl azide (359 mg, 1.27 mmol) were added, and the mixture was stirred for 1 hour. Then, tert-butanol (8 ml) was added, and the resulting mixture was stirred at 100°C for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25% ethyl acetate/hexane) to obtain 136 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.26 (5H, m), 5.13 (2H, s), 5.05 (1H, d, J=58.77Hz), 4.68 (1H, brs), 3.77 (1H , d, J=10.46Hz), 3.71-3.60 (2H, m), 3.57-3.44 (1H, m), 3.11-2.86 (1H, m), 2.29-2.02 (4H, m), 1.43 (9H, s ).

MS (EI); m/z: 401 (M+Na) ⁺ .

[Reference Example 93]

(1S,5R,6R)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane

[Formula 180]

Benzyl {(1S, 5R, 6R)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl}carboxylate (120mg, 0.32mmol ) was dissolved in methanol (10ml). 10% palladium-carbon (M, wet) (50 mg) was added, and the mixture was stirred under hydrogen atmosphere for 3 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure to obtain 77.5 mg of the title compound as a colorless oil.

MS (EI); m/z: 245 (M+H) ⁺ .

[Reference Example 94]

(1S,5R,6S)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane

[Formula 181]

Benzyl {(1S, 5R, 6S)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl}carboxylate (132mg, 0.35mmol ) was dissolved in methanol (10ml). 10% palladium-carbon (M, wet) (50 mg) was added, and the mixture was stirred under hydrogen atmosphere for 3 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure to obtain 85 mg of the title compound as a colorless oil.

MS (EI); m/z: 245 (M+H) ⁺ .

[Example 20]

7-{(1S, 5R, 6R)-1-amino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 182]

Dissolve (1S,5R,6R)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane (77.5 mg, 0.32 mmol) in dimethylsulfoxide (2ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (120.2mg, 0.33mmol) and triethylamine (96.3mg, 0.95mmol), the resulting mixture was stirred at 40°C for 18 hours. Then, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 3 hours. After evaporating the solvent under reduced pressure, 10% citric acid solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (5% methanol/chloroform). The obtained crude product was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.5 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting solid was washed with ether and dried under reduced pressure to obtain 96 mg of the title compound as a colorless solid.

mp: 179-181°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, s), 7.71 (1H, d, J = 13.67Hz), 5.10-5.07 (1H, m), 5.09 (1H, d, J = 52.00 Hz), 4.07-4.04(1H, m), 3.88(1H, t, J=9.64Hz), 3.68-3.63(4H, m), 3.57(1H, dd, J=16.97, 10.62Hz), 3.45(1H , d, J=11.72Hz), 2.63-2.56 (1H, m), 2.10-2.01 (4H, m), 1.61-1.51 (2H, m).

Anal _{. Calcd} . for _{C21H22F3N3O4-0.5H2O} : C, 56.50; _H , 5.19 _; N, 9.41; _F , 12.77. Found: C, 56.28; H, 5.17; N, 9.03; F, 12.47.

MS (EI); m/z: 438 (M+H) ⁺ .

IR (ATR) v: 3390, 2943, 2872, 1720, 1618, 1512, 1452, 1360, 1321, 1277, 1213 cm ^-1 .

[Example 21]

7-[(1S,5R,6S)-1-amino-6-fluoro-3-azabicyclo[3,3,0]octane-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 183]

Dissolve (1S,5R,6S)-1-tert-butoxycarbonylamino-6-fluoro-3-azabicyclo[3,3,0]octane (85.2 mg, 0.35 mmol) in dimethylsulfoxide (2ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (132.2mg, 0.37mmol) and triethylamine (105.9mg, 1.05mmol), and the resulting mixture was stirred at 40°C for 15 hours. Then, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 3 hours. The solvent was evaporated under reduced pressure and 10% citric acid solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (5% methanol/chloroform). The obtained crude product was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.5 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained solid was washed with ether and dried under reduced pressure to obtain 101 mg of the title compound as a colorless solid.

mp: 117-119°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.45 (1H, s), 7.70 (1H, d, J = 14.15Hz), 5.28 (1H, d, J = 53.41Hz), 5.07-4.73 (1H, m), 4.05-4.02(1H, m), 3.84-3.64(6H, m), 3.47(1H, d, J=10.73Hz), 2.59-2.53(1H, m), 2.26-2.06(3H, m) , 1.79-1.78 (1H, m), 1.58-1.46 (2H, m).

Anal _. Calcd _. for _{C21H22F3N3O4 - H2O} : C, _55.38 ; H, 5.31; N, 9.23; F, 12.51. Found: C, 55.43; H, 5.46; N, 9.00; F, 12.21.

MS (EI) m/z: 438 (M+H) ⁺ .

IR (ATR) v: 2966, 2839, 1720, 1614, 1576, 1537, 1508, 1446, 1362, 1319, 1271, 1207 cm ^-1 .

[Reference Example 95]

{(1S,5S)-6,6-difluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1-yl}methanol tert-butyl acid

[Formula 184]

{(1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1-yl} tert-Butyl formate (500mg, 1.46mmol) was dissolved in dichloromethane (20ml). Under nitrogen atmosphere, [bis(2-methoxymethyl)amino]sulfur trifluoride (966.3 mg, 4.37 mmol) was added at 0°C, and the resulting mixture was stirred at 20°C for 17 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium thiosulfate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the resulting residue was purified by short column chromatography on silica gel (25% ethyl acetate/hexane). The obtained crude product was dissolved in tetrahydrofuran (15ml). 1M Borane-tetrahydrofuran complex (4.37ml, 4.37mmol) was added under nitrogen atmosphere, and the mixture was stirred for 16 hours. 1M borane-tetrahydrofuran complex (4.37ml, 4.37mmol) was added, and the mixture was stirred for 9 hours. 1M borane-tetrahydrofuran complex (4.37ml, 4.37mmol) was added again, and the mixture was stirred for 16 hours. Ethanol (45ml), water (5ml) and triethylamine (5ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 4 hrs. Then, the solvent was evaporated under reduced pressure and saturated ammonium chloride solution was added to the residue. The organic layer was extracted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (15% ethyl acetate/hexane) to obtain 375.8 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.22 (5H, m), 3.28 (1H, d, J = 9.77Hz), 3.13 (1H, q, J = 6.51Hz), 3.01 (1H, dd , J=19.04, 7.08Hz), 2.60(1H, d, J=9.28Hz), 2.39-2.30(3H, m), 2.15-2.09(2H, m), 1.80-1.75(1H, m), 1.41( 9H, s), 1.33 (3H, d, J = 6.59 Hz).

MS (EI) m/z: 352 (M+H) ⁺ .

[Reference Example 96]

{(1S,5S)-3-Benzyloxycarbonyl-6,6-difluoro-3-azabicyclo[3,3,0]octane-1-yl}carboxylic acid tert Butyl ester

[Formula 185]

{(1S,5S)-6,6-difluoro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3,3,0]octane-1-yl}carboxylic acid The tert-butyl ester (370.0 mg, 1.05 mmol) was dissolved in dichloromethane (3 ml). Benzyloxycarbonyl chloride (898 mg, 5.26 mmol) was added, and the resulting mixture was stirred at 40°C for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 338 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.26 (5H, m), 5.13 (2H, s), 3.86 (2H, d, J=11.71Hz), 3.54-3.42 (2H, m), 3.16 -3.07 (1H, m), 2.37-2.11 (3H, m), 1.88-1.82 (1H, m), 1.45 (9H, s).

MS (EI) m/z: 404 (M+Na) ⁺ .

[Reference Example 97]

{(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octane-3-yl} Benzyl formate

[Formula 186]

Tert-butyl {(1S,5S)-3-benzyloxycarbonyl-6,6-difluoro-3-azabicyclo[3,3,0]octane-1-yl}carboxylate (332.0mg, 0.87 mmol) was dissolved in dichloromethane (10ml). Trifluoroacetic acid (2ml) was added and the mixture was stirred for 23 hours. The reaction solution was concentrated under reduced pressure. 1N sodium hydroxide solution was added, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in toluene (10 ml). Triethylamine (176.2 mg, 1.74 mmol) and diphenoxyphosphoryl azide (370.4 mg, 1.31 mmol) were added under nitrogen atmosphere, and the resulting mixture was stirred at 100°C for 20 hours. The reaction solution was concentrated under reduced pressure. Then, dioxane (10ml) and 6N hydrochloric acid (10ml) were added, and the resulting mixture was stirred at 40°C for 1.5 hours. After concentration under reduced pressure and azeotropic distillation with ethanol, 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (949.9 mg, 4.35 mmol) was added to the resulting residue, and the resulting mixture was stirred at 50°C for 16 hours. The reaction solution was purified by silica gel column chromatography (25% ethyl acetate/hexane) to obtain 67.0 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.17 (5H, m), 5.13 (2H, s), 4.80 (1H, s), 3.84-3.80 (1H, m), 3.71-3.65 (3H, m), 3.06-2.96 (1H, m), 2.39-2.31 (1H, m), 2.16-2.08 (3H, m), 1.44 (9H, s).

MS (EI) m/z: 397 (M+H) ⁺ .

[Reference Example 98]

(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octane

[Formula 187]

Benzyl [(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octane-3-yl]carboxylate (65.0 mg, 0.16mmol) was dissolved in methanol (10ml). 10% palladium-carbon (50% wet) (20 mg) was added, and the resulting mixture was stirred under hydrogen atmosphere for 1 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated under reduced pressure to obtain 43 mg of the title compound as a colorless solid.

MS (EI); m/z: 263 (M+H) ⁺ .

[Example 22]

7-[(1S,5R)-1-amino-6,6-difluoro-3-azabicyclo[3,3,0]octane-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 188]

Dissolve (1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3,3,0]octane (43.0mg, 0.16mmol) in dimethylmethylene Sulfone (1.8ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (62.2mg, 0.17mmol) and triethylamine (49.8mg, 0.49mmol), the resulting mixture was stirred at 40°C for 16 hours. Then, 90% aqueous ethanol (20 ml) and triethylamine (2 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 2.5 hours. The solvent was evaporated under reduced pressure and 10% citric acid solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The obtained crude product was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained solid was dissolved in ethanol-ammonia water, and the resulting solution was heated and stirred. After distilling off the ammonia, the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 15.2 mg of the title compound as a pale yellow solid.

mp: 239-241°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 7.73 (1H, d, J=13.67Hz), 5.07-4.91 (1H, m), 4.08-4.05 (1H, m), 3.91-3.88(1H, m), 3.79-3.77(1H, m), 3.72-3.70(1H, m), 3.68(3H, s), 3.55(1H, d, J=10.74Hz), 2.67-2.62( 1H, m), 2.36-2.33 (2H, m), 2.16-2.12 (1H, m), 1.96-1.89 (1H, m), 1.64-1.51 (2H, m).

_{Anal .} Calcd. for _{C21H21F4N3O4-0.25H2O} : C, _54.84 ; H _, 4.71; N, 9.14; _F , 16.52. Found: C, 54.97, H, 4.53; N, 9.09; F, 16.53.

MS (EI); m/z: 456 (M+H) ⁺ .

IR (ATR) v: 3392, 3031, 2883, 1718, 1618, 1510, 1450, 1360, 1333, 1306, 1250 cm ^-1 .

[Reference Example 99]

(1S,5R)-5-Methyl-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane tert-Butyl-1-ylformate

[Formula 189]

N,N-Dimethylformamide (2.0 ml) was added to sodium hydride (152 mg, 3.48 mmol) under argon atmosphere. Under ice cooling, (1S,5R)-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octan-1-yl A solution of tert-butyl formate (1.00 g, 2.91 mmol) in N,N-dimethylformamide (8.0 ml) was added dropwise to the suspension, and the resulting mixture was stirred at 0°C for 30 minutes. Then methyl iodide (0.217ml, 3.49mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was ice-cooled, and then the reactant was quenched with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to obtain 0.79 g of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.41-7.23 (5H, m), 5.48 (1H, q, J = 6.62Hz), 3.40 (1H, d, J = 10.54Hz), 3.13 (1H, d , J=10.54Hz), 2.63-2.40(3H, m), 1.96-1.83(1H, m), 1.54(3H, d, J=7.11Hz), 1.39(9H, s), 1.22(3H, s) .

[Reference Example 100]

(1S,5R)-6,6-Ethylenediyldimercapto-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-aza Methyl bicyclo[3.3.0]octane-1-ylcarboxylate

[Formula 190]

(1S,5R)-5-methyl-4,6-dioxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1- tert-Butyl carbamate (0.28 g, 0.78 mmol) was dissolved in toluene (14 mL). Toluenesulfonic acid monohydrate (155mg, 0.81mmol) and ethanedithiol (0.14ml, 1.7mmol) were added, and the mixture was heated to reflux for 9 hours. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (dichloromethane:methanol=98:2) to obtain the target 1-position carboxylic acid (289 mg) as a pale yellow solid. The carboxylic acid (289mg) was dissolved in tetrahydrofuran (10ml) and methanol (3.0ml). Trimethylsilyldiazomethane (1.7 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain 267 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.23 (5H, m), 5.52 (1H, q, J = 6.86Hz), 3.60 (3H, s), 3.55 (1H, d, J = 10.05Hz ), 3.44-3.31(1H, m), 3.28-3.19(1H, m), 3.16(1H, d, J=10.05Hz), 2.79-2.70(1H, m), 2.54-2.44(1H, m), 2.26-2.15 (1H, m), 1.81-1.70 (1H, m), 1.59-1.52 (2H, m), 1.56 (3H, d, J=7.11Hz), 1.33 (3H, s).

[Reference Example 101]

(1S,5R)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1- methyl carbamate

[Formula 191]

(1S, 5R)-6,6-ethanediyldimercapto-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3. 0] Octane-1-ylcarboxylate methyl ester (266mg, 0.68mmol) was dissolved in ethanol (10ml). Raney nickel (2.0ml) was added dropwise and the mixture was heated to reflux for 5.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain 133 mg of the title compound as a pale yellow solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.24 (5H, m), 5.56-5.44 (1H, m), 3.64 (3H, s), 3.51 (1H, d, J=10.05Hz), 3.02 -2.96 (1H, m), 2.49-2.26 (2H, m), 1.91-1.44 (4H, m), 1.52 (3H, d, J=7.35Hz), 1.12 (3H, s).

[Reference Example 102]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3- Azabicyclo[3.3.0]octane

[Formula 192]

(1S, 5R)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-ylcarboxylate The ester (130mg, 0.43mmol) was dissolved in methanol (5.0ml). 1N Sodium hydroxide solution (1.5 ml) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 4 hrs. Then, 1N sodium hydroxide solution (1.5 ml) was added dropwise, and the mixture was stirred at room temperature for 15 hr. Sodium hydroxide (93 mg) was added again, and the mixture was stirred at room temperature for 6 hours. Sodium hydroxide (90 mg) was added again, and the mixture was stirred at room temperature for 4 hours and then at 50°C for 1 hour. The reaction solution was weakly acidified with hydrochloric acid, and the solvent was evaporated under reduced pressure. The resulting residue was extracted with dichloromethane and dilute hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in toluene (5.0 ml). Triethylamine (0.132ml, 0.95mmol) and diphenoxyphosphoryl azide (0.111ml, 0.52mmol) were added, and the mixture was heated to reflux for 3 hours. The reaction solution was extracted with ethyl acetate and saturated aqueous sodium bicarbonate solution. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. 1,4-Dioxane (2.0 ml) and 6N hydrochloric acid (2.0 ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 15 hr. After extraction with water and ethyl acetate, the aqueous layer was basified with saturated sodium hydroxide solution and extracted twice with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Toluene (3.0 ml) and Red-Al ^™ (65% solution in toluene) (0.50 ml) were successively added to the obtained residue, and the resulting mixture was stirred at 80° C. for 2.5 hours. Under ice-cooling, 3N sodium hydroxide solution was added to the reaction solution, and the layers were separated with toluene. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in dichloromethane (10ml) and methanol (5.0ml). Di-tert-butyl dicarbonate (560 mg, 2.57 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was purified by silica gel column chromatography (dichloromethane:methanol=98:2) to obtain 77 mg of the title compound as a pale yellow solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.33-7.16 (5H, m), 4.79 (1H, brs), 3.17-3.00 (1H, m), 2.74-2.58 (2H, m), 2.53-2.44 ( 1H, m), 2.27-2.13 (1H, m), 2.08-1.89 (2H, m), 1.74-1.62 (2H, m), 1.60-1.24 (2H, m), 1.41 (9H, s), 1.28 ( 3H, d, J = 6.59 Hz), 1.07 (3H, s).

[Reference Example 103]

(1S,5S)-1-(tert-butoxycarbonylamino)-5-methyl-4-oxo-3-azabicyclo[3.3.0]octane

[Formula 193]

(1S, 5S)-1-(tert-butoxycarbonylamino)-5-methyl-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3 .0] Octane (77mg, 0.22mmol) was dissolved in ethanol (6.0ml). 10% palladium-carbon (50% wet) (69 mg) was added, and the resulting mixture was stirred at 45° C. for 19.5 hours under hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 50 mg of the title compound as a pale yellow oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.68 (1H, brs), 3.36-3.19 (1H, m), 3.00-2.58 (4H, m), 2.40-1.89 (4H, m), 1.81-1.26 ( 2H, m), 1.44 (9H, s), 1.07 (3H, s).

[Example 23]

7-[(1R,5R)-1-amino-3-aza-5-methylbicyclo[3.3.0]octane-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 194]

Triethylamine (0.092ml, 0.66mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methoxy-4- Oxoquinoline- ₃ -carboxylic acid-BF chelate (79.1mg, 0.22mmol) was added to (1R,5R)-1-(tert-butoxycarbonylamino)-5-methyl-3-azabicyclo [3.3.0] In a solution of octane (50.1 mg, 0.21 mmol) in dimethyl sulfoxide (2.0 ml). The mixture was stirred at 45°C for 24 hours. Ethanol (3.0ml), water (1.0ml) and triethylamine (1.0ml) were added to the reaction solution, and the mixture was heated under reflux for 2.5 hours. After evaporating the solvent under reduced pressure, the resulting residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane:methanol=99:1). The obtained oil (92.5 mg) was dissolved in concentrated hydrochloric acid (1.0 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 0.5 hr. The reaction solution was washed twice with chloroform, and then the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from ethanol to give 47 mg of the title compound as a pale yellow solid.

mp: 109-113°C (decomposition).

[α] _D ²⁴ +78.2° (c=0.135, 0.1N NaOH).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.45 (1H, s), 7.66 (1H, d, J=14.5Hz), 4.79-4.85 (1H, m), 4.00-4.10 (1H, m), 3.61 (3H, s), 3.51-3.75 (3H, m), 3.34-3.44 (1H, m), 1.94-2.07 (1H, m), 1.43-1.93 (7H, m), 1.10 (3H, s).

MS (FAB); m/z: 434 (M+H) ⁺ .

_{Anal .} Calcd. for _{C22H25F2N3O4-2H2O} : C, _56.28 ; _{H ,} 6.23; F, 8.09; N, 8.95. Found: C, 56.57; H, 6.24; F, 8.19; N, 9.01.

IR (ATR) v: 2942, 2877, 1612, 1573, 1448, 1434, 1392, 1349, 1342, 1311, 1301, 1290, 1272, 821, 804 ^{cm -1} .

[Reference Example 104]

(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 195]

Dissolve tert-butyl 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (4g, 13.82mol) in N,N-dimethylformamide (40ml) , and paraformaldehyde (0.83 g, 27.65 mmol) was suspended in the solution. Sodium hydride (0.60 g, 13.82 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Then, the reaction solution was poured into 10% citric acid solution (150 ml) at 0°C. The resulting mixture was extracted with ethyl acetate (300ml). The organic layer was washed with water (100ml x 2) and brine (100ml), dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (30% ethyl acetate/hexane→80% ethyl acetate/hexane) to obtain 1.03 g of the title compound as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.28 (5H, m), 5.51 (1H, q, J = 7.16Hz), 3.77 (1H, dd, J = 11.23, 5.37Hz), 3.61 (1H , dd, J=11.23, 7.81Hz), 3.39(1H, d, J=10.50Hz), 3.21(1H, d, J=10.25Hz), 2.78(1H, d, J=17.09Hz), 2.51(1H , dd, J=7.81, 5.37Hz), 2.40 (1H, d, J=17.33Hz), 1.53 (3H, d, J=7.33Hz), 1.35 (9H, s).

MS (EI); m/z: 320 (M+H) ⁺ .

[Reference Example 105]

(3S)-3-Formyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 196]

(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.0 g, 12.52 mmol) was dissolved in dichloro in methane. Triethylamine (6.34g, 62.62mmol), dimethylsulfoxide (3.91g, 50.09mmol) and SO ₃ -pyridine complex (3.99g, 25.05mmol) were added successively at 0°C, and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (60% ethyl acetate/hexane) to obtain 2.85 g of the title compound as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.62 (1H, s), 7.35-7.28 (5H, m), 5.47 (1H, q, J=7.00Hz), 3.79 (1H, t, J=9.52Hz ), 3.24 (1H, d, J = 10.50Hz), 2.93 (1H, d, J = 17.33Hz), 2.85 (1H, d, J = 17.33Hz), 1.53 (3H, d, J = 7.08Hz), 1.38 (9H, s).

MS (EI); m/z: 318 (M+H) ⁺ .

[Reference Example 106]

(3R)-5-Oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 197]

Methyltriphenylphosphonium bromide (187.4 mg, 0.52 mmol) was dissolved in tetrahydrofuran. Under nitrogen atmosphere, 2.62M n-butyllithium hexane solution (0.16ml, 0.42mmol) was added dropwise at -78°C, and the mixture was stirred for 1 hour. After heating to 0°C, (3S)-3-formyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (111mg, 0.35mmol ) in tetrahydrofuran, and the mixture was stirred for 1 hour. A saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (25% ethyl acetate/hexane) to obtain 54 mg of the title compound as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33-7.26 (5H, m), 5.96 (1H, dd, J=17.33, 10.74Hz), 5.52-5.45 (1H, m), 5.21-5.17 (2H, m), 3.45(1H, d, J=10.25Hz), 3.26(1H, d, J=10.01Hz), 3.01(1H, d, J=16.60Hz), 2.54(1H, d, J=16.60Hz) , 1.50 (3H, d, J=7.08Hz), 1.33 (9H, s).

MS (EI) m/z: 318 (M+H) ⁺ .

[Reference Example 107]

(3S,4S)-4-allyl-5-oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 198]

(3R)-5-Oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester (236.0mg, 0.75mmol) and allyl bromide (271.6 mg, 2.24 mmol) was dissolved in tetrahydrofuran. Under nitrogen atmosphere, 1M lithium hexamethyldisilazide solution in tetrahydrofuran (1.12ml, 1.12mmol) was added dropwise at 0°C. After stirring for 1.5 hours, saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to obtain 135 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33-7.26 (5H, m), 5.98-5.82 (2H, m), 5.47 (1H, q, J=7.00Hz), 5.24-4.97 (4H, m) , 3.35-3.25(2H, m), 3.03(1H, t, J=6.82Hz), 2.48-2.41(1H, m), 2.39-2.32(1H, m), 1.54(3H, d, J=7.08Hz ), 1.33 (9H, s).

MS (EI); m/z: 356 (M+H) ⁺ .

[Reference Example 108]

[(1S,5S)-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]methanol tert-butyl acid

[Formula 199]

(3S,4S)-4-allyl-5-oxo-1-[(1R)-1-phenylethyl]-3-vinylpyrrolidine-3-carboxylic acid tert-butyl ester (130.0mg, 0.37mmol) was dissolved in benzene (8ml). Second generation Grubbs catalyst (31.0 mg, 0.04 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (15% ethyl acetate/hexane) to obtain 93.2 mg of the title compound as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.28 (5H, m), 5.94-5.91 (1H, m), 5.60-5.59 (1H, m), 5.51 (1H, q, J=7.16Hz) , 3.34-3.24 (3H, m), 2.81-2.79 (2H, m), 1.45 (3H, d, J=7.32Hz), 1.38 (9H, s).

MS (EI) m/z: 328 (M+H) ⁺ .

[Reference Example 109]

[(1S,5S)-3-[(1R)-1-phenylethyl]-4-thio-3-azabicyclo[3.3.0]oct-7-en-1-yl]methanol tert-butyl acid

[Formula 200]

[(1S,5S)-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]formic acid tert Butyl ester (88.0mg, 0.27mmol) was dissolved in toluene (8ml). Lawson's reagent (81.5 mg, 0.20 mmol) was added, and the resulting mixture was stirred at 80°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to obtain 91.6 mg of the title compound as a yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.26 (5H, m), 6.41 (1H, q, J=7.08Hz), 5.95-5.94 (1H, m), 5.55-5.54 (1H, m) , 3.74 (1H, d, J = 8.30Hz), 3.60 (1H, d, J = 11.96Hz), 3.49 (1H, d, J = 12.21Hz), 3.15 (1H, d, J = 17.09Hz), 3.02 -2.98 (1H, m), 1.51 (3H, d, J=7.08Hz), 1.36 (9H, s).

MS (EI) m/z: 344 (M+H) ⁺ .

[Reference Example 110]

[(1S,5S)-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]tert-butyl formate ester

[Formula 201]

[(1S,5S)-3-[(1R)-1-phenylethyl]-4-thio-3-azabicyclo[3.3.0]oct-7-en-1-yl]formic acid tert Butyl ester (88.2 mg, 0.27 mmol) was dissolved in ethanol. Raney nickel was added and the mixture was stirred for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to obtain 55.4 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.21 (5H, m), 5.74 (1H, brs), 5.54 (1H, brs), 3.15 (1H, q, J=6.75Hz), 3.04 (1H , brs), 2.72-2.70(2H, m), 2.61(1H, t, J=7.81Hz), 2.53-2.51(2H, m), 2.18(1H, d, J=16.85Hz), 1.41(9H, s), 1.32 (3H, d, J = 6.59 Hz).

MS (EI) m/z: 314 (M+H) ⁺ .

[Reference Example 111]

[(1S,5S)-3-Benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester

[Formula 202]

[(1S,5S)-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester (370mg, 1.18mmol) was dissolved in dichloroethane (3ml). Benzyloxycarbonyl chloride (1.01 g, 5.90 mmol) was added, and the resulting mixture was stirred at 40°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to obtain 385 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.29 (5H, m), 5.79 (1H, brs), 5.64 (1H, brs), 5.12 (2H, s), 3.79-3.68 (3H, m) , 3.21-3.12 (2H, m), 2.74 (1H, dd, J = 17.44, 6.22Hz), 2.19 (1H, t, J = 18.54Hz), 1.43 (9H, s).

MS; (EI) m/z: 366 (M+Na) ⁺ .

[Reference Example 112]

Benzyl [(1S,5R)-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-7-en-3-yl]carboxylate ester

[Formula 203]

Dissolve tert-butyl [(1S,5S)-3-benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylate (380 mg, 1.11 mmol) in dichloromethane (8ml). Trifluoroacetic acid (1.5 ml) was added, and the mixture was stirred for 1 day. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide solution (100 ml) was added, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform (200ml×2). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in toluene (10 ml). Under a nitrogen atmosphere, triethylamine (223.3 mg, 2.21 mmol) and diphenoxyphosphoryl azide (469.5 mg, 1.66 mmol) were added, and the resulting mixture was stirred at 80°C for 20 hours. The reaction solution was concentrated under reduced pressure. Then, 1,4-dioxane (10 ml) and 6N hydrochloric acid (10 ml) were added, and the mixture was stirred for 3 days. After concentration under reduced pressure and azeotropic distillation with ethanol, 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (1204 mg, 5.52 mmol) was added to the resulting residue, and the resulting mixture was stirred at 50°C for 16 hours. The reaction solution was purified by silica gel column chromatography (20% ethyl acetate/hexane) to obtain 92.1 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.25 (5H, m), 5.84 (1H, s), 5.78 (1H, s), 5.10 (2H, s), 4.70 (1H, s), 3.87 (1H, dd, J=11.23, 8.79Hz), 3.79-3.76 (2H, m), 3.24-3.21 (1H, m), 2.87-2.72 (2H, m), 2.21-2.18 (1H, m), 1.43 (9H, s).

MS (EI); m/z: 359 (M+H) ⁺ .

[Reference Example 113]

(1S,5R)-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-7-ene

[Formula 204]

Benzyl [(1S,5R)-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-7-en-3-yl]carboxylate (85.0 mg, 0.24 mmol) was dissolved in THF (20ml). After passing liquid ammonia (20ml) at -78°C, sodium (17.1mg, 0.71mmol) was added, and the mixture was stirred for 1 hour. Saturated ammonium chloride solution (6 drops) was added, and the ammonia was evaporated in an ice-water bath. 1N sodium hydroxide solution was added, followed by extraction with chloroform twice. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure to obtain 52.9 mg of the title compound as a colorless solid.

MS (EI) m/z: 225 (M+H) ⁺ .

[Example 24]

7-[(1S,5R)-1-amino-3-azabicyclo[3.3.0]oct-7-en-3-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 205]

(1S,5R)-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-7-ene (52.9mg, 0.24mmol) was dissolved in dimethylsulfoxide (2ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (89.4mg, 0.25mmol) and triethylamine (71.6mg, 0.71mmol), the resulting mixture was stirred at 40°C for 20 hours. Then, 90% aqueous ethanol (20 ml) and triethylamine (2 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 2 hours. The solvent was evaporated under reduced pressure and 10% citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The obtained crude product was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 8 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was washed with ethanol-ether and dried under reduced pressure to obtain 57.8 mg of the title compound as a pale yellow solid.

mp: 206-208°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, s), 7.69 (1H, d, J = 13.67Hz), 5.90 (1H, brs), 5.69 (1H, brs), 4.96 (1H, d, J = 60.79Hz), 4.08-4.04 (1H, m), 3.77 (1H, t, J = 8.91Hz), 3.70 (3H, d, J = 10.25Hz), 3.64 (1H, s), 3.59- 3.57(1H, m), 3.54-3.51(1H, m), 2.91-2.87(1H, m), 2.55-2.53(1H, m), 2.30(1H, d, J=17.09Hz), 1.63-1.55( 2H, m).

Anal _. Calcd. for _{C21H21F2N3O4.0.25H2O.0.5EtOH} : C, _{59.39 ;} H _, 5.55; _N , 9.44; F, 8.54. Found: C, 59.32; H, 5.44; N, 9.50; F, 8.28.

MS (EI); m/z: 418 (M+H) ⁺ .

IR (ATR) v: 2929, 2848, 2758, 1726, 1614, 1577, 1537, 1504, 1435, 1392, 1352, 1315, 1269 ^{cm -1} .

[Reference Example 114]

(1R ^* , 5S ^* )-7-Benzyl-3-oxa-7-azabicyclo[3.3.0]octan-2-one

[Formula 206]

Trifluoroacetic acid (0.136ml) was added to N-benzyl-N-(methoxymethyl)-N-trimethylsilylamine (43.9g, 185mmol) and γ-crotonolactone (12.5g , 176 mmol) in 1,2-dichloromethane (176 ml), and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. Saturated sodium bicarbonate solution (250ml) was added to the reaction solution, followed by extraction with chloroform (200ml×2). The organic layer was washed with brine (400ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25→66:34→50:50) to obtain 37.1 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.30-7.26 (5H, m), 4.48 (1H, t, J=8.58Hz), 4.08 (1H, dd, J=9.19, 3.55Hz), 3.69 (1H , d, J = 13.24Hz), 3.54 (1H, d, J = 13.24Hz), 3.26 (1H, d, J = 9.31Hz), 3.08-2.98 (2H, m), 2.80 (1H, d, J = 9.56Hz), 2.49-2.38 (2H, m).

MS (ESI) m/z: 218 (M+H) ⁺ .

[Reference Example 115]

1-allyl-7-benzyl-3-oxa-7-azabicyclo[3.3.0]octan-2-one

[Formula 207]

Under salt ice cooling, allyl bromide (2.48ml, 29.3mmol) was added to (1R ^* , 5S ^* )-7-benzyl-3-oxa-7-azabicyclo[3.3.0] while stirring To a solution of octane-2-one (4.25g, 19.6mmol) in tetrahydrofuran (98ml), under cooling with ice-acetone, add dropwise a solution of 1M lithium hexamethyldisilazide in tetrahydrofuran (23.5ml, 23.5mmol) . The mixture was stirred for 2 hours while gradually warming to room temperature. Saturated ammonium chloride solution (200ml) was added to the reaction solution, followed by extraction with ethyl acetate (100ml x 2). The organic layer was washed with water (250ml) and brine (250ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25→66:34→50:50), 1.51 g of the title compound were obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.21 (5H, m), 5.80-5.70 (1H, m), 5.20-5.14 (2H, m), 4.35 (1H, t, J=8.95Hz) , 4.03 (1H, dd, J = 9.19, 3.55Hz), 3.63 (1H, d, J = 13.24Hz), 3.51 (1H, d, J = 13.24Hz), 3.26 (1H, d, J = 9.07Hz) , 2.81 (1H, d, J = 9.56Hz), 2.73-2.71 (1H, m), 2.57 (1H, dd, J = 13.73, 6.62Hz), 2.49 (1H, dd, J = 9.44, 6.74Hz), 2.30 (1H, dd, J = 13.85, 8.21 Hz), 2.23 (1H, d, J = 9.07 Hz).

MS (ESI); m/z: 258 (M+H) ⁺ .

[Reference Example 116]

7-Benzyl-1-(3-hydroxypropyl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one

[Formula 208]

A solution of 1-allyl-7-benzyl-3-oxa-7-azabicyclo[3.3.0]octan-2-one (11.0g, 42.7mmol) in tetrahydrofuran (142ml) was washed with ice-acetone cool down. Under nitrogen atmosphere, 0.5mol/L 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (264ml, 132mmol) was added, and the mixture was stirred at room temperature for 2 hours. After cooling with ice-acetone, under nitrogen atmosphere, 1 mol/L sodium hydroxide solution (142 ml) and 30% hydrogen peroxide solution were added, and the mixture was stirred at room temperature for 1 hour. The organic layer of the reaction solution was concentrated under reduced pressure and extracted with chloroform (300ml×1, 250ml×1). The organic layer was washed with brine (600ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→66:34→50:50→34:66→20:80) to obtain 12.9 g of a residue containing the title compound, which could be used directly in the next reaction.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.22 (5H, m), 4.41 (1H, t, J = 8.82Hz), 4.05 (1H, dd, J = 9.19, 3.55Hz), 3.81 (1H , t, J=8.95Hz), 3.68-3.63(3H, m), 3.51(1H, d, J=13.24Hz), 3.29(1H, d, J=9.31Hz), 2.83(1H, d, J=9.31Hz), 2.83(1H, d, J= 9.56Hz), 2.69 (1H, s), 2.49 (1H, t, J = 7.84Hz), 2.19 (1H, t, J = 8.58Hz), 1.93-1.82 (3H, m).

MS (ESI); m/z: 276 (M+H) ⁺ .

[Reference Example 117]

7-Benzyl-3-oxa-1-(3-hydroxypropyl)-7-azabicyclo[3.3.0]octan-2-one

[Formula 209]

The dichloromethane (113ml) solution was cooled with dry ice-methanol under a nitrogen atmosphere. Oxalyl chloride (11.2ml, 128mmol) and dimethylsulfoxide (15.2ml, 214mmol) were added, and the resulting mixture was stirred under cooling for 30 minutes. Dichloromethane ( 100 ml) of the residue, and the resulting mixture was stirred under ice-cooling for 1 hour. Triethylamine (35.8ml, 256mmol) was added under ice-cooling, and the resulting mixture was stirred under cooling for 1 hour and then at room temperature for 1 hour. Saturated ammonium chloride solution (200 ml) was added to the reaction solution, followed by extraction with chloroform (150 ml×2). The organic layer was washed with brine (450ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50) to obtain 8.91 g of a residue containing the title compound, which was directly used in the following one reaction.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.77 (1H, s), 7.32-7.22 (5H, m), 4.42 (1H, t, J=8.95Hz), 4.06 (1H, dd, J=9.31, 3.68Hz), 3.62(1H, d, J=12.99Hz), 3.53(1H, d, J=13.24Hz), 3.30(1H, d, J=9.31Hz), 2.84(1.0H, d, J=9.31 Hz), 2.73-2.62 (2.0H, m), 2.55-2.51 (2.0H, m), 2.04-2.00 (2H, m).

MS (ESI); m/z: 274 (M+H) ⁺ .

[Reference Example 118]

7-Benzyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one

[Formula 210]

Tetrahydrofuran (45.7ml) was added to methyltriphenylphosphonium iodide (6.16g, 15.2mmol) under nitrogen atmosphere. Under ice-cooling, a 1.57 mol/L hexane solution of butyl lithium (14.0 ml, 22.0 mmol) was added, and then the reaction solution was stirred for 15 minutes. Under ice cooling, dropwise added 7-benzyl-3-oxa-1-(3-oxopropyl)-7-azabicyclo[3.3.0]octan-2-one (5.00g, 18.3 mmol) of the residue in tetrahydrofuran (45.7 ml), and the mixture was stirred at room temperature for 1 hour. Water (150 ml) was added to the reaction solution, followed by extraction with ethyl acetate (150 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25) to obtain 1.09 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.22 (10.8H, m), 5.83-5.73 (1H, m), 5.07-4.96 (2.1H, m), 4.40 (1H, t, J=8.95 Hz), 4.04(1H,dd,J=9.19,3.55Hz), 3.63(1H,d,J=12.99Hz), 3.50(1H,d,J=13.24Hz), 3.29(1H,d,J=9.31 Hz), 2.83(1H, d, J=9.56Hz), 2.71-2.69(1H, m), 2.47(1H, dd, J=9.56, 6.62Hz), 2.23-2.02(3H, m), 1.92-1.88 (1H, m), 1.69-1.65 (1H, m).

MS (ESI); m/z: 272 (M+H) ⁺ .

[Reference Example 119]

7-Benzyloxycarbonyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one

[Formula 211]

Under nitrogen atmosphere, benzyl chloroformate (1.72ml, 12.0mmol) was added to 7-benzyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3. 0] Octan-2-one (1.09 g, 4.02 mmol) in dichloromethane (13.4 ml) and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25→66:34→50:50) to obtain 1.13 g of the title compound .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.82-5.72 (1H, m), 5.12-5.00 (4H, m), 4.42 (1H, t, J=8.33Hz) , 4.12 (1H, brs), 4.00 (1H, d, J = 11.77Hz), 3.83 (1H, dd, J = 11.77, 8.33Hz), 3.44 (2H, d, J = 37.75Hz), 2.95-2.89 ( 1H, m), 2.26-2.17 (1H, m), 2.10-2.06, (1H, m), 1.90-1.76 (2H, m).

MS (ESI); m/z: 316 (M+H) ⁺ .

[Reference Example 120]

1-Benzyloxycarbonyl-3-(3-buten-1-yl)-4-phenylselenomethyl-3-carboxylic acid methyl ester

[Formula 212]

N,N-Dimethylformamide (16.3ml) was added to diphenyl diselenide (946mg, 3.03mmol) under nitrogen atmosphere. The mixture was then depressurized to vacuum and refrigerated (x3) under cooling with liquid nitrogen. Sodium borohydride (229 mg, 6.05 mmol) was added thereto at room temperature. The resulting mixture was stirred at room temperature until gas evolution was complete, then depressurized to vacuum and refrigerated (×3) to prepare reaction solution A.

Separately, under cooling with liquid nitrogen, 7-benzyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one (955 mg, 3.03 mmol) in N,N-dimethylformamide (14.0 ml) was reduced to vacuum and refrigerated (3 times) to prepare reaction solution B.

Reaction solution B was added to reaction solution A, and the resulting mixture was stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, then 1N hydrochloric acid (10-20ml) was added, and extracted with ethyl acetate (100ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2→97:3→96:4) to obtain 2.08 g of the title compound, which was directly used in the esterification step. Trimethylsilyldiazomethane (9.09 ml) was added to a solution of 2.08 g of the residue in methanol (30.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25) to obtain 485 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.49-7.23 (5H, m), 5.73-5.69 (1H, m), 5.16-5.09 (2H, m), 4.98-4.95 (2H, m), 3.98 ( 1H, dd, J=21.33, 11.28Hz), 3.80(1H, ddd, J=24.08, 10.97, 7.05Hz), 3.70(3H, s), 3.32-3.21(2H, m), 3.12(1H, dd, J=12.38, 3.06Hz), 2.49(1H, t, J=12.01Hz), 2.34-2.29(1H, m), 2.10-2.05(1H, m), 1.96-1.92(2H, m), 1.38-1.35 (1H, m).

MS (ESI); m/z: 378 (M+H) ⁺ .

[Reference Example 121]

1-Benzyloxycarbonyl-3-(3-buten-1-yl)-4-methylenepyrrolidine-3-carboxylic acid methyl ester

[Formula 213]

0.5N sodium periodide (sodium periodide) solution (4.99ml, 2.50mmol) was added to 1-benzyloxycarbonyl-3-(3-buten-1-yl)-4-phenylselenomethyl- In a solution of methyl 3-carboxylate (485mg, 0.997mmol) in tetrahydrofuran (9.97ml). The mixture was stirred at room temperature for 5 hours, then at 40°C-50°C for 24 hours. Water (50ml) was added to the reaction solution, followed by extraction with ethyl acetate (50ml×2). The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25) to obtain 285 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.42-7.28 (5H, m), 5.79-5.75 (1H, m), 5.20-5.15 (4H, m), 5.03-4.98 (2H, m), 4.21- ( 1H, m).

MS (ESI) m/z: 330 (M+H) ⁺ .

[Reference Example 122]

{3-Benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-5-en-1-yl}methyl carboxylate

[Formula 214]

Under nitrogen atmosphere, the second generation Grubbs catalyst (29.6 mg, 0.871 mmol) was added to 1-benzyloxycarbonyl-3-(3-buten-1-yl)-4-methylenepyrrolidin-3- A solution of methyl formate (286mg, 0.871mmol) in dichloromethane (8.71ml). The mixture was stirred at room temperature for 19 hours and dichloromethane (17.4ml) was added. After stirring at 45°C for 6 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→87:13→85:15→83:17→80:20→75:25→66:34), 187 mg of the title compound were obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.72 (1H, d, J = 13.73Hz), 5.17-5.12 (2H, m), 4.20 (1H, dd, J = 10.79, 2.70Hz), 4.04-3.94 (2H, m), 3.68 (3H, d, J = 1.47Hz), 3.07 (1H, dd, J = 10.79, 7.11Hz), 2.95-2.87 (1H, m), 2.63-2.48 (2H, m), 1.88-1.83 (1H, m).

MS (ESI) m/z: 302 (M+H) ⁺ .

[Reference Example 123]

{3-Benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-5-en-1-yl}carboxylic acid

[Formula 215]

Under nitrogen atmosphere, 1N sodium hydroxide solution (1.86ml) was added to {3-benzyloxycarbonyl-3-azabicyclo[3.3.0]oct-5-en-1-yl}carboxylate (187mg , 0.620 mmol) in methanol (6.20 ml), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and then washed with ether (50ml×2). The aqueous layer was acidified with 1N hydrochloric acid under ice cooling, and then extracted with ethyl acetate (100ml×1, 80ml×1). The organic layer was washed with water (80ml) and brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 186 mg (quantitative) of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.30 (5H, m), 5.77 (1H, d, J = 17.16Hz), 5.21-5.10 (2H, m), 4.25 (1H, dd, J = 10.91, 5.02Hz), 4.02 (2H, t, J = 17.53Hz), 3.09 (1H, dd, J = 10.91, 7.72Hz), 2.93 (1H, brs), 2.60-2.54 (2H, m), 1.93- 1.83 (1H, m).

MS (ESI); m/z: 288 (M+H) ⁺ .

[Reference Example 124]

3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (optical isotropic Conform A, Optical Isomer B)

[Formula 216]

Under nitrogen atmosphere, triethylamine (0.181ml, 1.30mmol) and diphenoxyphosphoryl azide (0.181ml, 0.840mmol) were added to {3-benzyloxycarbonyl-3-azabicyclo[3.3. 0] In a solution of oct-5-en-1-yl}carboxylic acid (186mg, 0.647mmol) in toluene (3.23ml). The mixture was stirred at room temperature for 30 minutes, then at 100°C for 30 minutes. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of triethylamine and toluene (×3). 1,4-Dioxane (1.62 ml) and 6N hydrochloric acid (1.62 ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 1 hr. The reaction solution was distilled together with water (6.5 ml), and the organic layer was distilled off by concentrating under reduced pressure. The residue was washed with ether (20ml×2). The aqueous layer was basified with 1N sodium hydroxide solution under ice cooling, and extracted with chloroform (40ml×1, 30ml×1). The organic layer was washed with water (40ml) and brine (40ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (3.23ml) was added to the obtained residue, and di-tert-butyl dicarbonate (283mg, 1.30mmol) was added under nitrogen atmosphere. After stirring at room temperature for 17 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25) to obtain 120 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.31 (5H, m), 5.74 (1H, d, J=7.48Hz), 5.17-5.11 (2H, m), 4.58 (1H, s), 4.26 (1H, dd, J = 25.37, 11.40Hz), 4.02-4.01 (2H, m), 3.14 (1H, dd, J = 11.28, 8.82Hz), 2.80 (1H, brs), 2.55-2.52 (1H, m ), 2.37 (1H, brs), 1.94-1.91 (1H, m), 1.43 (9H, s).

The racemate 3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (108 mg, 0.301 mmol) obtained as described above was passed through the optical column Perform optical resolution (CHIRALCEL OJ, 20mm diameter × 250mm, hexane:isopropanol=90:10, flow rate=20ml/min, each resolution 20mg) to obtain 3-benzyloxycarbonyl-1-tert-butoxy Cylcarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (optical isomer A) (50.5mg, 1.41mmol, retention time = 8.0min) and its enantiomer 3-benzyloxycarbonyl -1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (optical isomer B) (55.6 mg, 0.155 mmol, retention time=11.5 min).

[Reference Example 125]

1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (derived from optical isomer A)

[Formula 217]

Under cooling with dry ice-acetone, 3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (optical isomer A) (50.5mg , 0.141mmol) into a solution of tetrahydrofuran (1.41ml) into ammonia gas, and 30-40ml of liquid ammonia was added to the solution. Under nitrogen atmosphere, sodium (17.0 mg, 0.709 mmol) was added and the mixture was stirred for 10 minutes. Saturated ammonium chloride solution (3 drops) was added at room temperature, and the mixture was stirred at room temperature to evaporate ammonia gas. 1N sodium hydroxide solution (12.0ml) was added, followed by extraction with chloroform (40ml×1, 20ml×1) and the lower layer of chloroform/methanol/water=7/3/1 (40ml×1, 20ml×1). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure to obtain 33 mg (quantitative) of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.58 (1H, brs), 4.62 (1H, brs), 3.47 (3H, tt, J=14.34, 9.68Hz), 2.96-2.87 (1H, m), 2.61 -2.57 (2H, m), 2.28-2.25 (1H, m), 1.85 (1H, dt, J=16.42, 6.62Hz), 1.45 (9H, s).

MS (ESI) m/z: 225 (M+H) ⁺ .

[Example 25]

7-[1-Amino-3-azabicyclo[3.3.0]oct-5-en-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct A)

[Formula 218]

Triethylamine (0.0595ml, 0.426mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-6,7-difluoro-1,4-dihydro- 8-Methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (51.2 mg, 0.142 mmol) was added to 1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0] Oct-5-ene (derived from optical isomer A) (33.0 mg, 0.135 mmol) in dimethyl sulfoxide (0.284 ml). The mixture was stirred at room temperature for 2 hours and at 40°C for 14 hours. A mixed solution of ethanol:water=4:1 (5ml) and triethylamine (0.5ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (15ml), water (15ml) and brine (15ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 61.4 mg of the obtained residue was dissolved in concentrated hydrochloric acid (1 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (15ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The basic solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform (80ml), chloroform/methanol=10/1 (80ml) and chloroform/methanol/water=7/3/1 (80ml×3) of the lower layer. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in hot ethanol (5ml) and 28% ammonia solution (1-2ml), and the insoluble matter was removed by filtration. The solvent was gradually evaporated under reduced pressure while heating and stirring. In addition, ammonia was azeotropically distilled (x 10) with ethanol (3-5 ml). Concentrate ethanol until crystals precipitate, then stir overnight at room temperature. Precipitated crystals were collected by filtration, washed with ethanol and diethyl ether, and then dried at 60°C under reduced pressure to obtain 9.65 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.40 (1H, d, J = 3.19Hz), 7.69 (1H, d, J = 14.46Hz), 5.62 (1H, s), 5.12-4.96 (1H, m), 4.50(1H, d, J=12.50Hz), 4.04-4.01(2H, m), 3.60(5H, dd, J=16.67, 9.31Hz), 2.91(1H, s), 2.62-2.59(1H , m), 2.15-2.07 (1H, m), 1.99-1.92 (1H, m), 1.58-1.54 (1H, m), 1.48-1.37 (1H, m).

Anal _. Calcd. for _{C21H21F2N3O4-1.5H2O} : C _{, 56.75} ; H, 5.44; N _, 99.45 _. Found: C, 56.53; H, 4.96; N, 9.01.

MS (ESI); m/z: 418 (M+H) ⁺ .

IR(ATR) v: 2935, 2852, 2755, 2657, 2572, 2103, 1716, 1614, 1569, 1531, 1498, 1463, 1455, 1361, 1324, 1116, 1043, 943, 919, 808 ^{cm -1} .

[Reference Example 126]

1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (derived from optical isomer B)

[Formula 219]

Under cooling with dry ice-acetone, 3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene (optical isomer B) (54.7mg , 0.153mmol) in tetrahydrofuran (1.53ml) solution was passed into ammonia gas, and 30-40ml liquid ammonia was added to the solution. Under nitrogen atmosphere, sodium (18.4 mg, 0.767 mmol) was added and the mixture was stirred for 10 minutes. Saturated ammonium chloride solution (10 drops) was added at room temperature, and the mixture was stirred at room temperature to evaporate ammonia gas. 1N Sodium hydroxide solution (3-4ml) was added, and the resulting mixture was concentrated under reduced pressure. Chloroform/methanol = 10/1 (10-20 ml) was added. After sonication, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to obtain 150 mg of a residue containing the title compound, which was directly used in the next reaction.

MS (ESI) m/z: 225 (M+H) ⁺ .

[Example 26]

7-[1-Amino-3-azabicyclo[3.3.0]oct-5-en-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct B)

[Formula 220]

Triethylamine (0.0641ml, 0.460mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4 -Oxoquinoline- ₃ -carboxylic acid-BF chelate (58.0mg, 0.161mmol) was added to 1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]oct-5-ene ( A solution of the residue derived from optical isomer B) (150mg, 0.153mmol) in dimethylsulfoxide (0.306ml). The mixture was stirred at room temperature for 1.5 hours. Dimethylsulfoxide (0.306ml) and triethylamine (0.0641ml, 0.460mmol) were added, and the resulting mixture was stirred at 40°C for 1 day. 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-formic acid-BF ₂ Chelate (174mg, 0.483mmol) was added to the reaction solution, and the resulting mixture was stirred at 40°C for 15 hours. A mixed solution of ethanol:water=4:1 (5ml) and triethylamine (0.5ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (20ml), water (20ml) and brine (20ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 194 mg of the obtained residue was dissolved in concentrated hydrochloric acid (1 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (30ml×5), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform (80ml), chloroform/methanol=10/1 (80ml) and chloroform/methanol/water=7/3/1 (50ml) of the lower layer. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by PTLC (chloroform/methanol/water in the lower layer=7/3/1). Chloroform/methanol (10/1) was added to the obtained residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. Ethanol (1 ml) was added to the obtained residue, and the mixture was stirred at room temperature overnight. Diethyl ether (2 ml) was added, and the precipitated crystals were collected by filtration, washed with ethanol and diethyl ether, and then dried at 50°C under reduced pressure to obtain 2.38 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.50 (1H, s), 7.70 (1H, d, J=14.46Hz), 5.62 (1H, s), 5.05-4.90 (1H, m), 4.65- 4.59(1H, m), 4.11(1H, s), 3.93(1H, d, J=14.95Hz), 3.70(1H, d, J=10.05Hz), 3.62(3H, s), 3.53(1H, d , J=10.79Hz), 3.00-2.82 (1H, m), 2.67-2.56 (1H, m), 2.15-2.12 (1H, m), 2.00-1.95 (1H, m), 1.72-1.58 (2H, m ).

MS (ESI); m/z: 418 (M+H) ⁺ .

[Reference Example 127]

6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.0 ^{1, 3} ] Nonane (derived from Optical isomer A)

[Formula 221]

The dichloromethane (3.52ml) solution was cooled with ice-acetone. Under nitrogen atmosphere, 1.0M diethylzinc n-hexane solution (0.88ml, 0.88mmol) and diiodomethane (0.071ml, 0.881mmol) were added slowly, and the mixture was stirred under cooling for 20 minutes. Under cooling, 3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.2.0]oct-5-ene (optical isomer A) (126 mg, 0.352 mmol) was added slowly dichloromethane (3.52ml), and the mixture was stirred at room temperature for 24 hours. Under cooling with ice-acetone, saturated aqueous sodium bicarbonate solution (10 ml) and 10% sodium thiosulfate solution (10 ml) were added, and the resulting mixture was stirred until vermilion disappeared. The organic layer was extracted with chloroform (50ml×1, 40ml×1). The organic layer was washed with brine (80ml), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. Under a nitrogen atmosphere, acetonitrile (7.04 ml) and di-tert-butyl dicarbonate (384 mg, 1.76 mmol) were sequentially added to 212 mg of the obtained residue. After stirring at room temperature for 19 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25) to obtain 95.2 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.31 (5H, m), 5.17-5.11 (2H, m), 4.93 (1H, brs), 4.21-4.11 (1H, m), 3.75 (1H, dd, J=10.91, 6.74Hz), 3.32-3.12 (2H, m), 2.47-2.31 (1H, m), 1.97-1.88 (1H, m), 1.81-1.78 (1H, m), 1.43 (9H, s), 1.35-1.31 (1H, m), 1.19-1.16 (1H, m), 0.82-0.76 (2H, m).

MS (ESI); m/z: 395 (M+Na) ⁺ .

[Reference Example 128]

6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.0 ^{1, 3} ] Nonane (derived from Optical isomer B)

[Formula 222]

The dichloromethane (4.18ml) solution was cooled with ice-acetone. Under nitrogen atmosphere, 1.0M diethylzinc n-hexane solution (1.05ml, 1.05mmol) and diiodomethane (0.0842ml, 1.05mmol) were added slowly, and the mixture was stirred under cooling for 20 minutes. Under cooling, 3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-3-azabicyclo[3.2.0]oct-5-ene (optical isomer B) (150 mg, 0.418 mmol) was added slowly dichloromethane (4.18ml), and the mixture was stirred at room temperature for 22 hours. Under cooling with ice-acetone, saturated aqueous sodium bicarbonate solution (10 ml) and 10% sodium thiosulfate solution (10 ml) were added, and the resulting mixture was stirred until vermilion disappeared. The organic layer was extracted with chloroform (60ml×1, 50ml×1). The organic layer was washed with brine (60ml), dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. Under a nitrogen atmosphere, acetonitrile (8.36 ml) and di-tert-butyl dicarbonate (274 mg, 1.25 mmol) were sequentially added to 256 mg of the obtained residue. After stirring at room temperature for 13 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25) to obtain 113 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.29 (5H, m), 5.13 (2H, t, J=6.74Hz), 4.93 (1H, d, J=16.18Hz), 4.23-4.09 (1H , m), 3.75 (1H, dd, J=11.03, 6.62Hz), 3.27-3.19 (2H, m), 2.43 (1H, brs), 1.98-1.88 (1H, m), 1.82-1.74 (2H, m ), 1.43 (9H, s), 1.37-1.22 (1H, m), 1.22-1.14 (1H, m), 0.81-0.77 (2H, m).

MS (ESI); m/z: 395 (M+Na) ⁺ .

[Reference Example 129]

6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^{1, 3} ] Nonane (derived from optical isomer A)

[Formula 223]

Under a nitrogen atmosphere, 10% palladium-carbon catalyst (47.6 mg, 50 wt %) was added to 6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.0 ^1,3 ] nonane (derived from optical isomer A) (95.2 mg, 0.255 mmol) in methanol (2.55 ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at room temperature for 1 hour. 10% palladium-carbon catalyst (28.6mg, 30wt%) was added. After replacing the original atmosphere with hydrogen, the mixture was stirred at room temperature for 1 hour. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 56.0 mg of the title compound as a black oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.98 (1H, brs), 3.63 (1H, s), 3.46-3.44 (1H, m), 2.92 (2H, dd, J=30.52, 11.15Hz), 2.37 (1H, brs), 2.00-1.96 (1H, m), 1.76-1.70 (1H, m), 1.44 (9H, s), 1.35-1.25 (1H, m), 1.21-1.15 (1H, m), 0.86 -0.69 (2H, m).

MS (ESI); m/z: 239 (M+H) ⁺ .

[Example 27]

7-[6-Amino-8-azatricyclo[4.3.0.0 ^{1, 3} ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct A)

[Formula 224]

Triethylamine (0.0984ml, 0.705mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4 -Oxoquinoline- ₃ -carboxylic acid-BF chelate (89.1 mg, 0.247 mmol) was added to 6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^1,3 ]nonane ( Derived from optical isomer A) 56.0 mg (0.235 mmol) in dimethyl sulfoxide (0.470 ml) solution. The resulting mixture was stirred at 35°C for 19 hours. A mixed solution of ethanol:water=4:1 (5.0ml) and triethylamine (0.5ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35ml) and washed with 10% citric acid solution (25ml), water (25ml) and brine (25ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1). Under ice-cooling, 80.5 mg of the obtained residue was dissolved in concentrated hydrochloric acid (1 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (30ml×4), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (60ml×2) and chloroform/methanol=10/1 (60ml×3). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (chloroform/methanol/water in the lower layer=7/3/1). The obtained residue was dissolved in chloroform/methanol = 10/1 (10 ml). Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in hot ethanol (20-30 ml), then concentrated and dried under reduced pressure. Ethanol (0.5 ml) and diethyl ether (5 ml) were added to the resulting residue, and the resulting mixture was sonicated and cooled with ice. Then, the precipitated crystals were collected by filtration and washed with diethyl ether. The crystals were dried under reduced pressure at 45°C to obtain 21.0 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.38 (1H, d, J = 2.94Hz), 7.67 (1H, d, J = 14.22Hz), 5.12-4.96 (1H, m), 4.32-4.29 ( 1H, m), 4.04-3.99(1H, m), 3.80(1H, d, J=10.30Hz), 3.61(3H, s), 3.44(1H, d, J=10.54Hz), 3.31(1H, d , J=10.30Hz), 2.02-1.89 (2H, m), 1.77 (1H, dd, J=12.62, 8.46Hz), 1.58-1.24 (4H, m), 0.82 (2H, dt, J=23.78, 5.82 Hz).

Anal _. Calcd. _{for C22H23F2N3O4 :} C, 57.64; H, 5.72; _F , _8.29 ; N, 9.17. Found: C, 57.70; H, 5.77; F, 8.57; N, 9.09.

MS (ESI); m/z: 432 (M+H) ⁺ .

IR (ATR) v: 2935, 2869, 1725, 1616, 1432, 1363, 1319, 1182, 1137, 1045, 943, 923, 806 ^{cm -1} .

[Reference Example 130]

6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^{1, 3} ] Nonane (derived from optical isomer B)

[Formula 225]

Under a nitrogen atmosphere, 10% palladium-carbon catalyst (27.7 mg, 30 wt %) was added to 6-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azatricyclo[4.3.0.0 ^1,3 ] nonane (derived from optical isomer B) (92.3mg, 0.248mmol) in methanol (2.48ml). The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. 10% palladium-carbon catalyst (18.5mg, 20wt%) was added, and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2.5 hours. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 64.4 mg of a residue containing the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.87 (1H, brs), 3.50 (1H, brs), 3.29 (1H, d, J=11.03Hz), 3.14-3.12 (1H, m), 2.76 (2H , dd, J=19.12, 11.28Hz), 2.47-1.66 (3H, m), 1.43 (9H, s), 1.32 (1H, dd, J=24.14, 10.17Hz), 1.08-1.04 (1H, m), 0.82-0.67 (2H, m).

MS (ESI); m/z: 239 (M+H) ⁺ .

[Example 28]

7-[6-Amino-8-azatricyclo[4.3.0.0 ^{1, 3} ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct B)

[Formula 224]

Triethylamine (0.104ml, 0.745mmol) and 1-[(1R,2S)-2-fluorocyclopropan-1-yl]-6,7-difluoro-8-methoxy-1,4-di Hydrogen-4-oxoquinoline- ₃ -carboxylic acid-BF chelate (89.5 mg, 0.248 mmol) was added to 64.4 mg of 6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^{1 ,3} ] A solution of the residue of nonane (0.248 mmol equivalent) in dimethyl sulfoxide (0.496 ml) was stirred at 35°C for 17 hours. A mixed solution of ethanol:water=4:1 (5.0ml) and triethylamine (0.5ml) was added to the reaction solution, and the mixture was heated under reflux for 1.5 hrs. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35ml) and washed with 10% citric acid solution (25ml), water (25ml) and brine (25ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1). Under ice-cooling, 75.5 mg of the obtained residue was dissolved in concentrated hydrochloric acid (1 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (30ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (80ml×1, 70ml×1, 50ml×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot ethanol (10 ml), and the insoluble material was removed by filtration. The solvent was gradually evaporated under reduced pressure while heating and stirring. The solution was then concentrated until about 0.5 mL of ethanol and then returned to room temperature. Diethyl ether (5 ml) was added, and the mixture was ice-cooled. Then, the precipitated crystals were collected by filtration and washed with diethyl ether. The crystals were dried under reduced pressure at 50°C to obtain 25.9 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.50 (1H, s), 7.67 (1H, d, J = 14.71Hz), 4.99-4.93 (1H, m), 4.39 (1H, dd, J = 10.30 , 3.43Hz), 4.09 (1H, q, J = 6.21Hz), 3.87 (1H, dd, J = 10.54, 2.94Hz), 3.63 (3H, s), 3.37 (1H, d, J = 10.54Hz), 3.23 (1H, d, J = 10.30Hz), 2.01-1.95 (2H, m), 1.79-1.58 (3H, m), 1.34-1.17 (2H, m), 0.82 (2H, dt, J = 22.22, 5.94 Hz).

_{Anal .} Calcd. for _{C22H23F2N3O4-0.5H2O} : C, _59.99 ; H, 5.49; _F , 8.63; _N , 9.54. Found: C, 60.28; H, 5.34; F, 8.57; N, 9.52.

MS (ESI); m/z: 432 (M+H) ⁺ .

IR (ATR) v: 2937, 2863, 1716, 1616, 1508, 1434, 1321, 1187, 1120, 1054, 939, 889, 804 ^{cm -1} .

[Reference Example 131]

[(1R ^* , 6R ^* )-8-Benzyl-8-azabicyclo[4.3.0]nonan-1-yl]methyl carboxylate

[Formula 227]

A catalytic amount of trifluoroacetic acid was added to methyl 1-cyclohexene-1-carboxylate (25.0 g, 178 mmol) and N-benzyl-N-(methoxymethyl)-N-trimethyl Silylmethylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 ml) was added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (200ml) was added to the reaction solution, followed by extraction with chloroform (150ml x 1, 100ml x 1). The organic layer was washed with brine (450ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→85:15→75:25) to obtain 21.3 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.24 (5H, m), 3.70-3.65 (5H, m), 2.92 (1H, d, J=9.31Hz), 2.73-2.68 (3H, m) , 1.93 (1H, td, J=9.01, 4.82Hz), 1.79-1.65 (2H, m), 1.53-1.21 (6H, m).

MS (ESI); m/z: 274 (M+H) ⁺ .

[Reference Example 132]

[(1R ^* , 6R ^* )-8-Benzyloxycarbonyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid methyl ester

[Formula 228]

Benzyl chloroformate (33.4ml, 234mmol) was added to [(1R ^* ,6R ^* )-8-benzyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid under nitrogen atmosphere A solution of the methyl ester (21.3 g, 77.9 mmol) in dichloromethane (259 ml) was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure. Then, the residue (58.0 g) was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25) to obtain 17.5 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.13 (2H, m), 3.71 (3H, d, J=3.19Hz), 3.63 (1H, dd, J=10.91, 8.21Hz), 3.52-3.28(3H, m), 2.72-2.64(1H, m), 1.93(1H, m), 1.75(1H, dq, J=20.41, 5.23Hz), 1.63-1.38(6H, m ).

MS (ESI); m/z: 318 (M+H) ⁺ .

[Reference Example 133]

[(1R ^* , 6R ^* )-8-benzyloxycarbonyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid

[Formula 229]

Under a nitrogen atmosphere, 1mol/L sodium hydroxide solution (70.8ml) and tetrahydrofuran (78.8ml) were added to [(1R ^* , 6R ^* )-8-benzyloxycarbonyl-8-azabicyclo[4.3.0 ]nonan-1-yl]methylformate (7.50g, 23.6mmol) in methanol (78.8ml) and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and then washed with ether (50ml×2). The aqueous layer was acidified with 3mol/L hydrochloric acid (28ml) under ice cooling, and then extracted with ethyl acetate (100ml×2). The organic layer was washed with brine (250ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 6.70 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5, m), 5.13 (2H, m), 3.70 (1H, dd, J=10.91, 4.78Hz), 3.51 (2H, m), 3.40 -3.30(1H,m), 2.68(1H,m), 2.00-1.96(1H,m), 1.78-1.76(1H,m), 1.65-1.60(1H,m), 1.51-1.45(5H,m) .

MS (ESI); m/z: 304 (M+H) ⁺ .

[Reference Example 134]

(1R ^* , 6S ^* )-8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane

[Formula 230]

Under nitrogen atmosphere, triethylamine (6.17ml, 44.2mmol) and diphenoxyphosphoryl azide (6.19ml, 28.7mmol) were added to [(1R ^* ,6R ^* )-8-benzyloxycarbonyl- 8-Azabicyclo[4.3.0]nonan-1-yl]carboxylic acid (6.70 g, 22.1 mmol) in toluene (110 ml) was stirred while cooling under ice. The mixture was stirred at room temperature for 40 minutes and at 90°C for 1 hour. The reaction solution was diluted with ethyl acetate (150ml) at room temperature, washed with saturated sodium bicarbonate solution (200ml), water (200ml) and brine (200ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 1,4-Dioxane (55.0 ml) and 6 mol/L hydrochloric acid (55.0 ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 2 hours. The reaction solution was co-distilled with water (55.0 ml) and concentrated under reduced pressure. Then, the residue was azeotropically dried with ethanol (x5). Dichloromethane (110ml) was added to the precipitated white solid (7.41g). Under nitrogen atmosphere, triethylamine (15.4ml, 110mmol) and di-tert-butoxycarbonyl (9.65g, 44.2mol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate (150 ml) was added. The mixture was washed with water (200ml) and brine (200ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→83:17→66:34) to obtain 6.65 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.29 (5H, m), 5.13 (2H, s), 4.55 (1H, d, J=13.97Hz), 3.69 (1H, d, J=11.28Hz ), 3.58-3.45 (2H, m), 3.30 (1H, ddd, J=21.33, 10.66, 6.74Hz), 2.03-1.99 (1H, m), 1.66-1.43 (17H, m).

MS (ESI); m/z: 374 (M+H) ⁺ .

[Reference Example 135]

(1R,6S)-/(1S,6R)-8-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0] Nonane (optical isomer A, optical isomer B)

[Formula 231]

Racemate (1R ^* , 6S ^* )-8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (6.65g, 17.8mmol) passed through the optical column Perform optical resolution (CHIRALPAK AD, 20mm diameter × 250mm, hexane:isopropanol=95:5, flow rate=20ml/min), to obtain the optically active 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino- 8-Azabicyclo[4.3.0]nonane (optical isomer A) (427mg, 1.14mmol, retention time = 14.2min) and its optical enantiomer 8-benzyloxycarbonyl-1-tert-butoxy Carbonylamino-8-azabicyclo[4.3.0]nonane (optical isomer B) (415 mg, 1.11 mmol, retention time = 19.4 min).

[Reference Example 136]

1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (derived from optical isomer A)

[Formula 232]

Under nitrogen atmosphere, 10% palladium-carbon catalyst (80.0 mg, 20 wt%) was added to 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane ( Optical isomer A) (400 mg, 1.07 mmol) in methanol (10.7 ml). After replacing the original atmosphere with hydrogen, the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain the title compound (quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.61 (1H, brs), 3.18-3.12 (2H, m), 3.02 (1H, d, J = 11.28Hz), 2.81 (1H, dd, J = 10.66, 6.74Hz), 2.16 (1H, brs), 2.01 (1H, brs), 1.57-1.43 (8H, m), 1.43 (9H, s).

MS (ESI); m/z: 241 (M+H) ⁺ .

[Example 29]

7-[1-Amino-8-azabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane-1- Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct A)

[Formula 233]

Triethylamine (0.407ml, 2.92mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methoxy Base-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (351 mg, 0.972 mmol) was added to 1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (derived from Optical isomer A) (277mg, 1.07mmol) was dissolved in dimethylsulfoxide (1.94ml), and the resulting mixture was stirred at 35°C for 17 hours. A mixed solution of ethanol:water=4:1 (20ml) and triethylamine (2ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (40ml) and washed with 10% citric acid solution (50ml), water (50ml) and brine (50ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 456 mg of the obtained residue was dissolved in concentrated hydrochloric acid (3.0 ml), and the resulting solution was stirred at room temperature for 15 minutes. The reaction solution was adjusted to pH 13.6 with saturated sodium hydroxide solution, and the alkaline solution was adjusted to pH 7.4 with hydrochloric acid, then chloroform (100ml), chloroform/methanol=10/1 (150ml×1, 100ml×2) and the lower layer Chloroform/methanol/water=7/3/1 (150ml) extraction. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot ethanol (67.5 ml), and the insoluble matter was removed by filtration. The solvent was gradually evaporated while heating and stirring. The solution was concentrated until ethanol was 10 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration, and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C to obtain 271 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.42 (1H, d, J = 1.96Hz), 7.65 (1H, d, J = 14.71Hz), 4.97 (1H, dt, J = 49.76, 17.89Hz) , 4.05-4.00(1H, m), 3.84(1H, t, J=7.48Hz), 3.71(1H, d, J=10.30Hz), 3.60(4H, t, J=12.01Hz), 3.36(1H, d, J=8.33Hz), 2.01 (1H, m), 1.77 (2H, m), 1.60-1.41 (8H, m).

Anal _. Calcd. for _{C22H25F2N3O4-0.5H2O} : C, _59.72 ; H, 5.92; _F , 8.59; _{N ,} 9.50. Found: C, 59.91; H, 5.97; F, 8.68; N, 9.39.

MS (ESI); m/z: 434 (M+H) ⁺ .

IR (ATR) v: 2927, 2856, 1724, 1616, 1508, 1430, 1324, 1268, 1186, 1120, 1049, 925, 877, 806 ^{cm -1} .

[Reference Example 137]

1-tert-butoxycarbonylamino-3-azabicyclo[4.3.0]nonane (derived from optical isomer B)

[Formula 234]

Under nitrogen atmosphere, 10% palladium-carbon catalyst (83.0 mg, 20 wt%) was added to 8-benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane ( Optical isomer B) (415 mg, 1.11 mmol) in methanol (11.1 ml). After replacing the original atmosphere with hydrogen, the mixture was stirred under hydrogen atmosphere at room temperature for 1 hour. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain the title compound (quantitative).

¹ H-NMR (CDCl ₃ ) δ: 4.60 (1H, brs), 3.17-3.12 (2H, m), 3.02 (1H, d, J=11.52Hz), 2.81 (1H, brs), 2.15 (1H, brs ), 2.00 (1H, s), 1.63-1.36 (8H, m), 1.43 (9H, s).

MS (ESI); m/z: 241 (M+H) ⁺ .

[Example 30]

7-[1-Amino-8-azabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane-1- Base]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (7-position substituent: derived from Construct B)

[Formula 235]

Triethylamine (0.422ml, 3.03mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methoxy Base-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (364 mg, 1.01 mmol) was added to 1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (derived from Optical isomer B) (273 mg, 1.11 mmol) was dissolved in dimethyl sulfoxide (1.94 ml), and the resulting mixture was stirred at 35°C for 17 hours. A mixed solution of ethanol:water=4:1 (20ml) and triethylamine (2ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (40ml) and washed with 10% citric acid solution (50ml), water (50ml) and brine (50ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 536 mg of the obtained residue was dissolved in concentrated hydrochloric acid (3.0 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (20ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7 with hydrochloric acid, and then extracted with chloroform/methanol=10/1 (150ml×1, 100ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot ethanol (67.5 ml), and the insoluble matter was removed by filtration. The solvent was gradually evaporated while heating and stirring. The solution was concentrated until ethanol was 10 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C to obtain 315 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.45 (1H, d, J = 1.47Hz), 7.64 (1H, d, J = 14.95Hz), 5.04-4.84 (1H, m), 4.06-3.99 ( 2H, m), 3.88 (1H, dd, J = 10.54, 2.21Hz), 3.57 (3H, s), 3.42 (1H, d, J = 10.54Hz), 3.20 (1H, d, J = 8.82Hz), 1.94 (1H, m), 1.83 (1H, m), 1.73 (1H, m), 1.67-1.46 (6H, m), 1.33 (2H, m).

_{Anal .} Calcd. for _{C22H25F2N3O4-0.75H2O} : C _{, 59.12} ; H, 5.98; F, 8.50; _N , 9.40. Found: C, 59.05; H, 6.12; F, 8.36; N, 9.20.

MS (ESI); m/z: 434 (M+H) ⁺ .

IR (ATR) v: 2927, 2859, 1724, 1616, 1573, 1509, 1432, 1369, 1355, 1319, 1267, 1118, 1049, 933, 879, 804 cm ^-1 .

[Reference Example 138]

(3S,4R)-3,4-Diallyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 236]

Under salt ice cooling, allyl bromide (1.36ml, 16.1mmol) was added to (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine - tert-butyl-3-carboxylate (4.05g, 12.3mmol) in tetrahydrofuran (41.0ml) and stirred. Under salt-ice cooling, a 1M tetrahydrofuran solution of lithium hexamethyldisilazide (16.0 ml, 16.0 mmol) was added dropwise and stirred, and the resulting mixture was stirred under salt-ice cooling for 15 minutes. Saturated ammonium chloride solution (40ml) and water (20ml) were added to the reaction solution, followed by extraction with ethyl acetate (40ml×1, 20ml×1). The organic layer was washed with brine (140ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→89:11→88:12→87:13→83:17→80:20→75:25), 2.02 g of the title compound were obtained.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32 (5H, m), 5.77-5.62 (2H, m), 5.48 (1H, q, J=7.11Hz), 5.13 (2H, dd, J=13.36, 11.89Hz), 5.02(1H, t, J=9.07Hz), 4.91(1H, dd, J=5.52, 2.76Hz), 3.21(1H, d, J=10.54Hz), 3.09(1H, d, J= 10.79Hz), 2.56(1H, dd, J=14.34, 6.01Hz), 2.40(3H, d, J=4.41Hz), 2.27(1H, dd, J=13.73, 8.33Hz), 1.50(3H, d, J = 7.11 Hz), 1.40 (9H, s).

MS (ESI); m/z: 370 (M+H) ⁺ .

[Reference Example 139]

[(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]methanol tert-butyl acid

[Formula 237]

Under nitrogen atmosphere, the second generation Grubbs catalyst (91.9 mg, 0.108 mmol) was added to (3S,4R)-3,4-diallyl-5-oxo-1-[(1R)-1-benzene Ethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.00 g, 5.41 mmol) in dichloromethane (54.1 ml) and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→75:25→66:34→50:50) to obtain 1.61 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.21 (5H, m), 5.75 (1H, m), 5.67-5.62 (1H, m), 5.49 (1H, q, J=7.19Hz), 3.22 (2H, dd, J = 13.97, 10.05Hz), 2.74 (1H, dd, J = 16.42, 5.15Hz), 2.62-2.54 (1H, m), 2.49 (1H, d, J = 5.39Hz), 2.42 ( 1H, m), 2.15-2.08 (1H, m), 1.48 (3H, d, J = 7.11 Hz), 1.18 (9H, s).

MS (ESI); m/z: 342 (M+H) ⁺ .

[Reference Example 140]

[(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]methanol acid

[Formula 238]

Under ice cooling, trifluoroacetic acid (18.0ml) was added to [(1S,6R)-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0 ]non-3-en-1-yl]formic acid tert-butyl ester (2.04g, 5.99mmol) in dichloromethane (18.0ml) and stirred, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (×3). Under ice-cooling, 1 mol/L sodium hydroxide solution (15.0 ml) was added to the obtained residue, and the obtained mixture was washed with diethyl ether (40 ml×2). The aqueous layer was acidified with 1 mol/L hydrochloric acid (20 ml) under ice cooling. Then, the precipitated crystals were collected by filtration and washed with 0.5 mol/L hydrochloric acid, ethyl acetate and ether. The obtained crystals were dried under reduced pressure at 50°C overnight to obtain 1.40 g of the title compound as white crystals. The aqueous layer of the filtrate was extracted with ethyl acetate (50ml). The organic layers were combined, washed with water (150ml) and brine (150ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 250 mg of the title compound as white crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.23 (5H, m), 5.81 (1H, m), 5.69 (1H, m), 5.51 (1H, q, J=7.11Hz), 3.27 (1H, d , J=10.05Hz), 3.18(1H, d, J=10.05Hz), 2.74(1H, dd, J=16.67, 4.90Hz), 2.59(1H, m), 2.47(1H, m), 2.22(1H , d, J = 16.67 Hz), 2.14 (1H, brs), 1.49 (3H, d, J = 7.11 Hz).

MS (ESI); m/z: 286 (M+H) ⁺ .

[Reference Example 141]

(1S,6R)-1-Amino-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene

[Formula 239]

Under nitrogen atmosphere, triethylamine (1.61ml, 11.5mmol) and diphenoxyphosphoryl azide (1.62ml, 7.52mmol) were added to [(1S,6R)-7-oxo- 8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-en-1-yl]carboxylic acid (1.65g, 5.78mmol) in toluene (28.9ml) With stirring, the resulting mixture was stirred at 100°C for 30 minutes. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of triethylamine and toluene (×3). 1,4-Dioxane (14.4ml) and 4mol/L hydrochloric acid (14.4ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 6 hours. The reaction solution was diluted with water (30.0 ml) and washed with ethyl acetate (50 ml×2). A 1mol/L sodium hydroxide solution (55.0ml) was added to the aqueous layer, followed by extraction with chloroform (100ml×1, 80ml×1). The organic layer was washed with brine (150ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.24 g of the title compound as an amorphous substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.23 (5H, m), 5.81-5.77 (1H, m), 5.67-5.62 (1H, m), 5.53 (1H, q, J=7.11Hz) , 3.70(2H, s), 3.23(1H, d, J=9.80Hz), 2.96(1H, d, J=9.80Hz), 2.45(2H, m), 2.33(1H, m), 2.27-2.16( 1H, m), 2.10 (1H, dd, J = 16.79, 5.02 Hz), 1.50 (3H, d, J = 7.11 Hz).

MS (ESI); m/z: 257 (M+H) ⁺ .

[Reference Example 142]

(1S,6S)-1-amino-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene

[Formula 240]

65% sodium bis(2-methoxyethoxy)aluminum hydride in toluene (2.87ml, 9.56mmol) was added to (1S,6R)-1-amino-7-oxo-8-[(1R) - In a solution of 1-phenylethyl]-8-azabicyclo[4.3.0]non-3-ene (612mg, 2.39mmol) in toluene (11.9ml), the resulting mixture was stirred at 80°C for 1 hour. Under ice cooling, 5 mol/L sodium hydroxide solution (15.0 ml) was added to the reaction solution and stirred, and extracted with toluene (30 ml×2). The organic layer was washed with brine (90ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 450 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.19 (5H, m), 5.72-5.59 (2H, m), 3.58 (1H, q, J=6.54Hz), 2.86 (1H, d, J= 9.07Hz), 2.70 (1H, dd, J = 9.56, 8.09Hz), 2.54-2.48 (2H, m), 2.22-1.73 (5H, m), 1.33 (3H, d, J = 6.62Hz).

MS (ESI); m/z: 243 (M+H) ⁺ .

[Reference Example 143]

(1S, 6S)-1-tert-butoxycarbonylamino-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonyl -3-ene

[Formula 241]

Under nitrogen atmosphere, di-tert-butyl dicarbonate (689 mg, 3.16 mmol) was added to (1S,6S)-1-amino-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] In a solution of non-3-ene (450 mg, 1.86 mmol) in dichloromethane (9.3 ml), the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→66:34→50:50→25:75→16:84) to obtain 456 mg of the title compound .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.29-7.18 (5H, m), 5.69-5.59 (2H, m), 4.43 (1H, s), 3.62 (1H, q, J=6.54Hz), 3.53 (1H, d, J = 10.54Hz), 3.04 (1H, dd, J = 8.95, 7.23Hz), 2.89 (1H, d, J = 18.38Hz), 2.60 (1H, d, J = 11.03Hz), 2.52 (1H, dd, J = 11.28, 9.31 Hz), 2.26-2.08 (2H, m), 1.99-1.83 (2H, m), 1.44 (9H, s), 1.32 (3H, d, J = 6.62 Hz).

MS (ESI); m/z: 343 (M+H) ⁺ .

[Reference Example 144]

(1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane

[Formula 242]

Under nitrogen atmosphere, 10% palladium-carbon catalyst (406mg, 100wt%) was added to (1S,6S)-1-tert-butoxycarbonylamino-8-[(1R)-1-phenylethyl]- 8-Azabicyclo[4.3.0]non-3-ene (406mg, 1.18mmol) in ethanol (11.8ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at 40°C-50°C for 7 hours under hydrogen atmosphere. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain the title compound (quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.24 (1H, brs), 3.59 (1H, brs), 3.01 (1H, dd, J=9.80, 7.60Hz), 2.67-2.62 (2H, m), 2.52 (1H, d, J = 11.28Hz), 1.79-1.53 (9H, m), 1.44 (9H, s).

MS (ESI); m/z: 241 (M+H) ⁺ .

[Example 31]

7-[(1S, 6S)-1-amino-8-azabicyclo[4.3.0]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclo Propyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 243]

Triethylamine (0.449ml, 3.22mmol) and 1-[(1R,2S)-2-fluorocyclopropan-1-yl]-6,7-difluoro-1,4-dihydro-8-methoxy Base-4-oxoquinoline- ₃ -carboxylic acid-BF chelate (387 mg, 1.07 mmol) was added to (1S, 6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0 ] nonane (301 mg, 1.18 mmol) in dimethyl sulfoxide (2.14 ml), and the resulting mixture was stirred at 35°C for 15 hours. A mixed solution of ethanol:water=4:1 (20ml) and triethylamine (2ml) was added to the reaction solution, and the mixture was heated under reflux for 1.5 hrs. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (40ml), water (40ml) and brine (40ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 506 mg of the obtained residue was dissolved in concentrated hydrochloric acid (3.0 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (20ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (150ml) and chloroform/methanol = 10/1 (100ml x 2). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot ethanol (45 ml), and the insoluble matter was removed by filtration. The solvent was gradually evaporated while heating and stirring. The solution was concentrated until ethanol was 10 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration, and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C-60°C to obtain 126 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.35 (1H, d, J = 3.92Hz), 7.65 (1H, d, J = 14.71Hz), 5.15-4.96 (1H, m), 3.99 (1H, dt, J=10.21, 4.47Hz), 3.62(3H, m), 3.54(3H, s), 3.44(1H, t, J=8.46Hz), 3.27(1H, d, J=9.56Hz), 1.87- 1.28 (11H, m).

_{Anal .} Calcd. for _{C22H25F2N3O4-0.25H2O} : C _{, 60.33} ; H, 5.87; F, 8.68; _N , 9.59. Found: C, 60.27; H, 5.84; F, 8.60; N, 9.58.

MS (ESI); m/z: 434 (M+H) ⁺ .

IR (ATR) v: 2929, 2859, 1722, 1617, 1508, 1432, 1363, 1319, 1045, 925, 804 cm ^-1 .

[Example 32]

7-[(1S,6S)-1-amino-8-azabicyclo[4.3.0]nonan-8-yl]-8-cyano-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 244]

Under nitrogen atmosphere, triethylamine (478 μl, 3.42 mmol) and 8-cyano-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1, 4-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (384 mg, 1.14 mmol) was added to (1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0] Nonane (302mg, 1.26mmol) in acetonitrile (2.28ml). The mixture was stirred at room temperature for 1 hour and at 45°C for 1 hour. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50→40:60→30:70) to obtain a pale yellow amorphous substance. Under ice-cooling, 1 mol/L sodium hydroxide solution (4.64 ml) was added to a solution of 644 mg of the amorphous substance in ethanol (5.80 ml), and the mixture was stirred at room temperature for 1 hr. Then, tetrahydrofuran (8.70 ml) was added, and the mixture was stirred at room temperature for 1 hr. A 10% citric acid solution (15 ml) was added to the reaction solution, followed by extraction with ethyl acetate (50 ml×1, 40 ml×1). The organic layer was washed with brine (80ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 554 mg of the obtained residue was dissolved in concentrated hydrochloric acid (2 ml), and the resulting solution was stirred at room temperature for 10 minutes. The solution was washed with chloroform (25ml x 2). The reaction solution was adjusted to pH 12.5 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with the lower layer of chloroform/methanol/water=7/3/1 (200ml×3). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Hot ethanol (80ml) and 28% ammonia water (5ml) were added to the residue, and the insoluble matter was removed by filtration. The solvent was gradually evaporated while heating and stirring. Ammonia was removed azeotropically several times with ethanol. The solution was concentrated to about 20 ml, then stirred at room temperature. Precipitated crystals were collected by filtration, and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C overnight to obtain 341 mg of the title compound as pale yellow crystals.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.29 (1H, d, J = 3.92Hz), 7.85 (1H, d, J = 15.44Hz), 5.18 (1H, ddd, J = 66.61, 6.92, 4.47 Hz), 4.01-3.88 (3H, m), 3.70-3.65 (1H, m), 3.46 (1H, t, J=5.27Hz), 1.95-1.32 (11H, m).

_Anal . Calcd. for _C22H22F2N4O3 · _1.25H2O · 0.25EtOH _{: C} , 58.91; _H , 5.71; F, 8.28; N, 12.21. Found: C, 58.71; H, 5.66; N, 11.96.

MS (ESI); m/z: 429 (M+H) ⁺ .

IR (ATR) v: 3623, 2938, 2886, 2202, 1641, 1610, 1556, 1535, 1515, 1490, 1461, 1353, 1342, 1301, ^{1261 cm -1} .

[Example 33]

7-[(1S, 6S)-1-amino-8-azabicyclo[4.3.0]nonan-8-yl]-1-[(1R,2S)-2-fluorocyclopropane Base]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 245]

Under nitrogen atmosphere, triethylamine (0.277ml, 1.98mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl- 4-Oxoquinoline-3-carboxylic acid (185mg, 0.663mmol) was added to (1S, 6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]nonane (175mg, 0.728mmol ) in dimethylsulfoxide (1.33ml), and the resulting mixture was stirred at 75°C for 12 days. The reaction solution was diluted with ethyl acetate (45ml), and washed with 10% citric acid solution (40ml), water (40ml) and saturated sodium hydroxide solution (40ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 260 mg (0.578 mmol) of the obtained residue was dissolved in concentrated hydrochloric acid (2.5 ml), and the resulting solution was stirred at room temperature for 10 minutes. After washing with chloroform (50ml×2), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform (100ml×2) and chloroform/methanol=10/1 (100ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by PTLC (using the developing layer of chloroform/methanol/water=7/3/1 in the lower layer). Fluorescent fractions were collected, and the lower layer of chloroform/methanol/water=7/3/1 (70ml) was added. After sonication, the silica gel was filtered off. The filtrate was concentrated under reduced pressure, then dried in vacuo. Ethanol (1 ml), diethyl ether and 2-propanol were added to the residue. Ether was added. After repeating sonication and ice cooling several times, the resulting mixture was stirred at 40°C for 30 minutes. After stirring at room temperature for 2 hours, the crystals were collected by filtration and dried under reduced pressure to obtain 88.7 mg of the title compound as pale yellow crystals.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.40 (1H, d, J = 3.68Hz), 7.98 (1H, d, J = 8.82Hz), 7.07 (1H, d, J = 9.31Hz), 5.17 -4.94 (1H, m), 4.06 (1H, dd, J = 13.97, 5.64Hz), 3.55 (2H, dd, J = 19.36, 10.30Hz), 3.22 (1H, t, J = 8.09Hz), 3.13 ( 1H, d, J = 9.56 Hz), 2.43 (3H, s), 1.92-1.19 (11H, m).

_{Anal . Calcd} . for _{C22H26FN3O3-0.25H2O} : C, _65.41 ; H, 6.61; F, 4.70; N, 10.40. Found: C, 65.18; H, 6.60; N, 10.48.

MS (ESI); m/z: 400 (M+H) ⁺ .

IR (ATR) v: 3380, 2927, 2863, 1712, 1614, 1509, 1428, 1396, 1359, 1348, 1340, 1315, 1301, 1035, 927 ^{cm -1} .

[Example 34]

10-[(1S,6S)-1-amino-8-azabicyclo[4.3.0]nonan-8-yl]-9-fluoro-2,3-dihydro-3-(S)- Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

[Formula 246]

Triethylamine (0.208ml, 1.49mmol) and 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3 -de][1,4]Benzoxazine-6-carboxylic acid-BF _chelate (164 mg, 0.498 mmol) was added to (1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo [4.3.0] In a solution of nonane (126 mg, 0.524 mmol) in dimethyl sulfoxide (0.996 ml), the resulting mixture was stirred at 35°C for 15 hours. A mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added to the reaction solution, and the mixture was heated under reflux for 3 hrs. The reaction solution was concentrated under reduced pressure, and then 10% citric acid solution (30 ml) was added to the residue, followed by extraction with ethyl acetate (30 ml). The interface portion was extracted with chloroform. The organic layer was washed with water (30ml) and brine (30ml) respectively, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 169 mg of the obtained residue was dissolved in concentrated hydrochloric acid (1 ml), and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (20ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (100ml×2) and chloroform/methanol=10/1 (100ml×3). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue (130 mg) was dissolved in ethanol/28% ammonia water=7/1 (60 ml), and the insoluble matter was removed by filtration. The filtrate was heated and stirred to gradually evaporate the solvent. Ammonia was removed azeotropically several times with ethanol. The solution was concentrated to 10ml and then returned to room temperature. Precipitated crystals were collected by filtration, washed with ethanol and ether, and then dried under reduced pressure to obtain 109 mg of the title compound as pale yellow crystals.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.30 (1H, s), 7.51 (1H, d, J = 14.46Hz), 4.62-4.54 (1H, m), 4.45 (1H, dd, J = 11.40 , 2.08Hz), 4.26 (1H, dd, J = 11.28, 2.21Hz), 3.74 (1H, dd, J = 10.05, 3.43Hz), 3.70-3.64 (1H, m), 3.43 (1H, t, J = 8.33Hz), 3.34 (1H, d, J = 8.33Hz), 1.87-1.63 (5H, m), 1.56-1.22 (4H, m), 1.52 (3H, d, J = 6.86Hz).

_{Anal . Calcd .} for _{C21H24FN3O4-0.25H2O} : C, 62.13; H, 6.08; F, 4.68; N, 10.35. Found: C, 62.03; H, 6.10; N, 10.31.

MS (ESI); m/z: 402 (M+H) ⁺ .

IR(ATR) v: 3590, 3295, 3222, 2929, 2883, 1614, 1554, 1471, 1344, 1311, 1259, 1234, 1110, 1041, 985, 815 cm ^-1 .

[Reference Example 145]

(1S,6S)-8-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]non-3-ene

[Formula 247]

Under nitrogen atmosphere, benzyl chloroformate (0.600ml, 4.20mmol) was added to (1S,6S)-1-tert-butoxycarbonylamino-8-[(1R)-1-phenylethyl]-8 -Azabicyclo[4.3.0]non-3-ene (479mg, 1.40mmol) in dichloromethane (4.66ml) and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→75:25→66:34) to obtain 401 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.43-7.18 (5H, m), 5.76-5.58 (2H, m), 5.19-5.09 (2H, m), 4.54-4.32 (2H, m), 3.70 ( 1H, dd, J=18.02, 7.97Hz), 3.17-2.97 (3H, m), 2.39-1.47 (4H, m), 1.41 (9H, s).

MS (ESI); m/z: 395 (M+Na) ⁺ .

[Reference Example 146]

(1S,6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0]non-3-ene

[Formula 248]

Under cooling with dry ice-methanol, (1S,6S)-1-tert-butoxycarbonylamino-8-benzyloxycarbonyl-8-azabicyclo[4.3.0]non-3-ene (400mg, 1.07 mmol) in tetrahydrofuran (5.35ml) was passed through ammonia gas for 10 minutes, and 30-40ml of liquid ammonia was added to the solution. Sodium (128mg, 5.34mmol) was added and the mixture was stirred for 10 minutes. Saturated ammonium chloride solution (15 drops) was added at room temperature, and the mixture was stirred at room temperature to evaporate the ammonia. Add 1mol/L sodium hydroxide solution (15.0ml), and then extract with chloroform (30ml×2). The aqueous layer was concentrated under reduced pressure. Add 1mol/L sodium hydroxide solution (5.0ml), and then extract with the lower layer of chloroform/methanol/water=7/3/1 (35ml×2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure to obtain 136 mg of the title compound as a white amorphous substance.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 5.74-5.63 (2H, m), 4.44-4.36 (1H, m), 3.12 (1H, dd, J=9.93, 7.72Hz), 3.02-2.88 (2H, m), 2.72(1H, t, J=10.79Hz), 2.60(2H, d, J=11.52Hz), 2.30(1H, t, J=11.52Hz), 2.18-1.82(4H, m), 1.39( 9H, s).

MS (ESI); m/z: 239 (M+H) ⁺ .

[Example 35]

7-[(1S, 6S)-1-amino-8-azabicyclo[4.3.0]non-3-en-8-yl]-6-fluoro-1-[(1R,2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 249]

Triethylamine (0.217ml, 1.55mmol) and 1-[(1R,2S)-2-fluorocyclopropan-1-yl]-6,7-difluoro-1,4-dihydro-8-methoxy Base-4-oxoquinoline- ₃ -carboxylic acid-BF chelate (187mg, 0.518mmol) was added to (1S, 6S)-1-tert-butoxycarbonylamino-8-azabicyclo[4.3.0 ]non-3-ene (136 mg, 0.571 mmol) in dimethyl sulfoxide (2.04 ml), and the resulting mixture was stirred at 35°C for 16 hours. A mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (30ml), water (30ml) and brine (30ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, 242 mg of the obtained residue was dissolved in concentrated hydrochloric acid (2.0 ml), and the resulting solution was stirred at room temperature for 10 minutes. After washing with chloroform (25ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform/methanol=10/1 (150ml×1, 75ml×1, 50ml×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot 2-propanol (40ml), and the insoluble material was removed by filtration. The solvent was gradually evaporated while heating and stirring. The solution was concentrated to 10 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration, washed with 2-propanol and diethyl ether, and then dried under reduced pressure to obtain 129 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.36 (1H, d, J = 3.68Hz), 7.66 (1H, d, J = 14.46Hz), 5.88-5.72 (2H, m), 5.15-4.94 ( 1H, m), 4.05-3.98 (1H, m), 3.80-3.61 (3H, m), 3.57 (3H, s), 3.45 (1H, d, J=9.31Hz), 2.48-1.97 (5H, m) , 1.55-1.48 (1H, m), 1.45-1.29 (1H, m).

_{Anal .} Calcd. for _{C22H23F2N3O4.0.5H2O.iPrOH} : C _{, 59.99 ;} H, 6.44; F, 7.59; N, 8.39. Found: C, 59.95; H, 6.30; F, 7.61; N, 8.25.

MS (ESI); m/z: 432 (M+H) ⁺ .

IR (ATR) v: 2962, 1725, 1612, 1450, 1436, 1386, 1351, 1309, 1035, 819 cm ^-1 .

[Reference Example 147]

(3S, 4R)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate;

(3S, 4S)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate

[Formula 250]

Under salt ice cooling, allyl bromide (11.0ml, 79.1mmol) was added to (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine - tert-butyl-3-carboxylate (20.0 g, 60.7 mmol) in tetrahydrofuran (303 ml) and stirred. Under salt ice cooling, a 1M tetrahydrofuran solution of lithium hexamethyldisilazide (78.9 ml, 78.9 mmol) was added dropwise and stirred, and the resulting mixture was stirred under ice cooling for 10 minutes. A saturated ammonium chloride solution (300 ml) was added to the reaction solution, followed by extraction with ethyl acetate (200 ml). The organic layer was washed with brine (600ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→84:16→75:25→66:34) to obtain 9.81 g of the title compound (3S, 4R)-isomer and 6.76 g Title compound (3R,4S)-isomer.

(3S,4R)-isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.21 (10H, m), 5.75-5.59 (1H, m), 5.51-5.41 (1H, m), 5.17-5.08 (1H, m), 5.06- 4.97(1H, m), 4.71(1H, s), 4.50(1H, dd, J=22.31, 11.77Hz), 3.97-3.95(1H, m), 3.85-3.83(1H, m), 3.35-3.04( 2H, m), 2.64-2.61 (1H, m), 2.45-2.37 (1H, m), 1.49 (1H, dd, J=7.11, 4.66Hz), 1.42 (3H, d, J=7.35Hz), 1.28 (9. H, s).

MS (ESI); m/z: 450 (M+H) ⁺ .

(3R,4S)-isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.27-6.96 (10H, m), 5.76-5.65 (1H, m), 5.52 (1H, q, J=7.03Hz), 5.17-5.12 (2H, m) , 4.42-4.35 (2H, m), 3.50 (1H, d, J = 10.05Hz), 3.04 (1H, d, J = 10.05Hz), 2.52 (1H, dd, J = 13.73, 6.37Hz), 2.45 ( 1H, t, J = 2.82 Hz), 2.36 (1H, dd, J = 13.73, 8.09 Hz), 1.51 (3H, d, J = 7.11 Hz), 1.38 (9H, s).

MS (ESI); m/z: 450 (M+H) ⁺ .

[Reference Example 148]

(3S,4R)-4-Benzyloxymethyl-3-hydroxyethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate

[Formula 251]

To (3S, 4R)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester ( 8.00 g, 17.8 mmol) in methanol (177 mL) was bubbled with oxygen for 10 minutes. Under cooling with dry ice-methanol, ozone was blown with stirring for 30 minutes, and then nitrogen was blown to drive off ozone. Under cooling with ice-acetone, sodium borohydride (1.68 g, 44.4 mmol) was added, and the resulting mixture was stirred under cooling for 1.5 hours. A saturated ammonium chloride solution (150 ml) was added to the reaction solution, and methanol was distilled off by concentration under reduced pressure. The mixture was extracted with ethyl acetate (200ml×1, 150ml×1). The organic layer was washed with brine (300ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50) to obtain 3.79 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.22 (5H, m), 5.46 (1H, q, J = 7.03Hz), 4.50 (2H, dd, J = 17.28, 11.64Hz), 3.97 (1H , dd, J=9.80, 4.41Hz), 3.84 (1H, dd, J=9.80, 2.45Hz), 3.60 (2H, t, J=6.37Hz), 3.42 (1H, d, J=9.31Hz), 3.26 (1H, d, J = 9.31Hz), 3.10 (1H, dd, J = 4.41, 2.45Hz), 2.11 (1H, dt, J = 15.52, 5.58Hz), 1.99-1.93 (1H, m), 1.41 ( 3H, d, J = 7.35 Hz), 1.28 (9H, s).

MS (ESI); m/z: 454 (M+H) ⁺ .

[Reference Example 149]

(3S,4R)-3-Benzyloxymethyl-3-methanesulfonyloxyethyl-5-oxo-1-[(1R)-1-phenyl Ethyl]pyrrolidine-3-carboxylate tert-butyl ester

[Formula 252]

Under nitrogen atmosphere, triethylamine (2.79ml, 19.9mmol) was added to (3S,4R)-4-benzyloxymethyl-3-hydroxyethyl-5-oxo-1-[(1R)- 1-Phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.57g, 10.0mmol) in dichloromethane (50.0ml). Under cooling with ice-acetone, methanesulfonyl chloride (1.17ml, 15.1mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water (150ml) was added to the reaction solution, followed by extraction with chloroform (150ml×1, 80ml×1). The organic layer was washed with brine (200ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 7.09 g of a residue containing the title compound, which was used in the next step without further purification.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.25 (10H, m), 5.45 (1H, q, J=7.11Hz), 4.50 (2H, dd, J=17.16, 11.52Hz), 4.23-4.20 (1H, m), 4.14-4.11 (1H, m), 3.99 (1H, dd, J=9.93, 4.29Hz), 3.81 (1H, dd, J=9.93, 2.57Hz), 3.37 (1H, d, J =9.56Hz), 3.25(1H, d, J=9.56Hz), 3.08(1H, dd, J=4.41, 2.45Hz), 2.90(3H, s), 2.33-2.26(1H, m), 2.21-2.17 (1H, m), 1.42 (3H, d, J = 7.11 Hz), 1.28 (9H, s).

MS (ESI); m/z: 532 (M+H) ⁺ .

[Reference Example 150]

(3S,4R)-4-Hydroxymethyl-3-methanesulfonyloxyethyl-5-oxo-1-[(1R)-1-phenylethyl] Pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 253]

Under nitrogen atmosphere, 20% palladium hydroxide-carbon catalyst (7.09 g, 100 wt%) was added to (3S,4R)-3-benzyloxymethyl-3-methanesulfonyloxyethyl-5-oxo In a solution of tert-butyl generation-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (7.09g) in ethanol (100ml). After replacing the original atmosphere with hydrogen, the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour, and then at 50°C for 1 hour. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite, concentrated and dried under reduced pressure to obtain 4.49 g of a residue containing the title compound, which was used in the next step without further purification.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.25 (5H, m), 5.48 (1H, q, J=7.03Hz), 4.30-4.19 (2H, m), 4.11-3.96 (2H, m) , 3.34(2H, dd, J=26.72, 10.54Hz), 2.99(3H, s), 2.98-2.95(1H, m), 2.31-2.24(1H, m), 2.17-2.10(1H, m), 1.56 (3H, d, J = 7.11 Hz), 1.37 (9H, s).

MS (ESI); m/z: 442 (M+H) ⁺ .

[Reference Example 151]

(1S, 6R)-{4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonane-1- tert-butyl formate

[Formula 254]

(3S,4R)-4-Hydroxymethyl-3-methanesulfonyloxyethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl A solution of the ester (4.49g) in pyridine (100ml) was stirred at 50°C for 15 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50→10:90) to obtain 1.75 g of the title compound as white crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.23 (5H, m), 5.58 (1H, q, J=7.11Hz), 4.38 (1H, d, J=11.77Hz), 3.83-3.79 (1H , m), 3.71 (1H, dd, J=12.01, 3.92Hz), 3.42 (1H, td, J=12.01, 2.21Hz), 3.04 (1H, d, J=10.05Hz), 2.96 (1H, d, J = 9.80Hz), 2.62 (1H, d, J = 3.43Hz), 1.97 (1H, d, J = 14.22Hz), 1.75 (1H, ddd, J = 15.44, 10.79, 3.19Hz), 1.54 (3H, d, J = 7.11 Hz), 1.44 (9H, s).

MS (ESI); m/z: 346 (M+H) ⁺ .

[Reference Example 152]

(1S, 6R}-{4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonane-1- methyl} formic acid

[Formula 255]

Under ice cooling, trifluoroacetic acid (6.63ml) was added to (1S,6R)-{4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8 -Azabicyclo[4.3.0]nonan-1-yl}carboxylate tert-butyl (763 mg, 2.21 mmol) in dichloromethane (6.63 ml) and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (3 times). Under ice-cooling, 1 mol/L sodium hydroxide solution (20 ml) was added to the obtained residue, and the obtained mixture was washed with diethyl ether (50 ml×2). The aqueous layer was acidified with 1mol/L hydrochloric acid (20ml) under ice cooling, and then extracted with ethyl acetate (60ml×1, 50ml×1). The combined organic layers were washed with brine (90ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 637 mg of the title compound as white crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.43-7.24 (5H, m), 5.58 (1H, q, J = 7.11Hz), 4.41 (1H, d, J = 12.26Hz), 3.83 (1H, dd , J=12.13, 2.82Hz), 3.70 (1H, dd, J=12.01, 3.68Hz), 3.44 (1H, td, J=12.13, 1.88Hz), 3.11 (1H, d, J=10.05Hz), 3.02 (1H, d, J = 10.05Hz), 2.69 (1H, d, J = 3.43Hz), 2.09-2.05 (1H, m), 1.84-1.76 (1H, m), 1.55 (3H, d, J = 7.11 Hz).

MS (ESI); m/z: 290 (M+H) ⁺ .

[Reference Example 153]

(1S,6R)-1-tert-butoxycarbonylamino-4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-nitrogen Heterobicyclo[4.3.0]nonane

[Formula 256]

Under nitrogen atmosphere, triethylamine (0.720ml, 5.16mmol) and diphenoxyphosphoryl azide (0.723ml, 3.35mmol) were added to (1S, 6R)-{4- Oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonan-1-yl}carboxylic acid (747 mg, 2.58 mmol) in toluene ( 12.9ml) solution. The mixture was stirred at room temperature for 30 minutes, then at 100°C for 30 minutes. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (3 times). 1,4-Dioxane (6.45ml) and 6mol/L hydrochloric acid (6.45ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 1 hour. The reaction solution was diluted with water (15ml) and washed with ethyl acetate (50ml x 2). The aqueous layer was basified with 1mol/L sodium hydroxide solution under ice cooling, and extracted with chloroform (50ml×2). The organic layer was washed with brine (80ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (14.9 ml) was added to the obtained residue, di-tert-butyl dicarbonate (813 mg, 3.73 mmol) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 4 days. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→75:25→60:40→50:50) to obtain 470 mg (51%) of the title compound .

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.25 (5H, m), 5.58 (1H, q, J = 7.19Hz), 4.81 (1H, brs), 4.31 (1H, dd, J = 12.26, 1.72Hz), 3.77(1H, td, J=7.54, 4.09Hz), 3.61(1H, dd, J=12.26, 3.92Hz), 3.48(2H, m), 3.09(1H, d, J=10.05Hz) , 2.39(1H, brs), 2.16-2.05(1H, m), 1.81(1H, ddd, J=15.26, 10.85, 3.62Hz), 1.53(3H, d, J=7.11Hz), 1.39(9H, s ).

MS (ESI); m/z: 361 (M+H) ⁺ .

[Reference Example 154]

(1S, 6R)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl]-7-thio-8-nitrogen Heterobicyclo[4.3.0]nonane

[Formula 257]

Add Lawson's reagent to (1S,6R)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl]-7-oxo-8-nitro A solution of heterobicyclo[4.3.0]nonane (470mg, 1.30mmol) in tetrahydrofuran (13.0ml) was stirred at 60°C for 2.5 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25→66:34) to obtain a residue containing the title compound, It was used directly in the next step.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.29 (5H, m), 6.97 (1H, dt, J=12.83, 4.60Hz), 6.44 (1H, q, J=7.03Hz), 4.39 (1H , d, J=9.31Hz), 3.87-3.82 (3H, m), 3.72-3.57 (2H, m), 2.70 (1H, brs), 2.03-1.94 (1H, m), 1.90-1.79 (1H, m ), 1.60 (3H, d, J = 7.11 Hz), 1.36 (9H, s).

MS (ESI); m/z: 377 (M+H) ⁺ .

[Reference Example 155]

(1S,6R)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] Nonane

[Formula 258]

Under nitrogen atmosphere, Raney nickel (14.2ml) was added to (1S,6R)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl]- In a solution of 7-thio-8-azabicyclo[4.3.0]nonane (700mg) in ethanol (28.4ml). The mixture was stirred vigorously at room temperature for 1 hour. The reaction solution was filtered through celite and concentrated under reduced pressure to obtain 423 mg of the title compound (quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.20 (5H, m), 4.66 (1H, brs), 3.75-3.40 (4H, m), 2.90 (2H, s), 2.78-2.69 (2H, m), 2.20-1.96 (3H, m), 1.41 (9H, s), 1.34 (3H, d, J=6.59Hz).

MS (ESI); m/z: 347 (M+H) ⁺ .

[Reference Example 156]

(1S,6S)-1-tert-butoxycarbonylamino-4-oxabicyclo[4.3.0]nonane

[Formula 259]

Under nitrogen atmosphere, 10% palladium-carbon catalyst (205 mg) was added to (1S,6R)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl ]-8-azabicyclo[4.3.0]nonane (205mg, 0.592mmol) in ethanol (5.92ml). After replacing the original atmosphere with hydrogen, the mixture was stirred under a hydrogen atmosphere at room temperature for 45 minutes, and then at 50° C. for 1 hour. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure. Under a nitrogen atmosphere, 10% palladium-carbon catalyst (205 mg) was added to a solution of the obtained residue in ethanol (5.92 ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at 50°C for 16 hours. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure. Under a nitrogen atmosphere, 20% palladium hydroxide-carbon catalyst (205 mg) was added to a solution of the obtained residue in ethanol (5.92 ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at 50° C. for 1 hour under a hydrogen atmosphere. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite, concentrated and dried under reduced pressure to obtain 128 mg of the title compound as a pale vermilion oil.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.83 (1H, brs), 3.68-3.57 (4H, m), 3.30-3.19 (3H, m), 3.00-2.98 (1H, m), 2.14-1.96 ( 3H, m), 1.44 (9H, s).

MS (ESI); m/z: 243 (M+H) ⁺ .

[Example 36]

7-[(1S,6R)-1-amino-4-oxa-8-azabicyclo[4.3.0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 260]

Triethylamine (0.198ml, 1.42mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4 -Oxoquinoline-3-carboxylic acid-BF ₂ chelate (171 mg, 0.474 mmol) was added to (1S, 6R)-8-aza-1-tert-butoxycarbonylamino-4-oxabicyclo[4.3 .0] nonane (126mg, 0.520mmol) in dimethylsulfoxide (0.948ml) and the resulting mixture was stirred at 35°C for 16 hours. A mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (30ml), water (30ml) and brine (30ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, trifluoroacetic acid (0.694ml, 3v/w) was added to a solution of 125mg of the obtained residue in dichloromethane (2.31ml) with stirring, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (×3). Under ice-cooling, pH 1 hydrochloric acid (20.0 ml) was added to the resulting residue, and the resulting mixture was washed with diethyl ether (40 ml×4). The aqueous layer was adjusted to pH 12 with 1 mol/L sodium hydroxide solution under ice cooling. The alkaline solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, and then extracted with chloroform (100ml×2) and chloroform/methanol=10/1 (100ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hot ethanol (10 ml), and the insoluble material was removed by filtration. The solvent was gradually evaporated while heating and stirring. The residue was concentrated until ethanol was 3-4 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration, washed with ethanol and ether, and then dried at 60°C under reduced pressure to obtain 20.5 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.45 (1H, s), 7.68 (1H, d, J = 14.71Hz), 5.08-4.92 (1H, m), 4.07 (1H, dd, J = 13.73 , 6.13Hz), 3.92(1H, dd, J=12.50, 3.68Hz), 3.83(4H, dd, J=13.85, 8.95Hz), 3.73-3.58(6H, m), 2.20-2.13(1H, m) , 2.06-1.99 (1H, m), 1.68-1.49 (3H, m).

Anal _. Calcd. for _{C21H23F2N3O5-0.75H2O} : C, _{56.18 ; H} , _5.50 ; N, 9.36. Found: C, 56.15; H, 5.46; N, 9.65.

MS (ESI); m/z: 436 (M+H) ⁺ .

IR (ATR) v: 2937, 2892, 2856, 1724, 1625, 1515, 1454, 1324, 1137, 1099, 1054, 985, 927, 887, 802 cm ^-1 .

[Reference Example 157]

(3S,4S)-4-Benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[(1R)-1-phenylethyl]pyrrole tert-butyl alkane-3-carboxylate

[Formula 261]

To (3S, 4S)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester ( 6.76 g, 15.0 mmol) in methanol (150 mL) was bubbled with oxygen for 5 minutes. Under cooling with dry ice-methanol, ozone was blown with stirring for 1.5 hours, and then nitrogen was blown to drive off ozone. Under cooling, dimethylsulfide (5.64ml, 76.8mmol) was added, and the mixture was stirred for 19 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→75:25→66:34→50:50) to obtain 4.58 g of the title compound as a transparent Oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.74 (1H, s), 7.37-7.15 (5H, m), 5.47 (1H, q, J=7.19Hz), 4.42 (2H, s), 3.92 (1H , dd, J=9.80, 3.68Hz), 3.81 (1H, dd, J=9.56, 6.62Hz), 3.68 (1H, d, J=10.54Hz), 3.21 (1H, t, J=8.58Hz), 3.13 (1H, d, J = 10.54Hz), 2.70 (1H, dd, J = 6.37, 3.68Hz), 2.61 (1H, d, J = 17.16Hz), 1.50 (3H, d, J = 7.11Hz), 1.27 (9H, s).

MS (ESI); m/z: 452 (M+H) ⁺ .

[Reference Example 158]

(3S,4S)-4-Benzyloxymethyl-3-carboxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine -3-tert-butyl carboxylate

[Formula 262]

Under ice cooling, 2-methyl-2-butene was added to (3S, 4S)-4-benzyloxymethyl-5-oxo-3-(2-oxoethyl)-1-[( 1R)-1-Phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 10.1 mmol) in tert-butanol (25.2 ml) and the resulting mixture was stirred. Sodium chlorite (2.29 g, 25.3 mmol) was added to a solution of sodium dihydrogenphosphate dihydrate (4.10 g, 26.3 mmol) in water (20.2 ml), and solutions were prepared separately. Under ice-cooling, this solution was added to the above solution, and the mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration, washed with water and hexane, and then dried under reduced pressure at 40°C to obtain 3.93 g of the title compound as white powdery crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.30-7.14 (5H, m), 5.48 (1H, q, J = 7.03Hz), 4.42 (2H, s), 3.90 (1H, dd, J = 9.68, 3.55Hz), 3.82(1H,dd,J=9.56,6.13Hz), 3.69(1H,d,J=10.54Hz), 3.27(1H,d,J=10.79Hz), 3.10(1H,d,J= 16.18Hz), 2.70(1H, dd, J=6.13, 3.68Hz), 2.58(1H, d, J=16.18Hz), 1.79(1H, brs), 1.52(3H, d, J=7.11Hz), 1.29 (9H, s).

MS (ESI); m/z: 468 (M+H) ⁺ .

[Reference Example 159]

(3S, 4S)-3-carboxymethyl-4-hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-methan tert-butyl acid

[Formula 263]

Under a nitrogen atmosphere, 10% palladium-carbon catalyst (3.93 g) was added to (3S,4S)-4-benzyloxymethyl-3-carboxymethyl-5-oxo-1-[(1R)- 1-Phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.93g, 8.41mmol) in methanol (84.0ml). After replacing the original atmosphere with hydrogen, the mixture was stirred under hydrogen atmosphere at room temperature for 3 days. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 2.54 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.27 (5H, m), 5.44 (1H, q, J = 7.11Hz), 3.88 (1H, dd, J = 11.28, 7.60Hz), 3.80 (1H , dd, J=11.28, 5.39Hz), 3.69(1H, d, J=10.79Hz), 3.26(1H, d, J=10.79Hz), 3.05(1H, d, J=16.91Hz), 2.68(1H , dd, J = 7.35, 5.39 Hz), 2.59 (1H, d, J = 16.91 Hz), 1.53 (3H, d, J = 7.11 Hz), 1.28 (9H, s).

MS (ESI); m/z: 378 (M+H) ⁺ .

[Reference Example 160]

{(1S,6S)-4-oxa-3,7-dioxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonane tert-butyl alk-1-yl}carboxylate

[Formula 264]

Under nitrogen atmosphere, triethylamine (1.32ml, 9.46mmol) and 2,4,6-trichlorobenzoyl chloride (1.16ml, 7.45mmol) were added to (3S,4S)-3-carboxymethyl-4 -Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.54g, 6.73mmol) in tetrahydrofuran (44.8ml). After stirring at room temperature for 30 minutes, further toluene (179ml) and 4-dimethylaminopyridine (1.23g, 10.1mmol) were added. After stirring at room temperature for 18 hours, the reaction solution was diluted with ethyl acetate (100ml) and washed with 1mol/L hydrochloric acid (150ml), water (150ml), saturated sodium bicarbonate solution (150ml), water (150ml) and brine (150ml) washing. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→66:34→50:50→34:66→25:75) to obtain 2.06 g of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.27 (5H, m), 5.43 (1H, q, J=7.19Hz), 4.76-4.72 (2H, m), 3.34-3.20 (3H, m) , 2.90 (1H, dd, J = 10.42, 7.97Hz), 2.56 (1H, d, J = 16.91Hz), 1.52 (3H, d, J = 7.35Hz), 1.24 (9H, s).

MS (ESI); m/z: 360 (M+H) ⁺ .

[Reference Example 161]

{(1S,6S)-3-Acetoxy-4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] tert-butyl nonan-1-yl}carboxylate

[Formula 265]

Under cooling with dry ice-methanol, add 0.97mol/L hexane solution of diisobutylaluminum hydride (1.65ml, 1.60mmol) into {(1S,6S)-4-oxa-3,7 -Dichloro dioxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonan-1-yl}carboxylate (500mg, 1.39mmol) methane (6.95ml) solution. After stirring for 1 hour under cooling, a 0.97 mol/L hexane solution of diisobutylaluminum hydride (0.716 ml, 0.695 mmol) was added. After stirring for 2 hours under cooling, a solution of pyridine (0.338ml, 4.18mmol) and 4-dimethylaminopyridine (204mg, 1.67mmol) in dichloromethane (3.5ml) and acetic anhydride (0.526ml, 5.56mmol) was added Solution in dichloromethane (1.8ml). The mixture was stirred under cooling for 1 hr, then ice-cooled, and a saturated tetraammonium chloride solution (20 ml) was added. After stirring for 30 minutes under ice cooling, the reaction solution was extracted with ethyl acetate (50ml×1, 40ml×1). The organic layer was washed with 10% citric acid (60ml), water (60ml), saturated sodium bicarbonate solution (60ml) and brine (60ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→60:40→50:50) to obtain 350 mg of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.74 (1H, dd, J=7.35, 4.17Hz), 5.45 (1H, dd, J=20.84, 10.42Hz), 4.29 -4.14(2H, m), 2.70-2.60(2H, m), 2.09(3H, s), 1.67(1H, dd, J=12.62, 7.23Hz), 1.48(3H, d, J=7.11Hz), 1.23 (9H, s).

MS (ESI); m/z: 404 (M+H) ⁺ .

[Reference Example 162]

(1S,5S)-3-Aza-4,10-dioxo-3-[(1R)-1-phenylethyl]-7,9-dioxatricyclo [6.2.1.0 ^1,5 ] Undecane

[Formula 266]

{(1S, 6S)-3-Acetoxy-7-oxa-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonan-1-yl } A solution of tert-butyl formate (663mg, 1.64mmol) in acetonitrile (8.20ml) was cooled with ice-acetone. Under nitrogen atmosphere, triethylsilane (0.787ml, 4.93mmol) and (trimethylsilyl) trifluoromethanesulfonate (0.595ml, 3.29mmol) were added, and the resulting mixture was stirred under cooling for 15 minutes. Saturated sodium bicarbonate solution (50 ml) was added to the reaction solution, followed by extraction with ethyl acetate (100 ml×1, 60 ml×1). The organic layer was washed with water (50ml) and brine (100ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→75:25→66:34→50:50→34:66) to obtain 413 mg of the title compound , as a transparent oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.17 (5H, m), 5.45 (1H, q, J=7.03Hz), 4.25 (1H, dd, J=11.28, 4.17Hz), 4.18-4.10 (1H, m), 3.97-3.92 (2H, m), 3.31-3.25 (2H, m), 2.61 (1H, dd, J=10.66, 4.29Hz), 2.19 (1H, d, J=13.24Hz), 1.80 (1H, td, J = 12.62, 4.66 Hz), 1.48 (3H, d, J = 7.11 Hz).

[Reference Example 163]

{(1S,6S)-4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonane-1- methyl} formic acid

[Formula 267]

(1S,5S)-3-Aza-4,10-dioxo-3-[(1R)-1-phenylethyl]-7,9-dioxatricyclo[6.2.1.0 ^{1, 5} ] A solution of undecane (413mg, 1.44mmol) in dichloromethane (7.20ml) was cooled with dry ice-methanol. Under a nitrogen atmosphere, triethylsilane (0.690ml, 4.32mmol) and 1.0mol/L titanium tetrachloride in dichloromethane (2.88ml, 2.88mmol) were added, and the resulting mixture was stirred under cooling for 30 minutes. Saturated sodium bicarbonate solution (50 ml) was added to the reaction solution, and the resulting mixture was washed with ethyl acetate (100 ml×2). The aqueous layer was acidified with 6mol/L hydrochloric acid and 1mol/L hydrochloric acid, and then extracted with chloroform (100ml×1, 60ml×1). The organic layer was washed with water (100ml) and brine (150ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was further concentrated under reduced pressure and dried under reduced pressure to obtain 235 mg of the title compound as white crystals.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33-7.23 (5H, m), 5.46 (1H, d, J=7.35Hz), 4.26 (1H, dd, J=11.03, 4.41Hz), 3.97-3.91 (2H, m), 3.33-3.24 (3H, m), 2.60 (1H, dd, J = 10.66, 4.29Hz), 2.19 (1H, d, J = 12.50Hz), 1.85-1.67 (2H, m), 1.49 (3H, d, J = 7.11 Hz).

MS (ESI); m/z: 290 (M+H) ⁺ .

[Reference Example 164]

(1S,6S)-1-tert-butoxycarbonylamino-4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-nitrogen Heterobicyclo[4.3.0]nonane

[Formula 268]

Under nitrogen atmosphere, triethylamine (0.330ml, 2.36mmol) and diphenoxyphosphoryl azide (0.330ml, 1.53mmol) were added to [(1S, 6S)-4- Oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid (340 mg, 1.18 mmol) in toluene ( 5.90ml) solution. The mixture was stirred at room temperature for 30 minutes, then at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of triethylamine and toluene (×3). 1,4-Dioxane (2.95ml) and 6mol/L hydrochloric acid (2.95ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 1 hour. The reaction solution was diluted with water (9.0ml) and washed with ether (40ml×2). The aqueous layer was basified with 1mol/L sodium hydroxide solution under ice cooling, and then extracted with chloroform (80ml×1, 60ml×1). The organic layer was washed with water (80ml) and brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Dichloromethane (5.90ml) was added to the obtained residue, and di-tert-butyl dicarbonate (773mg, 3.54mmol) was added under nitrogen atmosphere. The mixture was stirred at room temperature for 14 hours, then at 50°C for 7 hours, and added Di-tert-butyl dicarbonate (515mg, 2.36mmol). After stirring at 50°C for 17 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90 :10→80:20→66:34→60:40) to obtain 320 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.44 (1H, q, J=6.95Hz), 4.53 (1H, brs), 4.16-4.11 (1H, m), 3.81 (1H, dd, J=12.13, 3.80Hz), 3.62 (3H, tt, J=14.83, 6.37Hz), 3.15 (1H, d, J=10.30Hz), 2.69 (1H, dd, J=11.52, 4.41 Hz), 1.71 (1H, td, J = 12.68, 4.98Hz), 1.49 (3H, d, J = 7.11Hz), 1.26 (9H, s).

MS (ESI); m/z: 361 (M+H) ⁺ .

[Reference Example 165]

(1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenylethyl]-8-azabicyclo [4.3.0] Nonane

[Formula 269]

(1S, 6S)-1-tert-butoxycarbonylamino-4-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4.3.0 ] A solution of nonane (331mg, 0.918mmol) in THF (3.0ml) was cooled with ice-acetone. Under a nitrogen atmosphere, a 1.2 mol/L solution of borane in tetrahydrofuran (3.83 ml, 4.59 mmol) was added, and the mixture was stirred at room temperature for 19 hours. After cooling with ice-acetone again, a 1.2 mol/L tetrahydrofuran solution of borane (3.83 ml, 4.59 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Then, a mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added, and the mixture was heated under reflux for 1.5 hours. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate solution (50 ml) was added to the residue, followed by extraction with chloroform (50 ml×1, 40 ml×1). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→→90:10→60:40→50:50→34:66→25:75→16:84→10:90→ 5:95→2:98→0:100) to obtain 255 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.31-7.21 (5H, m), 4.35 (1H, s), 3.81 (2H, ddd, J=22.43, 11.64, 4.04Hz), 3.62 (2H, td, J=11.95, 2.37Hz), 3.49(1H, t, J=11.52Hz), 3.37(1H, d, J=10.05Hz), 2.91(1H, t, J=8.33Hz), 2.55-2.42(2H, m), 2.17 (1H, t, J = 5.88Hz), 1.56-1.50 (1H, m), 1.47 (9H, s), 1.32 (3H, d, J = 6.37Hz).

MS (ESI); m/z: 347 (M+H) ⁺ .

[Reference Example 166]

(1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-bicyclo[4.3.0]nonane

[Formula 270]

Under nitrogen atmosphere, 20% palladium hydroxide-carbon catalyst (262 mg) was added to (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-[(1R)-1-phenyl Ethyl]-8-azabicyclo[4.3.0]nonane (262mg, 0.756mmol) in ethanol (7.56ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at 45° C. for 2.5 hours under a hydrogen atmosphere. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite, concentrated under reduced pressure and dried under reduced pressure to obtain 183 mg of the title compound.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.33 (1H, brs), 3.95 (1H, dd, J=11.64, 4.29Hz), 3.84 (1H, dd, J=12.50, 4.66Hz), 3.72 (1H , q, J=7.03Hz), 3.62-3.55(2H, m), 3.49(1H, t, J=11.64Hz), 3.06(1H, dd, J=9.93, 7.97Hz), 2.68-2.57(3H, m), 2.13-2.04 (1H, m), 1.57 (1H, td, J=12.93, 4.74Hz), 1.45 (9H, s).

MS (ESI); m/z: 243 (M+H) ⁺ .

[Example 37]

7-[(1S,6S)-1-amino-4-oxa-8-azabicyclo[4.3.0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 271]

Triethylamine (0.165ml, 1.18mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4 -Oxoquinoline-3-carboxylic acid-BF ₂ chelate (142 mg, 0.393 mmol) was added to (1S, 6S)-1-tert-butoxycarbonylamino-4-oxa-8-bicyclo[4.3.0 ] nonane (142 mg, 0.421 mmol) in dimethyl sulfoxide (0.787 ml), and the mixture was stirred at room temperature for 14 hours. A mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (30ml), water (30ml) and brine (30ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, trifluoroacetic acid (0.975ml, 3v/w) was added to a solution of 174mg of the obtained residue in dichloromethane (3.25ml) with stirring, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (×3). Under ice-cooling, 1N hydrochloric acid (25.0 ml) was added to the obtained residue, and the obtained mixture was washed with diethyl ether (50 ml×5). The aqueous layer was adjusted to pH 12 with 1 mol/L sodium hydroxide solution under ice cooling. The alkaline solution was adjusted to pH 7.4 with 1mol/L hydrochloric acid, and then extracted with chloroform (100ml×2, 50ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform/methanol = 10/1, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure and dissolved in hot ethanol. The solvent was gradually evaporated while heating and stirring. Then, the solution was concentrated until about 10 ml of ethanol was stirred at room temperature for 3 hours. Precipitated crystals were collected by filtration, and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C overnight to obtain 55.3 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.36 (1H, d, J = 3.68Hz), 7.67 (1H, d, J = 14.46Hz), 5.15-4.96 (1H, m), 4.00 (3H, ddd, J=20.71, 11.03, 4.53Hz), 3.84-3.63(4H, m), 3.58(3H, s), 3.53(1H, t, J=8.58Hz), 3.39(1H, d, J=9.31Hz ), 2.32-2.20 (1H, m), 1.99-1.85 (2H, m), 1.58-1.43 (1H, m), 1.43-1.27 (1H, m).

Anal _. Calcd. for _{C21H23F2N3O5-0.25H2O} : C, _57.33 ; _H , _5.38 ; N, 9.55 _. Found: C, 57.55; H, 5.40; N, 9.47.

MS (ESI); m/z: 436 (M+H) ⁺ .

IR (ATR) v: 3052, 2927, 2869, 1727, 1614, 1594, 1508, 1446, 1428, 1363, 1322, 1110, 1078, 1043, 989, 948, 910, ^{809 cm -1} .

[Example 38]

7-[(1S,6S)-1-amino-4-oxa-8-azabicyclo[4.3.0]nonan-8-yl]-8-cyano-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 272]

Under nitrogen atmosphere, triethylamine (0.263ml, 1.88mmol) and 8-cyano-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1 , ethyl 4-dihydro-4-oxoquinoline-3-carboxylate (211 mg, 0.627 mmol) was added to (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-aza In a solution of bicyclo[4.3.0]nonane (151mg, 0.628mmol) in acetonitrile (1.25ml). The mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→60:40→50:50→34:66→25:75→16:84). Under ice-cooling, 1 mol/L sodium hydroxide solution (1.94 ml) was added to a solution of the obtained residue in ethanol (2.42 ml), and the mixture was stirred at room temperature for 1 hr. A 10% citric acid solution (30ml) was added to the reaction solution, followed by extraction with ethyl acetate (40ml x 1, 30ml x 1). The organic layer was washed with brine (45ml), then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, trifluoroacetic acid (1.38ml, 3v/w) was added to a solution of 243mg of the obtained residue in dichloromethane (4.58ml) with stirring, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. Then, under ice-cooling, hydrochloric acid of pH 1 was added to the obtained residue, and the obtained mixture was washed with chloroform (40 ml×3). The aqueous layer was adjusted to pH 12 with 1 mol/L sodium hydroxide solution under ice cooling. The alkaline solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, and then extracted with chloroform (100ml×1, 70ml×1, 50ml×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The aqueous layer was concentrated under reduced pressure. The obtained residue was dissolved in chloroform/methanol=10/1, and the insoluble matter was removed by filtration (×2). The residues obtained from the organic layer and the aqueous layer were purified by PTLC, respectively (chloroform/methanol/water in the lower layer=7/3/1). They were combined and redissolved in dichloromethane (20ml), which was removed azeotropically with ethanol (3 times). Ethanol (5 ml) was added to the resulting residue, and the resulting mixture was sonicated and then cooled. The precipitated solid was collected by filtration, washed with ethanol and ether, and dried at 60°C under reduced pressure to obtain 122 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.30 (1H, d, J = 3.92Hz), 7.90 (1H, d, J = 15.44Hz), 5.19 (1H, dd, J = 63.24, 3.43Hz) , 4.06-3.97 (5H, m), 3.81-3.74 (3H, m), 3.58 (1H, d, J=10.30Hz), 2.33-2.31 (1H, m), 2.03-1.73 (3H, m), 1.61 -1.49 (1H, m).

Anal _. Calcd. for _{C21H20F2N4O4-0.25H2O} : C, _58.00 ; _H , 4.75; F _, 8.74; N _, 12.88. Found: C, 58.07; H, 4.60; F, 8.70; N, 12.74.

MS (ESI); m/z: 431 (M+H) ⁺ .

IR (ATR) v: 3081, 2960, 2873, 2211, 1725, 1629, 1446, 1400, 1307, 1261, 927, 912, 804 ^{cm -1} .

[Example 39]

7-[(1S, 6S)-1-amino-4-oxa-8-azabicyclo[4.3.0]nonan-8-yl]-1-[(1R,2S)-2-fluoro Cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 273]

Under nitrogen atmosphere, triethylamine (0.0737ml, 0.528mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl- 4-Oxoquinoline-3-carboxylic acid (49.0mg, 0.175mmol) was added to (1S,6S)-1-tert-butoxycarbonylamino-4-oxa-8-azabicyclo[4.3.0]nonane Alkane (42.2mg, 0.176mmol) in dimethyl sulfoxide (0.352ml) and the resulting mixture was stirred at 75°C for 2 days. Dimethylsulfoxide (0.352ml) and triethylamine (0.147ml, 1.06mmol) were added to the reaction solution, and the resulting mixture was stirred at 75°C for 4 days. Dimethylsulfoxide (0.352ml) and triethylamine (0.147ml, 1.06mmol) were added to the reaction solution, and the resulting mixture was stirred at 75°C for 2 days. 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (24.6mg, 0.0881mmol ) and triethylamine (0.147ml, 1.06mmol) were added to the reaction solution, and the mixture was stirred for 5 days. The reaction solution was diluted with ethyl acetate (30ml), and washed with 10% citric acid solution (25ml), water (25ml) and saturated sodium hydroxide solution (25ml). Further, from the washed 10% citric acid solution and the washed water, the organic layer was extracted with ethyl acetate (40 ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). Under ice-cooling, trifluoroacetic acid (0.402 ml, 3 v/w) was added to a solution of 67.5 mg of the obtained residue in dichloromethane (1.32 ml) with stirring, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (×3). Under ice-cooling, 6 mol/L hydrochloric acid was added to the obtained residue, and the obtained mixture was washed with chloroform (30 ml×5). The aqueous layer was adjusted to pH 12 with 1 mol/L sodium hydroxide solution under ice cooling. The alkaline solution was adjusted to pH 7.4 with 1 mol/L hydrochloric acid, and then extracted with chloroform (100ml×2) and chloroform/methanol=10/1 (50ml). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (chloroform/methanol/water in the lower layer=7/3/1) and concentrated under reduced pressure. The obtained residue was dissolved in hot ethanol, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, dissolved in hot ethanol (1 ml), sonicated, and cooled with ice water. Then, the resulting slurry was washed with diethyl ether (10 ml). After stirring overnight at room temperature, the precipitated crystals were collected by filtration, washed with ethanol and ether, and then dried at 60°C under reduced pressure to obtain 12.4 mg of the title compound.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.41 (1H, d, J = 3.68Hz), 8.00 (1H, d, J = 8.58Hz), 7.09 (1H, d, J = 8.82Hz), 5.16 -4.96(1H, m), 4.10-3.95(3H, m), 3.83-3.77(2H, m), 3.66(1H, d, J=9.80Hz), 3.59(1H, t, J=10.91Hz), 3.26(2H, dd, J=15.32, 8.70Hz), 2.45(3H, s), 2.33-2.23(1H, m), 2.02-1.87(3H, m), 1.68-1.57(1H, m), 1.33- 1.21(1H, m).

_{Anal . Calcd} . for _{C21H24FN3O4-1.5H2O} : C, 58.87; H, 6.35; N, 9.81 _. Found: C, 58.97; H, 5.98; N, 9.40.

MS (ESI); m/z: 402 (M+H) ⁺ .

IR (ATR) v: 2937, 2865, 1710, 1608, 1508, 1428, 1388, 1349, 1315, 1257, ^{794 cm -1} .

[Reference Example 167]

(3S)-3-Ethoxycarbonylmethoxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate

[Formula 274]

(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.0g, 6.26mmol) and bromoethyl acetate The ester (2.09g, 12.52mmol) was dissolved in tetrahydrofuran (40ml). At 0°C, sodium hydride (0.33 g, 7.51 mmol) was added, and the mixture was stirred at room temperature for 18 hours. A saturated ammonium chloride solution (100 ml) was added to the reaction solution at 0°C, followed by extraction with ethyl acetate (300 ml). The organic layer was washed with water (100ml) and brine (100ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to obtain 1.74 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.30 (5H, m), 5.49 (1H, q, J = 6.99Hz), 4.21 (2H, q, J = 7.15Hz), 4.08 (2H, s), 3.68(2H, brs), 3.46(1H, d, J=10.24Hz), 3.31(1H, d, J=10.24Hz), 2.80(1H, d, J=17.07Hz), 2.56(1H, d, J = 17.07 Hz), 1.53 (3H, d, J = 7.32 Hz), 1.35 (9H, s), 1.28 (3H, t, J = 7.19 Hz).

MS (EI) m/z: 406 (M+H) ⁺ .

[Reference Example 168]

{(1S)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4,3,0]non-5-ene-1- tert-butyl formate

[Formula 275]

(3S)-3-Ethoxycarbonylmethoxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (9.31g, 25.9 mmol) was dissolved in tetrahydrofuran (200ml). Under a nitrogen atmosphere, a 1M tetrahydrofuran solution (64.7 ml) of lithium hexamethyldisilazide was added dropwise at 0°C, and the mixture was stirred for 1.5 hours. Saturated ammonium chloride solution (300ml) was added, followed by extraction with ethyl acetate (900ml). The organic layer was washed with water (300ml) and brine (100ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (200ml). At 0°C, sodium borohydride (1.27 g, 33.67 mmol) was added, and the mixture was stirred for 1 hour. A saturated ammonium chloride solution (200 ml) was added to the reaction solution, followed by extraction with ethyl acetate (600 ml). The organic layer was washed with water (200ml) and brine (200ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (40% ethyl acetate/hexane). The concentrate was dissolved in dichloromethane (150ml). Triethylamine (5.69ml, 41.02mmol) was added, and methanesulfonyl chloride (1.90ml, 24.61mmol) was added dropwise at -10°C. After stirring for 1 hour, saturated ammonium chloride solution (200 ml) was added to the reaction solution, followed by extraction with ethyl acetate (600 ml). The organic layer was washed with water (200ml) and brine (200ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene (150ml). DBU (12.24ml, 82.03mmol) was added and the resulting mixture was stirred at 40°C for 15 hours. The reaction solution was concentrated under reduced pressure, then a saturated ammonium chloride solution (150 ml) was added, followed by extraction with ethyl acetate (400 ml). The organic layer was washed with water (150ml) and brine (150ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (75% ethyl acetate/hexane) to obtain 3.28 g of the title compound as a colorless solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.32-7.29 (5H, m), 6.60 (1H, t, J=2.32Hz), 5.57 (1H, q, J=7.16Hz), 4.50-4.45 (2H , m), 4.24 (1H, dd, J = 18.55, 2.44Hz), 3.26 (1H, d, J = 10.25Hz), 3.21 (1H, d, J = 10.01Hz), 3.13 (1H, d, J = 10.01 Hz), 1.51 (3H, d, J = 7.08 Hz), 1.27 (9H, s).

MS (EI) m/z: 344 (M+H) ⁺ .

[Reference Example 169]

{(1S,6S)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4,3,0]nonane-1- tert-butyl formate;

{(1S,6R)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[43,0]nonane-1- tert-butyl formate

[Formula 276]

{(1S)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4,3,0]non-5-ene-1 tert-Butyl-yl}carboxylate (231 mg, 0.67 mmol) was dissolved in THF. 10% palladium-carbon (50% wet) (100 mg) was added, and the resulting mixture was stirred under hydrogen atmosphere for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (20% ethyl acetate/hexane→50%) to obtain 187 mg of the title compound (1S, 6S)-isomer (colorless solid) and 44 mg of the title compound (1S, 6R) - isomer (colorless solid).

(1S,6S)-isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.29-7.24 (5H, m), 5.48 (1H, q, J = 7.24Hz), 4.41 (1H, d, J = 10.24Hz), 4.10 (1H, dd , J=10.98, 4.39Hz), 3.38-3.33(2H, m), 3.17(1H, d, J=9.76Hz), 3.08(1H, d, J=10.00Hz), 2.28-2.19(2H, m) , 1.96-1.92 (1H, m), 1.46 (3H, d, J=7.32Hz), 1.23 (9H, s).

MS (EI) m/z: 346 (M+H) ⁺ .

(1S,6R)-isomers:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.26 (5H, m), 5.54 (1H, q, J = 7.07Hz), 4.12 (1H, d, J = 11.71Hz), 3.82-3.77 (1H , m), 3.39 (1H, m), 3.29 (1H, d, J=11.71Hz), 3.02 (1H, t, J=4.63Hz), 2.91 (2H, dd, J=18.29, 10.24Hz), 2.03 -2.01 (2H, m), 1.53 (3H, d, J=7.07Hz), 1.41 (9H, s).

MS (EI) m/z: 346 (M+H) ⁺ .

[(1S,6S)-3-Oxa-8-benzyloxycarbonyl-8-azabicyclo[4,3,0]nonan-1-yl]carboxylic acid tert-butyl ester

[Formula 277]

Under nitrogen atmosphere, [(1S,6S)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4,3,0] Nonan-1-yl] tert-butyl formate (3.36g, 9.73mmol) was dissolved in tetrahydrofuran (50ml), and a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (48.63ml) was added dropwise. After stirring for 3 days, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80° C. for 2 hr. The reaction solution was concentrated under reduced pressure, then saturated ammonium chloride solution (100 ml) was added, followed by extraction with ethyl acetate (300 ml). The organic layer was washed with water (100ml) and brine (100ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by short column chromatography on silica gel (35% ethyl acetate/hexane). The obtained crude product was dissolved in 1,2-dichloroethane (18ml). Benzyloxycarbonyl chloride (3.40 g, 19.91 mmol) was added, and the resulting mixture was stirred at 40°C for 1 day. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (35% ethyl acetate/hexane) to obtain 2.39 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.24 (5H, m), 5.14 (2H, s), 3.88 (1H, dd, J=20.63, 11.84Hz), 3.77-3.54 (6H, m) , 3.48 (1H, t, J=10.50Hz), 3.41-3.33 (1H, m), 2.81-2.70 (1H, m), 1.93-1.80 (1H, m), 1.44 (9H, s).

MS (EI) m/z: 384 (M+Na) ⁺ .

[Reference Example 171]

{(1S,6R)-8-Benzyloxycarbonyl-3-oxa-8-azabicyclo[4,3,0]nonan-1-yl}carboxylic acid tert-butyl ester

[Formula 278]

Under nitrogen atmosphere, {(1S,6R)-3-oxa-7-oxo-8-[(1R)-1-phenylethyl]-8-azabicyclo[4,3,0] Nonan-1-yl}carboxylate tert-butyl (709 mg, 2.05 mmol) was dissolved in tetrahydrofuran (20 ml), and a 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (10.26 ml) was added dropwise. After stirring for 3 days, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80° C. for 2 hr. The reaction solution was concentrated under reduced pressure, then saturated ammonium chloride solution (80 ml) was added, followed by extraction with ethyl acetate (240 ml). The organic layer was washed with water (80ml) and brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (35% ethyl acetate/hexane). The resulting fraction was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (4 ml). Benzyloxycarbonyl chloride (788mg, 4.62mmol) was added, and the resulting mixture was stirred at 40°C for 4 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to obtain 435 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33-7.28 (5H, m), 5.13 (2H, d, J=3.42Hz), 4.48 (1H, dd, J=20.75, 10.50Hz), 4.10-4.07 (1H, m), 3.77 (1H, dd, J = 24.05, 11.11Hz), 3.62-3.52 (2H, m), 3.38 (1H, td, J = 11.66, 2.77Hz), 3.22 (1H, dd, J =10.50, 6.84Hz), 3.07 (1H, dd, J = 10.99, 3.42Hz), 2.24-2.21 (1H, m), 1.98-1.96 (1H, m), 1.63-1.60 (1H, m), 1.44 ( 9H, s).

MS (EI); m/z: 384 (M+Na) ⁺ .

[Reference Example 172]

[(1S,6R)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]methanol benzyl ester

[Formula 279]

Tert-butyl {(1S,6S)-8-benzyloxycarbonyl-3-oxa-8-azabicyclo[4,3,0]nonan-1-yl}carboxylate (2.30g, 6.94mmol) Dissolve in dichloromethane (20ml). Trifluoroacetic acid (10 ml) was added, and the mixture was stirred for 1 day. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide solution (100 ml) was added, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform (200ml×2). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in acetonitrile (40ml). Under nitrogen atmosphere, 1,1-carbonylbis-1H-imidazole (1.55 g, 9.53 mmol) was added at 0° C., the mixture was stirred for 1 hour, and then ammonia gas was bubbled at room temperature. Ethyl acetate and water were added, and the resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. After evaporating the solvent under reduced pressure, the resulting residue was purified by short column chromatography on silica gel (ethyl acetate). The resulting crude product was dissolved in tert-butanol (50ml). Lead tetraacetate (3.98 g, 8.97 mmol) was added, and the resulting mixture was stirred at 80° C. for 1 hour under a nitrogen atmosphere. Sodium bicarbonate (3.52 g, 41.86 mmol) and ethyl acetate were added to the reaction solution, and the resulting mixture was filtered through celite. Then, the filtrate was washed with saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.70 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.31 (5H, m), 5.13 (2H, s), 4.66 (1H, d, J=7.57Hz), 3.86-3.57 (7H, m), 3.36 (1H, dq, J=23.01, 5.45Hz), 2.63-2.55 (1H, m), 1.87-1.79 (1H, m), 1.54-1.50 (1H, m), 1.43 (9H, s).

MS (EI) m/z: 399 (M+Na) ⁺ .

[Reference Example 173]

Benzyl {(1S,6S)-1-tert-butoxycarbonylamino-3-oxa-8-bicyclo[4,3,0]nonan-8-yl}carboxylate ester

[Formula 280]

Dissolve tert-butyl {(1S,6R)-8-benzyloxycarbonyl-3-oxa-8-bicyclo[4,3,0]nonan-1-yl}carboxylate (725mg, 2.01mmol) in di Chloromethane (20ml). Trifluoroacetic acid (4ml) was added, and the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure, 1N sodium hydroxide solution (50 ml) was added, and the resulting mixture was washed with chloroform. The aqueous layer was acidified with hydrochloric acid solution, and extracted with chloroform (50ml×2). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene (20 ml). Under nitrogen atmosphere, triethylamine (406 mg, 4.01 mmol) and diphenoxyphosphoryl azide (740 mg, 2.61 mmol) were added, and the resulting mixture was stirred at 110°C for 1.5 hours. The reaction solution was concentrated under reduced pressure. Then, dioxane (20ml) and 6N hydrochloric acid (20ml) were added, and the resulting mixture was stirred at 50°C for 2 hours. After concentration under reduced pressure and azeotropic distillation with ethanol, 1N sodium hydroxide solution (50 ml) was added, followed by extraction with chloroform (100 ml×2). After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure. Di-tert-butyl dicarbonate (2189 mg, 10.03 mmol) was added to the resulting residue, and the resulting mixture was stirred at 50°C for 1.5 hr. The reaction solution was purified by silica gel column chromatography (60% ethyl acetate/hexane) to obtain 623 mg of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.52-7.26 (5H, m), 5.13 (2H, s), 4.55 (1H, dd, J=19.51, 11.22Hz), 4.45 (1H, d, J= 10.73Hz), 4.25(1H, t, J=12.44Hz), 4.13-4.08(1H, m), 3.70-3.62(1H, m), 3.36-3.34(1H, m), 3.16-3.09(3H, m ), 2.02-1.97 (1H, m), 1.69-1.62 (2H, m), 1.43 (9H, s).

MS (EI) m/z: 399 (M+Na) ⁺ .

[Reference Example 174]

(1S,6R)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonane

[Formula 281]

Benzyl [(1S,6R)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]carboxylate (401mg, 1.07mmol) Dissolve in methanol (20ml). 10% palladium-carbon (50% wet) (200 mg) was added, and the resulting mixture was stirred under hydrogen atmosphere for 2.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure to obtain 256 mg of the title compound as a colorless solid.

MS (EI) m/z: 243 (M+H) ⁺ .

[Example 40]

7-[(1S,6R)-1-amino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 282]

Dissolve (1S,6R)-8-aza-1-tert-butoxycarbonylamino-3-oxabicyclo[4,3,0]nonane (252mg, 1.04mmol) in dimethylsulfoxide (8ml )middle. Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (450.6mg, 1.25mmol) and triethylamine (315.7mg, 3.12mmol), the resulting mixture was stirred at 40°C for 17 hours. Then, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 5 hours. The solvent was evaporated under reduced pressure, and then 10% citric acid solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The resulting fraction was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 8 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was washed with ethanol and ether and dried under reduced pressure to obtain 302 mg of the title compound as pale yellow crystals.

mp: 132-134°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.41 (1H, s), 7.66 (1H, d, J = 14.63Hz), 4.99 (1H, d, J = 63.90Hz), 4.04-4.03 (2H, m), 3.91-3.88(1H, m), 3.82(2H, t, J=11.22Hz), 3.68-3.62(2H, m), 3.59(3H, s), 3.51(1H, d, J=11.95Hz ), 3.37 (1H, d, J=10.98Hz), 2.23-2.20 (1H, m), 1.93-1.91 (1H, m), 1.57-1.47 (3H, m).

Anal _{. Calcd} . _{for C21H23F2N3O5-0.5H2O0.4CHCl3} : C, _55.42 ; H _, 5.30; N, 9.06; F, 8.19 _. Found: C, 55.19; H, 5.19; N, 9.09; F, 8.32.

MS (EI) m/z: 436 (M+H) ⁺ .

IR (ATR) v: 2943, 2887, 2845, 1720, 1622, 1516, 1452, 1346, 1323, 1275 cm ^-1 .

[Example 41]

7-[(1S,6R)-1-amino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 283]

Dissolve (1S,6R)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonane (187mg, 0.77mmol) in dimethylsulfoxide (4ml )middle. Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (316.5mg, 0.92mmol) and triethylamine (93.6mg, 0.92mmol), the mixture was stirred for 14 days. Then, 90% aqueous ethanol (18 ml) and triethylamine (2 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 2 hours. The solvent was evaporated under reduced pressure, and a 10% citric acid solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Then, the residue was purified by PTLC (5% methanol/chloroform), and the resulting fraction was dissolved in concentrated hydrochloric acid and washed twice with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.9 with hydrochloric acid, and extracted twice with 5% methanol/chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. Precipitated crystals were collected by filtration and dried under reduced pressure to obtain 51 mg of the title compound as colorless crystals.

mp: 158-160°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.44 (1H, d, J = 3.17Hz), 7.67 (1H, d, J = 14.16Hz), 5.01 (1H, d, J = 64.94Hz), 4.16 (1H, t, J=6.71Hz), 4.07(1H, dt, J=9.93, 4.46Hz), 4.01(1H, d, J=10.01Hz), 3.95-3.92(1H, m), 3.85(1H, d, J = 11.96Hz), 3.62-3.54 (1H, m), 3.47 (1H, d, J = 11.72Hz), 3.17 (1H, d, J = 9.77Hz), 3.06 (1H, d, J = 10.01 Hz), 2.48 (3H, s), 2.20-2.15 (1H, m), 1.89-1.82 (1H, m), 1.65-1.60 (2H, m), 1.26-1.19 (1H, m).

_{Anal. Calcd} . for _{C21H23F2N3O4.0.75H2O.0.25EtOH} : C, _58.10 ; H, 5.90 _{; N} , 9.45; F, 8.55. Found: C, 58.35; H, 5.86; N, 9.19; F, 8.53.

MS (EI) m/z: 420 (M+H) ⁺ .

IR (ATR) v: 3365, 2945, 2839, 1716, 1616, 1510, 1466, 1454, 1431, 1342, 1311, 1265, 1215 cm ^-1 .

[Reference Example 175]

(1S,6S)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonane

[Formula 284]

Benzyl {(1S,6S)-1-tert-butoxycarbonylamino-3-oxa-8-bicyclo[4,3,0]nonan-8-yl}carboxylate (610mg, 1.62mmol) was dissolved in in methanol (20ml). 10% palladium-carbon (50% wet) (200 mg) was added, and the mixture was stirred under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. 1N sodium hydroxide solution was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and filtering, the solvent was evaporated under reduced pressure to obtain 362 mg of the title compound as a colorless solid.

MS (EI) m/z: 243 (M+H) ⁺ .

[Example 42]

10-[(1S,6S)-1-amino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]-9-fluoro-2,3-dihydro -3-Methyl-(S)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

[Formula 285]

Dissolve (1S,6S)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonane (147.7 mg, 0.61 mmol) in dimethylsulfoxide ( 2.5ml). Add 9,10-difluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxa Oxazine-6-carboxylic acid-BF ₂ chelate (211.3mg, 0.64mmol) and triethylamine (185.7mg, 1.83mmol), the resulting mixture was stirred at 40°C for 18 hours. Then, 90% aqueous ethanol (33 ml) and triethylamine (3 ml) were added to the reaction mixture, which was stirred at 80°C for 4 hours. The solvent was evaporated under reduced pressure and 10% citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The resulting fraction was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethanol-ammonia, and the resulting solution was heated and stirred. After distilling off the ammonia, the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 180 mg of the title compound as colorless crystals.

mp: >300°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.31 (1H, s), 7.51 (1H, d, J = 14.63Hz), 4.58 (1H, d, J = 7.07Hz), 4.45 (1H, dd, J = 11.34, 1.83Hz), 4.27 (1H, d, J = 11.22Hz), 4.08 (1H, dd, J = 11.22, 3.66Hz), 3.93 (1H, d, J = 10.49Hz), 3.78 (1H, dd, J=10.37, 3.05Hz), 3.75-3.68(1H, m), 3.55(1H, d, J=10.98Hz), 3.49-3.43(2H, m), 3.29(1H, d, J=10.00Hz ), 2.04-2.01 (1H, m), 1.81-1.72 (2H, m), 1.52 (3H, d, J=6.59Hz).

_{Anal . Calcd} . for _{C20H22FN3O5-1.5H2O} : C, _55.81 ; H, 5.85; N, 9.76; F, 4.41. Found: C, 55.80; H, 5.89; N, 9.74; F, 4.34.

MS (EI) m/z: 404 (M+H) ⁺ .

IR(ATR) v: 3498, 3407, 3224, 3045, 2956, 2877, 1616, 1573, 1523, 1473, 1379, 1352, 1306, 1261 ^{cm -1} .

[Example 43]

7-[(1S,6S)-1-amino-8-aza-3-oxabicyclo[4,3,0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 286]

(1S,6S)-8-Aza-1-tert-butoxycarbonylamino-3-oxabicyclo[4,3,0]nonane (108.8 mg, 0.45 mmol) was dissolved in dimethylsulfoxide ( 4ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (210.7mg, 0.58mmol) and triethylamine (136.3mg, 1.35mmol), the resulting mixture was stirred at 40°C for 18 hours. Then, 90% aqueous ethanol (30 ml) and triethylamine (3 ml) were added to the reaction solution, and the resulting mixture was stirred at 80°C for 5 hours. The solvent was evaporated under reduced pressure, and 10% citric acid solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The obtained crude product was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The resulting residue was purified by recrystallization from ethanol, and dried under reduced pressure to obtain 121 mg of the title compound as pale yellow crystals.

mp: 190-192°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.36 (1H, d, J = 3.66Hz), 7.65 (1H, d, J = 14.40Hz), 5.06 (1H, dd, J = 64.09, 3.54Hz) , 4.09(1H, dd, J=11.35, 4.03Hz), 4.02-3.95(2H, m), 3.67-3.51(8H, m), 3.24(1H, d, J=10.25Hz), 2.14-2.11(1H , m), 1.88-1.71 (2H, m), 1.54-1.48 (1H, m), 1.36-1.32 (1H, m).

Anal _. Calcd _. for _{C21H23F2N3O5-0.25H2O} : C _{, 57.33} ; H, 5.38; N, 9.55; _F , 8.64. Found: C, 57.28; H, 5.39; N, 9.27; F, 8.48.

MS (EI) m/z: 436 (M+H) ⁺ .

IR(ATR) v: 3502, 3374, 3091, 2948, 2881, 2850, 1716, 1617, 1513, 1450, 1365, 1321, 1309, 1268, 1223 cm ^-1 .

[Example 44]

7-[(1S,6S)-1-amino-3-oxa-8-azabicyclo[4,3,0]nonan-8-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 287]

Dissolve (1S,6S)-1-tert-butoxycarbonylamino-3-oxa-8-azabicyclo[4,3,0]nonane (184.7 mg, 0.76 mmol) in dimethylsulfoxide ( 4ml). Add 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-BF ₂ Chelate (289.4mg, 0.84mmol) and triethylamine (115.7mg, 1.14mmol), the mixture was stirred for 7 days. Then, 90% aqueous ethanol (22 ml) and triethylamine (2 ml) were added to the reaction solution, and the resulting mixture was stirred at 75°C for 2 hr. The solvent was evaporated under reduced pressure and 10% citric acid solution was added, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by short silica gel column chromatography (3% methanol/chloroform). The resulting fraction was dissolved in concentrated hydrochloric acid and washed with chloroform. The aqueous layer was adjusted to pH 12 with aqueous sodium hydroxide solution at 0°C, then adjusted to pH 7.5 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethanol-ammonia water, and the solution was heated and stirred. After distilling off the ammonia, the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 94.7 mg of the title compound as colorless crystals.

mp: 159-161°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.42 (1H, s), 7.67 (1H, d, J = 14.15Hz), 5.03 (1H, d, J = 60.24Hz), 4.10-4.08 (2H, m), 3.96(1H, d, J=10.49Hz), 3.82(1H, d, J=9.27Hz), 3.68(1H, t, J=10.49Hz), 3.61(1H, d, J=10.49Hz) , 3.49(1H, t, J=11.10Hz), 3.26(1H, t, J=8.17Hz), 3.08(1H, d, J=9.51Hz), 2.45(3H, s), 2.21-2.18(1H, m), 1.84-1.57 (3H, m), 1.23 (1H, d, J = 26.10 Hz).

_{Anal .} Calcd. for _{C21H23F2N3O4-1.25H2O} : C _{, 57.07} ; H _, 5.82; N, 9.51; F, 8.60. Found: C, 56.87; H, 5.99; N, 9.49; F, 8.43.

MS (EI) m/z: 420 (M+H) ⁺ .

IR(ATR) v: 3518, 3251, 3059, 2935, 2885, 1720, 1614, 1540, 1508, 1441, 1387, 1358, 1325, 1306, 1273 cm ^-1 .

[Reference Example 176]

(5,6-dihydro-4H-pyran-2-yl)methyl methanesulfonate

[Formula 288]

Under salt ice cooling, methanesulfonyl chloride (17.9ml, 232mmol) was added dropwise to (5,6-dihydro-4H-pyran-2-yl)methanol (25.51g, 193mmol) over 15 minutes [see Synlett , Vol. 5, p. 533 (1997)] and triethylamine (40.4ml, 290mmol) in dichloromethane (600ml). After stirring at the same temperature for 2 hours, triethylamine (18.8ml, 135mmol) and methanesulfonyl chloride (7.5ml, 97mmol) were added, and the resulting mixture was further stirred for 30 minutes. Water (300 ml) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (300ml) and brine (300ml). The organic layer was dried over anhydrous sodium sulfate, then filtered, and the solvent was evaporated under reduced pressure. The resulting crude title compound was used in the next reaction without purification.

[Reference Example 177]

2-Azidomethyl-5,6-dihydro-4H-pyran

[Formula 289]

Water (35ml) and sodium azide (15.1g, 232mmol) were added to crude (5,6-dihydro-4H-pyran-2-yl)methyl methanesulfonate (about 193mmol) N,N -Dimethylformamide (350ml) solution, the mixture was stirred at room temperature for 20 hours. Water (300 ml) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (3 x 200ml) and brine (200ml). The organic layer was dried over anhydrous sodium sulfate, then filtered and the solvent was evaporated to about 300ml under reduced pressure. The resulting crude title compound solution was used in the next reaction without purification.

[Reference Example 178]

2-Aminomethyl-5,6-dihydro-4H-pyran

[Formula 290]

Tetrahydrofuran (500ml), water (50ml) and triphenylphosphine (35.4g, 135mmol) were sequentially added to crude 2-azidomethyl-5,6-dihydro-4H-pyran (about 193mmol), The resulting mixture was heated and stirred on a 60°C oil bath for 2 hours. Ethyl acetate (1 L) was added to the reaction solution, and the aqueous layer was removed. Then, the organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude title compound was used in the next reaction without further purification.

[Reference Example 179]

2-(tritylamino)methyl-5,6-dihydro-4H-pyran

[Formula 291]

Triethylamine (37.7ml, 270mmol) and trityl chloride (41.4g, 149mmol) were sequentially added to crude 2-aminomethyl-5,6-dihydro-4H-pyran (ca. Chloromethane (500ml) solution was added, and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with dichloromethane (500ml), washed with water (2 x 500ml) and brine (500ml), then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90) to obtain 22.2 g (4 steps, 32%) of the title compound as a colorless transparent gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.16-7.49 (15H, m), 4.81 (1H, brs), 3.97 (2H, t, J=5.1Hz), 2.66 (2H, brs), 2.02-2.04 (2H, m), 1.76-1.82 (2H, m).

[Reference Example 180]

2-(tritylamino)methyl-3,4,5,6-tetrahydro-2H-pyran-3-ol

[Formula 292]

A solution of borane-tetrahydrofuran complex in tetrahydrofuran (1M, 187ml, 187mmol) was added dropwise to 2-(tritylamino)methyl-5,6-dihydro- 4H-pyran (22.2g, 62.4mmol) in tetrahydrofuran (180ml) solution. After stirring at room temperature for 2.5 hours, the reaction solution was ice-cooled, and 3N sodium hydroxide solution (208ml, 624mmol) was added dropwise within 10 minutes. Then, at the same temperature, 31% hydrogen peroxide solution (69 ml, 629 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ether (2 x 300ml). The combined organic layers were washed with water (300ml) and brine (300ml), then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was suspended in a mixed solvent of dichloromethane/hexane (1:1, 80ml). Insoluble materials were removed by filtration, and the filtrate was evaporated under reduced pressure to give 18.54 g (80%) of the title compound as a pale yellow gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.41-7.46 (6H, m), 7.26-7.33 (6H, m), 7.18-7.23 (3H, m), 3.81-3.84 (1H, m), 3.73- 3.76(1H, m), 3.60-3.66(1H, m), 3.25-3.32(1H, m), 3.05-3.10(1H, m), 2.64(1H, dd, J=11.6, 7.7Hz), 2.35( 1H, dd, J=11.7, 4.9 Hz), 2.13-2.21 (1H, m), 1.83-1.86 (1H, m), 1.62-1.68 (1H, m), 1.38-1.48 (1H, m).

[Reference Example 181]

2-(tritylamino)methyl-5,6-dihydro-2H-pyran-3(4H)-one

[Formula 293]

Under a nitrogen atmosphere, a solution of sulfur trioxide-pyridine complex (23.7 g, 149 mmol) in dimethyl sulfoxide (150 ml) was added to 2-(tritylamino)methyl-3 at room temperature, 4,5,6-Tetrahydro-2H-pyran-3-ol (18.54g, 49.6mmol) and triethylamine (45ml, 323mmol) in dimethylsulfoxide (150ml). The mixture was stirred at the same temperature for 10 hours. The reaction solution was poured into ice water (1 L), then extracted with ethyl acetate (2 x 1 L). Then, the organic layers were combined and washed with water (2 x 1 L) and brine (1 L). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95→10:90→20:80) to obtain 9.56 g (52%) of the title compound as a colorless transparent gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.44-7.47 (6H, m), 7.15-7.28 (9H, m), 3.93-4.00 (2H, m), 3.65-3.72 (1H, m), 2.41- 2.61 (4H, m), 1.99-2.20 (2H, m).

[Reference Example 182]

6-(tritylamino)methyl-7-oxa-1,3-diazaspiro[4.5]decane-2,4-dione

[Formula 294]

Under nitrogen atmosphere, 2-(tritylamino)methyl-5,6-dihydro-2H-pyran-3(4H)-one (9.56g, 25.7mmol), sodium cyanide (2.52g , 51.4mmol), ammonium chloride (2.75g, 51.4mmol), ammonium carbonate (10.18g, 128.7mmol), a mixture of concentrated ammonia (50ml) and ethanol (50ml) was stirred on an oil bath at 60°C for 4.5 hours. Ammonium carbonate (10.18 g, 128.7 mmol) was added, and the mixture was further stirred at the same temperature for 19.5 hours. The resulting reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (300ml, 100ml). Then, the organic layers were combined and washed with water (2 x 100ml) and brine (100ml). The obtained organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the solvent was evaporated under reduced pressure to obtain 11.35 g (quantitative) of the title compound as a colorless amorphous.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.65 (1H, s), 7.38-7.49 (6H, m), 7.15-7.30 (9H, m), 5.79 (1H, s), 3.97 (1H, dm, J=13.2Hz), 3.68 (1H, dd, J=7.1, 5.1Hz), 3.51 (1H, dt, J=11.2, 4.4Hz), 2.34 (1H, dd, J=12.1, 5.0Hz), 2.18- 2.23 (1H, m), 2.05-2.14 (1H, m), 1.81 (1H, brd, J=13.4Hz), 1.55-1.70 (2H, m).

[Reference Example 183]

(2R ^* , 3R ^* )-3-amino-2-(tert-butoxycarbonylamino)methyl-3,4,5,6-tetrahydro-2H-pyran-3- formic acid

[Formula 295]

At room temperature, 6-(tritylamino)methyl-7-oxa-1,3-diazaspiro[4.5]decane-2,4-dione (10.69 g, 24.2 mmol) was dissolved in In trifluoroacetic acid (50ml), the mixture was stirred for 15 minutes. Water (50 ml) was added to the reaction solution, and the solvent was evaporated under reduced pressure. Then, water (200ml) was added to the residue, and the resulting mixture was washed with diethyl ether (2 x 100ml).

Sodium hydroxide (40 g, 1.0 mol) was added to the resulting solution (about 250 ml), and the resulting mixture was heated to reflux on an oil bath at 130° C. for 16 hours. The reaction solution was ice-cooled, then gradually added concentrated hydrochloric acid to adjust the pH to 7.0, and the solvent was evaporated under reduced pressure.

The resulting residue was suspended in 1N sodium hydroxide solution (75 ml) and 1,4-dioxane (150 ml). Di-tert-butyl dicarbonate (52.8 g, 242 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 5 days. The solvent was concentrated under reduced pressure. Then, the residue was suspended in 1N sodium hydroxide solution (300ml), and the resulting mixture was washed with diisopropyl ether (3x300ml). Under ice-cooling, concentrated hydrochloric acid was gradually added to the resulting aqueous layer to adjust the aqueous layer to pH 7.0. The solvent was evaporated under reduced pressure. The residue was suspended in methanol (100ml), then filtered to remove most of the sodium chloride (2x). The residue was then purified by ion exchange resin HP-20 (eluting with methanol) to afford 1.21 g (18% over three steps) of the title compound as a beige solid.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 3.99-4.03 (1H, m), 3.69-3.73 (1H, m), 3.53 (1H, t, J=12.0Hz), 3.00-3.12 (2H, m ), 2.00-2.06 (1H, m), 1.70-1.87 (2H, m), 1.52-1.56 (1H, m), 1.43 (9H, s).

[Reference Example 184]

(2R ^* , 3R ^* )-3-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)methyl-3,4,5,6-tetra Hydrogen-2H-pyran-3-carboxylic acid

[Formula 296]

Under ice cooling, N-(benzyloxycarbonyloxy)succinimide (1.49g, 5.98mmol) was added to (2R ^* ,3R ^* )-3-amino-2-(tert-butoxycarbonylamino) Methyl-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (1.09g, 3.99mmol) and triethylamine (1.11ml, 7.96mmol) in tetrahydrofuran (10ml)/water (10ml) solution, the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate (150ml) and washed with 1N hydrochloric acid (50ml). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=2:98→5:95), then dissolved in 1N sodium hydroxide solution (50ml) and washed with ether (2×20ml) to remove residual benzyl alcohol. The resulting aqueous layer was adjusted to pH 1-2 with concentrated hydrochloric acid, and extracted with dichloromethane (2 x 80ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure to afford 1.08 g (66%) of the title compound as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.28 (5H, m), 5.53 (1H, brs), 5.20-5.07 (2H, m), 4.94 (1H, brs), 3.99 (1H, dd, J=11.1, 4.5Hz), 3.65(1H, m), 3.55-3.30(2H, m), 3.17(1H, m), 2.59(1H, m), 2.06(1H, m), 1.73(1H, m ), 1.57-1.51 (1H, m), 1.43 (9H, m).

MS (ESI); m/z: 309 (M-Boc+2H) ⁺ .

[Reference Example 185]

(1R ^* , 6R ^* )-6-(benzyloxycarbonylamino)-2-oxa-7-oxo-8-azabicyclo[4.3.0]nonane

[Formula 297]

At room temperature, (2R ^* , 3R ^* )-3-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)methyl-3,4,5,6-tetrahydro-2H-pyridine Furan-3-carboxylic acid (1.08 g, 2.64 mmol) was dissolved in 4N hydrogen chloride in 1,4-dioxane. The mixture was stirred at the same temperature for 20 minutes, and then the solvent was evaporated under reduced pressure. The resulting residue was distilled azeotropically with dioxane (2 times) to give 921 mg (quantitative) of a residue.

691 mg (2.00 mmol) of the obtained residue and N,N-diisopropylethylamine (1.75 ml, 10.0 mmol) were dissolved in dichloromethane (25 ml). At room temperature, bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (1.02 g, 4.01 mmol) was added, and the mixture was stirred at the same temperature for 18 hours. The reaction solution was diluted with chloroform (50ml), and washed successively with 1N hydrochloric acid (30ml), water (30ml), saturated sodium bicarbonate solution (30ml) and brine (30ml). The resulting organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure at room temperature. The residue was purified by silica gel column chromatography (methanol:chloroform=2:98→5:95) to obtain 834 mg (quantitative) of the title compound as a light brown gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.23 (5H, m), 5.60 (1H, brs), 5.42 (1H, brs), 5.12 (2H, s), 4.06 (1H, dd, J= 11.7, 5.4Hz), 3.67-3.55(2H, m), 3.43-3.38(1H, m), 3.33(1H, t, J=4.2Hz), 2.76-2.68(1H, m), 1.94-1.82(1H , m), 1.65-1.55 (2H, m).

MS (ESI); m/z: 291 (M+H) ⁺ .

[Reference Example 186]

(1R ^* , 6R ^* )-8-benzyl-6-(benzyloxycarbonylamino)-2-oxa-7-oxo-8-azabicyclo [4.3.0] Nonane

[Formula 298]

Under ice cooling, sodium hydride (55% dispersion in mineral oil, 111 mg, 2.54 mmol) was added to (1R ^* ,6R ^* )-6-(benzyloxycarbonylamino)-2-oxa-7-oxo- In a solution of 8-azabicyclo[4.3.0]nonane (818 mg, about 1.96 mmol) in N,N-dimethylformamide, the mixture was stirred at the same temperature for 20 minutes. Then, benzyl bromide (0.304ml, 2.56mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into 10% citric acid solution (30ml), followed by extraction with ethyl acetate (100ml). The resulting organic layer was washed with water (2 x 30ml) and brine (30ml), dried over anhydrous sodium sulfate and filtered, then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=50:50→methanol:chloroform=1:99→2:98) to obtain 224 mg (0.59 mmol, three steps, 30%) of the title compound as colorless Transparent gel-like solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.16 (5H, m), 5.38 (1H, brs), 5.20-5.09 (2H, m), 4.46 (2H, s), 4.02 (1H, dd, J=11.5, 5.7Hz), 3.57-3.50(2H, m), 3.23(1H, t, J=9.2Hz), 3.13(1H, dd, J=9.2, 6.7Hz), 2.75(1H, m), 1.94-1.84(1H, m), 1.68-1.61(1H, m), 1.56-1.53(1H, m),

MS (ESI); m/z: 381 (M+H) ⁺ .

[Reference Example 187]

(1R ^* , 6R ^* )-6-amino-8-benzyl-2-oxa-7-oxo-8-azabicyclo[4.3.0]nonane

[Formula 299]

10% palladium-carbon catalyst (50% wet, 80 mg) was added to (1R ^* ,6R ^* )-8-benzyl-6-(benzyloxycarbonylamino)-2-oxa-7-oxo-8 -Azabicyclo[4.3.0]nonane (220mg, 0.58mmol) in methanol (10ml) solution, the resulting mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 143 mg (quantitative) of the title compound as a colorless transparent gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.24 (5H, m), 4.58 (1H, d, J = 15.1Hz), 4.38 (1H, d, J = 14.9Hz), 4.09 (1H, dd , J=11.6, 5.5Hz), 3.58-3.40 (3H, m), 3.17 (1H, dd, J=8.1, 6.1Hz), 2.53 (2H, brs), 2.15-2.04 (2H, m), 1.79- 1.72 (1H, m), 1.60-1.55 (1H, m).

MS (ESI); m/z: 247 (M+H) ⁺ .

[Reference Example 188]

(1R ^* , 6S ^* )-8-benzyl-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo[4.3.0]nonane alkyl

[Formula 300]

Under ice cooling, lithium aluminum hydride (65 mg, 1.71 mmol) was added to (1R ^* , 6R ^* )-6-amino-8-benzyl-2-oxa-7-oxo-8-azabicyclo[4.3 .0] a solution of nonane (140mg, 0.57mmol) in THF (6ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled. Water (0.06ml), 15% sodium hydroxide solution (0.06ml) and water (0.18ml) were carefully added successively, and the mixture was stirred at room temperature overnight. Then, anhydrous magnesium sulfate was added, and the mixture was stirred for 10 minutes. The resulting mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.

The resulting residue was dissolved in dichloromethane (3ml). Di-tert-butyl dicarbonate (252 mg, 1.15 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After evaporating the solvent under reduced pressure, the resulting residue was purified by PTLC (methanol:chloroform=2:98) to obtain 50 mg (0.152 mmol, two steps, 26%) of the title compound as a colorless transparent gummy solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.30-7.20 (5H, m), 4.93 (1H, brs), 4.02 (1H, dd, J=11.6, 5.2Hz), 3.81 (2H, s), 3.61 -3.48(3H, m), 3.07(1H, t, J=8.0Hz), 2.71-2.67(2H, m), 2.52(1H, m), 1.90-1.55(3H, m), 1.47(9H, s ).

MS (ESI); m/z: 333 (M+H) ⁺ .

[Example 45]

7-[(1R ^* , 6S ^* )-6-amino-2-oxa-8-azabicyclo[4.3.0]nonan-3-yl]-1-cyclopropyl-6- Fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 301]

10% palladium-carbon catalyst (50% wet, 50 mg) was added to (1R ^* ,6S ^* )-8-benzyl-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo [4.3.0] In a solution of nonane (50 mg, 0.152 mmol) in methanol (10 ml), the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 45 mg of (1R ^* ,6S ^* )-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo[4.3.0]nonane.

The obtained (1R ^* ,6S ^* )-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo[4.3.0]nonane (45 mg), 1-cyclopropyl-6, 7-Difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-BF ₂ chelate (572mg, 1.67mmol), triethylamine (0.128ml, 0.92mmol ) and dimethylsulfoxide (0.5ml) was stirred on a 40°C oil bath for 19 hours. Then, ethanol (16ml), water (4ml) and triethylamine (2ml) were added to the reaction solution, and the resulting mixture was heated to reflux on an oil bath at 110°C and stirred for 2.5 hours. The solvent was evaporated under reduced pressure, and then 10% citric acid solution (20 ml) was added to the obtained residue, followed by extraction with ethyl acetate (60 ml). The organic layer was washed with water (20ml x 2) and brine (20ml), dried over anhydrous sodium sulfate and filtered. Then, the solvent was evaporated under reduced pressure. The resulting residue was dissolved in concentrated hydrochloric acid (10 ml) at room temperature. The resulting acidic solution was transferred to a separatory funnel and washed with chloroform (5 x 30ml, 3 x 50ml). The aqueous layer was adjusted to pH 12.0 with 10 mol/L sodium hydroxide solution under ice cooling, and then adjusted to pH 7.4 with hydrochloric acid. Then, the solvent was evaporated under reduced pressure. The residue was suspended in methanol and filtered, and the filtrate was evaporated under reduced pressure. The residue was then resuspended in methanol and filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by PTLC (lower solvent chloroform:methanol:water=7:3:1), further crystallized and purified with diethyl ether to obtain 10 mg (16%) of the title compound as a pale yellow powder.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.78 (1H, s), 7.79 (1H, d, J=12.9Hz), 4.20-3.60 (5H, m), 3.58 (3H, s), 3.50-3.40 (3H, m), 2.02 (2H, m), 1.80-1.60 (2H, m), 1.35-1.05 (3H, m), 0.81 (1H, m).

_{Anal .} Calcd. _{for C21H24FN3O5} · _0.25H2O · 0.25Et2O: C, 59.99; H, _6.18 ; N, 9.54. Found: C, 59.94; H, 5.94; N, 9.12.

MS (EI) m/z: 417 (M ⁺ ).

_HRMS (FAB) Calcd _{for C2iH24FN3O5} : 417.1700 _. Found value: 417.1695.

[Example 46]

(3S)-10-[6-Amino-8-azatricyclo[4.3.0.01,3]nonan-8-yl]-9-fluoro-2,3-dihydro-3-(S)- Methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid

[Formula 302]

Triethylamine (0.266ml, 1.91mmol) and (3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3 -de][1,4]benzoxazine-6-carboxylic acid-BF ₂ chelate (209 mg, 0.635 mmol) was added to 6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^{1 , 3} ] into a solution of nonane (160 mg, 0.666 mmol) in dimethyl sulfoxide (1.27 ml), and the resulting mixture was stirred at 35° C. for 16 hours. A mixed solution of ethanol:water=4:1 (10ml) and triethylamine (1ml) was added to the reaction solution, and the mixture was heated under reflux for 2.5 hrs. The reaction solution was concentrated under reduced pressure, and then 10% citric acid solution (40 ml) was added to the residue, followed by extraction with ethyl acetate (50 ml). The interface portion was extracted with chloroform. The organic layer was washed with water (40ml) and brine (40ml) respectively, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99.5:0.5→99:1→98:2→96:4→92:8). The obtained residue (224 mg) was dissolved in concentrated hydrochloric acid (1.5 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (25ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (80ml×3, 60ml×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue (190 mg) was dissolved in hot ethanol (about 100 ml), and the insoluble matter was removed by filtration through a grooved filter paper. The filtrate was heated and stirred, and the solvent was gradually distilled off. The solution was concentrated to about 10-20 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration and washed with ethanol and ether. The crystals were dried under reduced pressure at 60°C overnight to obtain 120 mg of the title compound as pale yellow crystals.

¹ H-NMR (0.1N NaOD) δ: 8.32 (1H, s), 7.53 (1H, d, J = 14.46Hz), 4.61-4.59 (1H, m), 4.48 (1H, dd, J = 11.52, 1.96 Hz), 4.32-4.30 (2H, m), 3.85 (1H, dd, J=10.54, 2.70Hz), 3.49 (1H, d, J=9.80Hz), 3.29 (1H, d, J=10.30Hz), 1.95-1.91(2H, m), 1.75(1H, dd, J=12.50, 8.58Hz), 1.52(3H, d, J=6.86Hz), 1.31-1.17(3H, m), 0.82-0.76(2H, m).

_{Anal .} Calcd. _{for C2iH22FN3O4 :} C, 63.15; H, 5.55; F, 4.76; N, 10.52. Found: C, 62.94; H, 5.53; F, 4.62; N, 10.40.

MS (ESI) m/z: 400 (M+H) ⁺ .

IR(ATR): 3370, 2933, 2877, 1708, 1618, 1523, 1463, 1444, 1396, 1353, 1311, 1274, 1228, 1145, 1085, 1045, 985, 970, 956, 860, 831 ^{, 800cm-1} .

[Reference Example 189]

(3S)-3-(3-Oxo-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 303]

Under nitrogen atmosphere, dichloromethane (35ml) was cooled with dry ice-methanol. Oxalyl chloride (3.45ml, 39.5mmol) and dimethylsulfoxide (4.68ml, 66.0mmol) were added, and the resulting mixture was stirred under cooling for 15 minutes. (3S)-3-(3-Hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.58 g, 13.2 mmol) in dichloromethane (31 ml), and the resulting mixture was stirred under cooling for 1 hour. Triethylamine (11.1 ml, 79.5 mmol) was added under cooling, and the resulting mixture was stirred under cooling for 1 hour and then at room temperature for 1 hour. Saturated ammonium chloride solution (100ml) was added to the reaction solution, followed by extraction with chloroform (100ml x 1, 80ml x 1). The organic layer was washed with brine (120ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→60:40→50:50→40:60→34:66→25:75), 4.59 g of the title compound were obtained as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 9.76 (1H, s), 7.35-7.24 (5H, m), 5.49 (1H, q, J=7.19Hz), 3.34 (1H, d, J=10.05Hz), 3.13 (1H, d, J = 10.05Hz), 2.94 (1H, d, J = 16.91Hz), 2.44 (2H, dt, J = 11.52, 4.72Hz), 2.29 (1H, d, J = 16.91Hz), 2.12-2.05 (1H, m), 1.99-1.91 (1H, m), 1.52 (3H, d, J=7.11Hz), 1.32 (9H, s).

MS (ESI) m/z: 346 (M+H) ⁺ .

[Reference Example 190]

(3S)-3-(3-oxo-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate

[Formula 304]

Under nitrogen atmosphere, mix 1,8-diazobicyclo[5.4.0]-7-undecene (2.17ml, 14.5mmol) and Eschenmoser salt (3.66g, 19.8mmol) ) added to (3S)-3-(3-oxo-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl Dichloromethane (88.0 ml) solution was added, and the mixture was stirred at room temperature for 16 hours. Then, Eschen Moser's salt (1.22 g, 6.59 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (150ml) was added to the reaction solution, followed by extraction with chloroform (100ml x 1, 150ml x 1). The organic layer was washed with brine (200ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→60:40→50:50→34:66) to obtain 3.14 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 9.51 (1H, s), 7.34-7.24 (5H, m), 6.31 (1H, s), 6.12 (1H, s), 5.47 (1H, q, J=7.08Hz ), 3.31(1H, d, J=10.50Hz), 3.22(1H, d, J=10.25Hz), 2.89(1H, d, J=17.09Hz), 2.75-2.64(2H, m), 2.41(1H , d, J = 17.09 Hz), 1.51 (3H, d, J = 7.08 Hz), 1.30 (9H, s).

MS (ESI) m/z: 358 (M+H) ⁺ .

[Reference Example 191]

(3S)-3-(3-Hydroxy-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3- tert-butyl formate

[Formula 305]

Under nitrogen atmosphere, ethanol (43.9ml) was added to sodium borohydride (644mg, 17.0mmol), and the resulting mixture was cooled with ice-acetone. Under cooling, cesium chloride heptahydrate (6.55 g, 17.6 mmol) and (3S)-3-(3-oxo-2-methylene-1-propyl)-5-oxo-1- [(1R)-1-Phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.14 g, 6.55 mmol). The mixture was stirred under cooling for 1 hour, then cesium chloride heptahydrate (1.64 g, 4.40 mmol) and sodium borohydride (166 mg, 4.39 mmol) were added. The mixture was stirred under cooling for 30 minutes, and then ice-cooled. A saturated ammonium chloride solution (150 ml) was added to the reaction solution. The mixture was concentrated under reduced pressure and ethanol was removed. The mixture was extracted with ethyl acetate (150ml×1, 100ml×1). The organic layer was washed with brine (200ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→66:34→50:50→34:66→25:75→17:83→5:95), 2.83 g of the title compound were obtained.

¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m), 5.49 (1H, q, J = 7.11Hz), 5.15 (1H, d, J = 1.23Hz), 4.87 (1H, d, J =1.23Hz), 3.98(2H,d,J=6.37Hz), 3.33(1H,d,J=10.30Hz), 3.22(1H,d,J=10.30Hz), 2.94(1H,d,J=17.16 Hz), 2.62(1H, d, J=14.95Hz), 2.46(1H, d, J=15.44Hz), 2.44(1H, d, J=17.16Hz), 1.72(1H, t, J=6.25Hz) , 1.52 (3H, d, J = 7.11 Hz), 1.32 (9H, s).

MS (ESI) m/z: 360 (M+H) ⁺ .

[0751]

[Reference Example 192]

(3S)-3-(3-Bromo-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-methan tert-butyl acid

[Formula 306]

Under ice-water cooling, carbon tetrabromide (3.24g, 9.77mmol) and triphenylphosphine (2.57g, 9.80mmol) were added to (3S)-3-(3-hydroxy-2- Methyl-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester in dichloromethane (113ml). The mixture was stirred under ice-water cooling for 15 minutes, then concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→80:20→75:25→66:34) to obtain 3.22 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.22 (5H, m), 5.48 (1H, q, J=7.19Hz), 5.26 (1H, s), 4.89 (1H, s), 3.88 (2H, s ), 3.36 (1H, d, J = 10.05Hz), 3.21 (1H, d, J = 10.30Hz), 2.99 (1H, d, J = 16.91Hz), 2.72 (1H, d, J = 15.44Hz), 2.57 (1H, d, J = 15.44Hz), 2.44 (1H, d, J = 16.91Hz), 1.51 (3H, d, J = 7.35Hz), 1.30 (9H, s).

MS (ESI) m/z: 422 (M ⁺ ).

[Reference Example 193]

[(1S,5S)-7-Methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-aza-bicyclo[3.3.0]octane -1-yl] tert-butyl formate

[Formula 307]

Under cooling with ice-acetone, under a nitrogen atmosphere, a THF solution of 1M lithium hexamethyldisilazide (9.15ml, 9.15mmol) was added to (3S)-3-(3-bromo-2-methylene (1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.22g, 7.62mmol) in THF (76.2ml) , the mixture was stirred for 10 minutes. A 10% citric acid solution (120ml) was added to the reaction solution, followed by extraction with ethyl acetate (100ml x 2). The organic layer was washed with brine (200ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→83:17→80:20→75:25) to obtain 2.47 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.23 (5H, m), 5.46 (1H, q, J = 7.11Hz), 4.88 (2H, d, J = 1.72Hz), 3.31 (1H, d, J = 10.30Hz), 3.13 (2H, t, J = 6.37Hz), 3.08 (2H, d, J = 10.30Hz), 2.89 (1H, d, J = 15.69Hz), 2.72 (2H, d, J = 6.13 Hz), 2.30 (1H, d, J = 15.93 Hz), 1.47 (3H, d, J = 7.11 Hz), 1.35 (9H, s).

MS (ESI) m/z: 342 (M+H) ⁺ .

[Reference Example 194]

[(1S,5S)-7-Methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane -1-yl]formic acid

[Formula 308]

Under ice-cooling, trifluoroacetic acid (26.0ml) was added to [(1S,5S)-7-methylene-4-oxo-3-[(1R)-1-phenylethyl]- In a solution of tert-butyl 3-aza-bicyclo[3.3.0]octan-1-yl]carboxylate (2.47g, 8.66mmol) in dichloromethane (26.0ml), the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, followed by azeotropic distillation of trifluoroacetic acid and toluene (×3). Under ice-cooling, 1 mol/L sodium hydroxide solution (15.0 ml) was added to the obtained residue, and the obtained mixture was washed with diethyl ether (60 ml×2). The aqueous layer was acidified with 6mol/L hydrochloric acid (4ml) under ice cooling, and then extracted with ethyl acetate (100ml×2). The organic layers were combined, washed with water (100ml) and brine (100ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.15 g of the title compound as white crystals.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m), 5.48 (1H, q, J = 7.03Hz), 4.93 (2H, s), 3.40 (1H, d, J = 10.30Hz), 3.27(1H,dd,J=7.48,4.78Hz), 3.16(1H,d,J=10.54Hz), 3.02(1H,d,J=15.93Hz), 2.77(2H,d,J=5.39Hz), 2.38 (1H, d, J = 15.93 Hz), 1.50 (3 H, d, J = 7.11 Hz).

MS (ESI) m/z: 342 (M+H) ⁺ .

[Reference Example 195]

(1S,5S)-1-Amino-7-methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0] Octane

[Formula 309]

Under nitrogen atmosphere, triethylamine (0.489ml, 3.50mmol) and diphenoxyphosphoryl azide (0.491ml, 2.28mmol) were added to [(1S, 5S)-7- Methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-1-yl]carboxylic acid (500mg, 1.75mmol) in toluene (8.75ml) solution. The mixture was stirred at room temperature for 30 minutes, then at 100°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and triethylamine and toluene were azeotropically removed (×3). 1,4-Dioxane (4.37ml) and 6mol/L hydrochloric acid (4.37ml) were added to the obtained residue, and the resulting mixture was stirred at 50°C for 1 hour. The reaction solution was diluted with water (18.0ml) and washed with ether (60ml×2). The aqueous layer was basified with 1mol/L sodium hydroxide solution, and then extracted with chloroform (80ml×1, 70ml×1). The organic layer was washed with water (80ml) and brine (80ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 238 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.24 (5H, m), 5.53 (1H, q, J = 7.11 Hz), 4.92 (2H, brs), 3.25 (1H, d, J = 10.05 Hz), 2.79-2.73 (3H, m), 2.58 (1H, dd, J = 9.44, 4.04 Hz), 2.40 (2H, dd, J = 35.17, 15.57 Hz), 1.48 (3H, d, J = 7.11 Hz).

MS (ESI) m/z: 257 (M+H) ⁺ .

[Reference Example 196]

(1S,5R)-1-Amino-7-methylene-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane

[Formula 310]

Add 65% sodium bis(2-methoxyethoxy)aluminum hydride in toluene (0.539ml, 1.79mmol) to (1S,5S)-1-amino-7-methylene-4-oxo- 3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (115mg, 0.449mmol) in toluene (2.24ml) solution, the mixture was stirred at room temperature for 30 minutes , and stirred at 80° C. for 30 minutes. Under ice cooling, 5 mol/L sodium hydroxide solution (15.0 ml) was added to the reaction solution while stirring, and extracted with toluene (30 ml×1, 20 ml×1). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 106 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.19 (5H, m), 4.80-4.78 (2H, m), 3.14 (1H, q, J=6.45Hz), 2.78 (1H, t, J=8.21Hz ), 2.65-2.56 (2H, m), 2.47 (1H, d, J=14.71Hz), 2.33 (1H, d, J=9.07Hz), 2.22 (1H, d, J=14.95Hz), 2.13-2.06 (3H, m), 1.31 (3H, d, J = 6.62 Hz).

MS (ESI) m/z: 243 (M+H) ⁺ .

[Reference Example 197]

(1S,5R)-1-tert-butoxycarbonylamino-7-methylene-3-[(1R)-1-phenylethyl]-3-azabis cyclo[3.3.0]octane

[Formula 311]

Under nitrogen atmosphere, di-tert-butyl dicarbonate (191 mg, 0.875 mmol) was added to (1S,5R)-1-amino-7-methylene-3-[(1R)-1-phenylethyl] - in a solution of 3-azabicyclo[3.3.0]octane (106mg, 0.437mmol) in dichloromethane (2.18ml), and the mixture was stirred at room temperature for 22 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→88:12→84:16→80:20→75:25) to obtain 203 mg of the title compound , as a transparent oil.

¹ H-NMR (CDCl ₃ ) δ: 7.29-7.22 (5H, m), 4.86 (1H, brs), 4.79 (2H, d, J=7.84Hz), 3.16 (1H, q, J=6.45Hz), 2.92(1H, d, J=9.07Hz), 2.76(4H, t, J=8.58Hz), 2.67-2.57(4H, m), 2.40(2H, d, J=9.56Hz), 2.08-1.99(2H , m), 1.43 (9H, s), 1.31 (3H, d, J=6.62Hz).

MS (ESI) m/z: 343 (M+H) ⁺ .

[Reference Example 198]

(1S,5R)-3-Benzyloxycarbonyl-1-tert-butoxycarbonylamino-7-methylene-3-azabicyclo [3.3.0] Octane

[Formula 312]

Under nitrogen atmosphere, benzyl chloroformate (0.250ml, 1.75mmol) was added to (1S,5R)-1-tert-butoxycarbonylamino-7-methylene-3-[(1R)-1- Phenylethyl]-3-azabicyclo[3.3.0]octane residue (200mg, equivalent to 0.437mmol) in dichloromethane (1.94ml) solution, the mixture was stirred at room temperature for 15 hours, and then Stir at 40°C for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→87:13→86:14→83:17→80:20→75:25) to give 95.1 mg of the title compound as a clear oil.

¹ H-NMR (CDCl ₃ ) δ: 7.36-7.30 (7H, m), 5.12 (2H, s), 4.92 (2H, d, J=8.82Hz), 4.67 (1H, brs), 3.74-3.72 (2H , m), 3.56 (1H, d, J=11.77Hz), 3.27-3.24 (1H, m), 2.72-2.68 (4H, m), 2.19-2.17 (1H, m), 1.43 (9H, s).

MS (ESI) m/z: 373 (M+H) ⁺ .

[Reference Example 199]

(1S,5R)-3-Benzyloxycarbonyl-1-tert-butoxycarbonylaminospiro(3-azabicyclo[3.3.0]octane -7,1'-cyclopropane)

[Formula 313]

In an open system, N-methyl-N'-nitro-N-nitrosoguanidine (50% aqueous mixture, 6 g) was added to 40% potassium hydroxide solution (18 ml) and From a two-layer solution of ether (60 mL), diazomethane in ether was prepared.

In an open system, palladium acetate (5.26 mg, 0.0234 mmol) was added to (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylamino-7-methylene-3 under ice cooling -Azabicyclo[3.3.0]octane (175mg, 0.469mmol) in diethyl ether (4.69ml). Under ice-cooling, diazomethane diethyl ether solution (20 ml) prepared previously was slowly added to the solution, and the mixture was stirred at room temperature for 16 hr. After filtering through celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→88:12→87:13→86:14→85:15→83:17→80: 20→75:25), to obtain 138 mg of the title compound as a transparent oil.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 5.13 (2H, s), 4.80 (1H, d, J=9.31Hz), 3.77-3.72 (3H, m), 3.37-3.35 (1H, m), 2.66 (1H, s), 2.05-1.97 (3H, m), 1.60 (1H, s), 1.43 (10H, s), 0.47-0.46 (4H, m).

MS (ESI) m/z: 387 (M+H) ⁺ .

[Reference Example 200]

(1S,5R)-1-tert-butoxycarbonylaminospiro(3-azabicyclo[3.3.0]octane-7,1′-cyclopropane)

[Formula 314]

Under nitrogen atmosphere, 10% palladium-carbon catalyst (45.6mg, 30wt%) was added to (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylaminospiro(3-azabicyclo[ 3.3.0] Octane-7,1'-cyclopropane) (152mg, 0.393mmol) in methanol (3.93ml). After replacing the original atmosphere with hydrogen, the mixture was stirred at room temperature for 30 minutes. After replacing the original atmosphere with nitrogen, the reaction solution was filtered through celite and concentrated under reduced pressure to obtain 97.9 mg of the title compound as a transparent oil.

MS (ESI) m/z: 253 (M+H) ⁺ .

[Example 47]

7-[(1S,5R)-1-aminospiro(3-azabicyclo[3.3.0]octane-7,1′-cyclopropane)-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[Formula 315]

Triethylamine (0.162ml, 0.388mmol) and 1-[(1R,2S)-2-fluorocyclopropan-1-yl]-6,7-difluoro-8-methoxy-1,4-di Hydrogen-4-oxoquinoline-3-carboxylic acid-BF _chelate (140mg, 0.388mmol) was added to (1S,5R)-1-tert-butoxycarbonylaminospiro(3-azabicyclo[3.3. 0] Octane-7,1'-cyclopropane) (97.9 mg, 0.388 mmol) in dimethyl sulfoxide (0.776 ml), and the resulting mixture was stirred at 35°C for 14 hours. A mixed solution of ethanol:water=4:1 (10.0ml) and triethylamine (1.0ml) was added to the reaction solution, and the mixture was heated under reflux for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30ml) and washed with 10% citric acid solution (30ml), water (30ml) and brine (30ml). The organic layer was dried over anhydrous sodium sulfate, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:0→99:1→98:2). The obtained residue (165 mg) was dissolved in concentrated hydrochloric acid (1.0 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (25ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (80ml×5) and chloroform/methanol=10/1 (60ml×1). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in hot ethanol (20 ml), and filtered through a grooved filter paper to remove insolubles. The filtrate was heated and stirred, and the solvent was gradually distilled off. The solution was concentrated to about 5 ml, then stirred overnight at room temperature. Precipitated crystals were collected by filtration and washed with ethanol and ether. The crystals were dried under reduced pressure at 50°C overnight to obtain 86.0 mg of the title compound as pale yellow crystals.

¹ H-NMR (0.1N NaOD) δ: 8.46 (1H, s), 7.70 (1H, d, J=14.15Hz), 5.06-5.04 (1H, m), 4.09-4.04 (1H, m), 3.92- 3.86(1H, m), 3.70-3.68(4H, m), 3.58(1H, d, J=10.73Hz), 3.53-3.49(1H, m), 2.54-2.46(1H, m), 2.15-2.09( 1H, m), 1.86-1.76 (2H, m), 1.67-1.46 (3H, m), 0.57-0.45 (4H, m).

Anal _. Calcd. for _{C23H25F2N3O4-0.5H2O} : _C , _60.79 ; H, 5.77; F _, 8.36; _N , 9.25. Found: C, 60.82; H, 5.73; F, 8.17; N, 9.23.

MS (ESI) m/z: 446 (M+H) ⁺ .

IR (ATR): 2931, 2850, 1725, 1616, 1508, 1434, 1342, 1315, 1270, 1209, 1186, 1120, 1052, 1014, 987, 927, 881, 850, 806, 746 ^{cm -1} .

[Example 48]

7-[(1S,5R)-1-amino-3-azabicyclo[3.3.0]octane-3-yl]-1-cyclopropyl-6,8-difluoro-1,4- Dihydro-4-oxoquinoline-3-carboxylic acid

[Formula 316]

10% palladium-carbon catalyst (M, ca. A solution of bicyclo[3.3.0]octane (363mg, 1.01mmol) in methanol (10.1ml) was stirred at room temperature for 45 minutes in a rubber balloon under an atmosphere of hydrogen. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 229 mg of a residue containing (1S, 5R)-1-(tert-butoxycarbonylamino)-3-azabicyclo[3.3.0]octane as colorless and transparent Gel-like solid.

Under nitrogen atmosphere, triethylamine (0.423ml, 3.03mmol) and 1-cyclopropyl-6,7,8-trifluoro-8-methoxy-1,4-dihydro-4-oxoquine Oline-3-carboxylic acid (272 mg, 0.960 mmol) was added to the residue (229 mg) obtained above containing (1S,5R)-1-tert-butoxycarbonylamino-3-azabicyclo[3.3.0]octane acetonitrile (3.84ml) solution, the mixture was heated to reflux for 6 hours. The reaction solution was ice-cooled, and the precipitated crystals were collected by filtration and washed with acetonitrile and diethyl ether. The crystals were dried overnight at 50°C under reduced pressure. The obtained residue (410 mg) was dissolved in concentrated hydrochloric acid (3 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 15 minutes. After washing with chloroform (40ml×3), the aqueous layer was adjusted to pH 12 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and then extracted with chloroform (80ml×2) and chloroform/methanol=10/1 (100ml×6). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Hot ethanol (150ml) and 28% ammonia water (3-5ml) were added to the residue, and the insolubles were removed by filtration through a grooved filter paper. The solvent was gradually evaporated while heating and stirring. Ammonia was removed azeotropically several times with ethanol. The solution was concentrated to about 10 ml, then stirred at room temperature for 4 hours. Precipitated crystals were collected by filtration and washed with ethanol and ether. The crystals were dried under reduced pressure at 45°C overnight to obtain 289 mg of the title compound as pale yellow crystals.

¹ H-NMR (0.1N NaOD) δ: 8.44 (1H, s), 7.62 (1H, d, J = 13.73Hz), 3.97-3.86 (2H, m), 3.59 (1H, d, J = 10.30Hz) , 3.49 (1H, d, J = 10.30Hz), 3.32 (1H, d, J = 5.64Hz), 2.31-2.26 (1H, m), 2.02 (1H, dt, J = 20.43, 7.48Hz), 1.90- 1.84(1H, m), 1.81-1.74(2H, m), 1.70-1.63(1H, m), 1.51-1.48(1H, m), 1.19(2H, t, J=7.11Hz), 1.07(2H, s).

Anal _. Calcd. for _{C20H21F2N3O3-0.75H2O} : C, _59.62 ; H, 5.63; F, _9.43 ; _{N ,} 10.43. Found: C, 59.69; H, 5.58; F, 9.31; N, 10.35.

MS (ESI) m/z: 390 (M+H) ⁺ .

IR (ATR): 2956, 1612, 1573, 1542, 1508, 1459, 1402, 1351, 1317, 1274, 1201, 1166, 1106, 1031, 979, 817, ^{732 cm -1} .

[Reference Example 201]

(3S, 4S)-3-allyl-4-(tert-butyldimethylsilyloxy)methyl-2-oxo -1-[(1R)-1-phenylethyl]pyrrolidine

[Formula 317]

(4S)-4-(tert-butyldimethylsilyloxy)methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (333.5g, 1.00mol ) and allyl bromide (90.9ml, 1.05mol) were dissolved in tetrahydrofuran (1.10L). At -15°C, lithium hexamethyldisilazide (1.0 M in tetrahydrofuran) (1.10 L, 1.10 mol) was added dropwise, and the resulting mixture was stirred at -5°C for 1 hour. The reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to obtain 327 g of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.42-7.32 (5H, m), 5.93-5.80 (1H, m), 5.57 (1H, q, J=7.1Hz), 5.22-5.12 (2H, m) , 3.56 (1H, dd, J = 10.0, 4.9Hz), 3.48-3.43 (1H, m), 3.34 (1H, dd, J = 10.3, 8.1Hz), 2.82 (1H, dd, J = 9.8, 5.9Hz ), 2.65-2.57(1H, m), 2.48-2.40(2H, m), 2.32-2.24(1H, m), 1.59(3H, d, J=7.6Hz), 0.86(9H, s), 0.00( 6H, s).

[Reference Example 202]

(3S, 4S)-3-allyl-4-(tert-butyldimethylsilyloxy)methyl-1-[(1R)-1-phenyl Ethyl]pyrrolidine

[Formula 318]

Under a nitrogen atmosphere, 65% Red-Al ^™ in toluene (788ml, 2.63mol) was added dropwise to (3S,4S)-3-allyl-4-(tert-butyldimethyl Silyloxy)methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidine (327g, 875mmol) in toluene (1500ml). The reaction solution was stirred at 45°C for 5 hours, then cooled to 0°C and 20% (+)-potassium sodium tartrate tetrahydrate solution (2.00 L) was added. The reaction solution was poured into a mixture of ethyl acetate and brine, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→4:1) to obtain 213 g of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.29-7.10 (5H, m), 5.73-5.63 (1H, m), 4.97-4.87 (2H, m), 3.49 (2H, d, J=6.8Hz) , 3.09(1H, q, J=6.6Hz), 2.57-2.49(2H, m), 2.39(1H, t, J=8.5Hz), 2.20-2.13(1H, m), 2.09-2.00(2H, m ), 1.91-1.83(1H, m), 1.78-1.68(1H, m), 1.28(3H, d, J=6.6Hz), 0.85(9H, s), 0.27(6H, d, J=1.0Hz) .

[Reference Example 203]

(3S,4S)-3-allyl-1-benzyloxycarbonyl-4-hydroxymethylpyrrolidine

[Formula 319]

(3S,4S)-3-allyl-4-(tert-butyldimethylsilyloxy)methyl-1-[(1R)-1-phenylethyl]pyrrolidine (213g, 592mmol) was dissolved in dichloromethane (420ml). Benzyl chloroformate (169.2ml, 1.19mol) was added dropwise, and the resulting mixture was stirred at 55°C for 10 hours and then at room temperature for 14 hours. 1M ethanol solution of hydrochloric acid (250ml, 250mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 24 hours. The reaction solution was extracted with saturated sodium bicarbonate solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to obtain 140 g of the title compound as a pale yellow oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.25 (5H, m), 5.75 (1H, brs), 5.13-5.02 (4H, m), 3.76-3.54 (4H, m), 3.31-3.23 ( 1H, m), 3.15-3.07 (1H, m), 2.32-2.26 (1H, m), 2.14-2.03 (3H, m).

[Reference Example 204]

(3S,4S)-4-Allyl-1-benzyloxycarbonylpyrrolidine-3-carboxylate tert-butyl

[Formula 320]

Oxalyl dichloride (48.0ml, 559mmol) was dissolved in dichloromethane (1000ml). At -70°C, dimethylsulfoxide (39.7ml, 559mmol) was added dropwise, and the mixture was stirred for 15 hours. A solution of (3S, 4S)-3-allyl-1-benzyloxycarbonyl-4-hydroxymethylpyrrolidine (140g, 508mmol) in dichloromethane (400ml) was added dropwise to the reaction solution, and the mixture was stirred 50 minutes. Triethylamine (354ml, 2.54mol) was added dropwise to the reaction solution, and the resulting mixture was stirred at -10°C for 10 minutes. The reaction solution was extracted with water and dichloromethane. Then, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The obtained residue was dissolved in a mixed solution of tert-butanol (250 ml) and tetrahydrofuran (750 ml). Add 2-methyl-2-butene (538ml, 5.08mol), then at 0°C, add sodium chlorite (60.3g, 533mmol) and sodium dihydrogenphosphate dihydrate (238g, 1.52mol) in water ( 250 ml), and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, then added with 1N hydrochloric acid solution, and extracted with ether. The organic layer was washed with 5% sodium thiosulfate solution and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The resulting residue was dissolved in dichloromethane (1000ml). N,N'-diisopropyl-O-tert-butylisourea (509 g, 2.54 mol) was added dropwise, and the resulting mixture was stirred at 50°C for 4 hours and then at room temperature for 15 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→4:1) to obtain 126 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.31 (5H, m), 5.81-5.65 (1H, m), 5.14-5.07 (2H, m), 5.06-5.00 (2H, m), 3.77- 3.63(2H, m), 3.58-3.49(1H, m), 3.13-3.01(1H, m), 2.71-2.59(1H, m), 2.48(1H, brs), 2.36-2.26(1H, m), 2.16-2.04 (1H, m), 1.45 (9H, s).

[Reference Example 205]

(3S,4R)-1-Benzyloxycarbonyl-4-(1-formylvinyl)pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 321]

(3S,4S)-4-allyl-1-benzyloxycarbonylpyrrolidine-3-carboxylic acid tert-butyl ester (70.0 g, 203 mmol) was dissolved in a mixed solution of tetrahydrofuran (350 ml) and water (350 ml). Sodium metaperiodate (86.7 g, 406 mmol) and osmium tetroxide (catalytic amount) were added sequentially, and the mixture was stirred at room temperature for 20 hours. A 10% sodium bisulfite solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The resulting residue was dissolved in dichloromethane (700ml). N, N-dimethylmethylene ammonium iodide (56.3g, 305mmol) and 1,8-diazobicyclo[5.4.0]undecene (33.4ml, 223mmol) were added dropwise, and the mixture was heated at room temperature Stirring was continued for 59 hours. A saturated ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1→4:1) to obtain 56.7 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 9.55 (1H, d, J = 5.1Hz), 7.40-7.28 (5H, m), 6.38 (1H, d, J = 2.0Hz), 6.15 (1H, d , J=3.2Hz), 5.13(2H, d, J=4.1Hz), 3.89-3.74(2H, m), 3.60(1H, t, J=9.6Hz), 3.49-3.41(1H, m), 3.29 (1H, dt, J = 30.0, 9.7 Hz), 3.15-3.07 (1H, m), 1.41 (9H, s).

[Reference Example 206]

(3S,4R)-1-Benzyloxycarbonyl-4-[1-(hydroxymethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 322]

Cerium(III) chloride heptahydrate (57.0 g, 153 mmol) was dissolved in ethanol (700 ml). At 0°C, sodium borohydride (5.79 g, 153 mmol) was added, and the mixture was stirred for 10 minutes. At 0°C, a solution of (3S, 4R)-1-benzyloxycarbonyl-4-(1-formylvinyl)pyrrolidine-3-carboxylic acid tert-butyl ester (55.0g, 153mmol) in ethanol (700ml) was dropped This was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was extracted with 10% citric acid solution, water and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1→2:1) to obtain 42.2 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.20 (1H, brs), 5.17-5.10 (2H, m), 5.04 (1H, d, J=5.4Hz), 4.16 -4.09(3H, m), 3.87-3.77(2H, m), 3.52(1H, dd, J=17.2, 8.9Hz), 3.29(1H, q, J=10.9Hz), 3.18-2.98(2H, m ), 1.43 (9H, s).

[Reference Example 207]

(3S,4R)-1-Benzyloxycarbonyl-4-[1-(bromomethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 323]

Dissolve (3S, 4R)-1-benzyloxycarbonyl-4-[1-(hydroxymethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (30.0g, 83.0mmol) in dichloromethane (300ml )middle. Triphenylphosphine (23.2 g, 87.2 mmol) and carbon tetrabromide (29.4 g, 87.2 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→1:1) to obtain 26.9 g of the title compound as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.30 (5H, m), 5.34 (1H, s), 5.16-5.12 (3H, m), 3.99 (2H, q, J=10.6Hz), 3.91 -3.78 (2H, m), 3.59-3.53 (1H, m), 3.34-3.22 (2H, m), 3.08-2.96 (1H, m), 1.44 (9H, s).

[Reference Example 208]

(1S,5S)-3-Benzyloxycarbonyl-6-methylene-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester

[Formula 324]

(3S, 4R)-1-benzyloxycarbonyl-4-[1-(bromomethyl)vinyl]pyrrolidine-3-carboxylic acid tert-butyl ester (22.8g, 53.7mmol) and 1,3-dimethyl Ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (19.5ml, 161mmol) was dissolved in a mixed solution of tetrahydrofuran (220ml) and toluene (220ml). At -78°C, lithium hexamethyldisilazide (1.0 M in tetrahydrofuran) (80.6 ml, 80.6 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=24:1→2:1) to obtain 8.34 g of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.37-7.24 (5H, m), 5.14 (2H, d, J=2.4Hz), 4.98-4.88 (2H, m), 3.93-3.76 (2H, m) , 3.66(1H, d, J=11.7Hz), 3.59-3.54(1H, m), 3.45-3.38(1H, m), 3.24(1H, dt, J=16.4, 2.6Hz), 2.67-2.57(1H , m), 1.46 (9H, s).

[Reference Example 209]

(1S,5S,6R)-3-Benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl Ester/(1S,5S,6S)-3-Benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert Butyl ester

[Formula 325]

Dissolve tert-butyl (1S,5S)-3-benzyloxycarbonyl-6-methylene-3-azabicyclo[3.2.0]heptane-1-carboxylate (2.00 g, 5.82 mmol) in tetrahydrofuran ( 40ml). A 9-borabicyclo[3.3.1]nonane dimmer (0.5M in tetrahydrofuran) (17.5ml, 8.73mmol) was added dropwise, and the mixture was stirred for 2 hours. At 0°C, 3M sodium hydroxide solution (3.49ml, 10.5mmol) and 30% aqueous hydrogen peroxide solution (2.47ml) were added dropwise to the reaction solution, and the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with water and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1→1:2) to obtain 1.58 g of isomer A (the less polar isomer) of the title compound and 50.0 mg of the isomer B (the more polar isomer) the title compound, all are colorless syrupy substances.

Isomer A; ¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.30 (5H, m), 5.17 (2H, s), 4.00 (1H, d, J=12.4Hz), 3.75-3.54 (4H , m), 3.42 (1H, d, J = 11.7Hz), 3.29 (1H, dd, J = 12.6, 7.9Hz), 3.09 (1H, t, J = 8.2Hz), 2.74-2.64 (1H, m) , 2.67-2.54 (1H, m), 1.47 (9H, s).

Isomer B; ¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.28 (5H, m), 5.17 (2H, s), 3.86-3.56 (6H, m), 3.38 (1H, dd, J= 11.6, 6.0Hz), 2.85-2.78 (1H, m), 2.32-2.22 (1H, m), 2.19-2.09 (1H, m), 1.45 (9H, s).

[Reference Example 210]

(1S,5S)-3-Benzyloxycarbonyl-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (derived from isomer A)

[Formula 326]

(1S,5S)-3-Benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (isomer A) (1.51g, 4.18 mmol) was dissolved in dichloromethane (30ml). Triethylamine (1.28ml, 9.20mmol) and chloromethylsulfonyl chloride (746µl, 8.36mmol) were added dropwise at 0°C, and the mixture was stirred for 15 minutes. At 0°C, the reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The resulting residue was dissolved in tetrahydrofuran (20 ml). At 0° C., tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (16.7 ml, 16.7 mmol) was added dropwise, and the mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1→1:1) to obtain 1.01 g of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.31 (5H, m), 5.18 (2H, s), 4.48-4.26 (2H, m), 3.99 (1H, d, J=12.7Hz), 3.72 (1H, brs), 3.43 (1H, d, J = 12.6Hz), 3.31 (1H, dd, J = 13.2, 7.8Hz), 3.11 (1H, t, J = 8.0Hz), 2.96-2.79 (1H, m), 2.62-2.53 (1H, m), 1.69-1.60 (1H, m), 1.48 (9H, s).

[Reference Example 211]

(1S,5S)-3-Benzyloxycarbonyl-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (derived from isomer B)

[Formula 327]

(1S,5S)-3-Benzyloxycarbonyl-6-hydroxymethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (isomer B) (180 mg, 498 μmol) Dissolve in dichloromethane (4ml). At 0°C, triethylamine (153 µl, 1.10 mmol) and chloromethanesulfonyl chloride (89.0 µl, 996 µmol) were added dropwise, and the mixture was stirred for 15 minutes. The reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate at 0°C. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The resulting residue was dissolved in tetrahydrofuran (4 ml). At 0° C., tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (1.99 ml, 1.99 mmol) was added dropwise, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1→1:1) to obtain 80.6 mg of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.31 (5H, m), 5.17 (2H, s), 4.52-4.31 (2H, m), 3.89-3.56 (3H, m), 3.38 (1H, dd, J = 12.0, 6.6 Hz), 2.89 (1H, t, J = 5.6 Hz), 2.40-2.25 (2H, m), 2.06-2.02 (1H, m), 1.46 (9H, s).

[Reference Example 212]

(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo [3.2.0] Heptane (derived from isomer A)

[Formula 328]

Under ice cooling, trifluoroacetic acid (4ml) was added dropwise to (1S,5S)-3-benzyloxycarbonyl-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert Butyl ester (derived from isomer A) (887 mg, 2.44 mmol) in dichloromethane (4 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then 1M sodium hydroxide solution was added to the residue under ice-cooling. The solution was washed with ether, and under ice-cooling, the aqueous layer was adjusted to pH 2-3 with concentrated hydrochloric acid, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

1,1'-Carbonylbis-1H-imidazole (594 mg, 3.66 mmol) was added to a solution of the obtained residue in acetonitrile (16 ml), and the mixture was stirred for 1 hr. Ammonia gas was bubbled through the reaction solution for 1.5 hours. Then, water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Lead tetraacetate (2.16 g, 4.88 mmol) was added to a solution of the obtained residue in tert-butanol (16 ml), and the resulting mixture was heated and stirred at 80° C. for 15 minutes. After allowing to cool, sodium bicarbonate (2.50 g) and diethyl ether were added to the reaction solution, and the resulting mixture was stirred under ice-cooling for 30 minutes. Insoluble materials were removed by filtration through celite, and the filtrate was washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1→1:1) to obtain 754 mg of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.40-7.29 (5H, m), 5.16 (2H, s), 4.89-4.79 (1H, m), 4.53-4.27 (2H, m), 3.91 (1H, d,J=12.5Hz), 3.77(1H,d,J=11.5Hz), 3.51-3.40(1H,m), 3.33-3.26(1H,m), 3.00-2.86(2H,m), 2.37-2.23 (1H, m), 1.87 (1H, dd, J = 13.1, 6.7 Hz), 1.45 (9H, s).

[Reference Example 213]

(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo [3.2.0] Heptane (derived from isomer B)

[Formula 329]

Under ice cooling, trifluoroacetic acid (3ml) was added dropwise to (1S,5S)-3-benzyloxycarbonyl-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert Butyl ester (derived from isomer B) (660 mg, 1.82 mmol) in dichloromethane (3 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then 1M sodium hydroxide solution was added to the residue under ice-cooling. The solution was washed with ether, and under ice-cooling, the aqueous layer was adjusted to pH 2-3 with concentrated hydrochloric acid, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

1,1'-Carbonylbis-1H-imidazole (443 mg, 2.73 mmol) was added to a solution of the obtained residue in acetonitrile (12 ml), and the mixture was stirred for 1 hr. Ammonia gas was bubbled through the reaction solution for 1.5 hours. Then, water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Lead tetraacetate (1.61 g, 3.64 mmol) was added to a solution of the obtained residue in tert-butanol (12 ml), and the resulting mixture was heated and stirred at 80° C. for 15 minutes. After allowing to cool, sodium bicarbonate (2.00 g) and diethyl ether were added to the reaction solution, and the resulting mixture was stirred under ice-cooling for 30 minutes. Insoluble materials were filtered off through celite, and the filtrate was washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=16:1→1:1) to obtain 590 mg of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.30 (5H, m), 5.15 (2H, s), 4.89-4.74 (1H, m), 4.58-4.32 (2H, m), 3.91 (1H, d, J=11.7Hz), 3.76-3.46(3H, m), 2.83-2.66(1H, m), 2.31(1H, dd, J=10.7, 8.8Hz), 2.19-2.05(2H, m), 1.43 (9H, s).

[Reference Example 214]

(1S, 5R)-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derivative Autoisomer A)

[Formula 330]

(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derived from isomer A ) (625mg, 1.65mmol) was dissolved in tetrahydrofuran (12ml). 20% Palladium hydroxide-carbon (50% wet) (200 mg) was added, and the resulting mixture was stirred under hydrogen atmosphere for 1 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Under ice-cooling, 1M sodium hydroxide solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 403 mg of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.89-4.78 (1H, m), 4.66-4.39 (2H, m), 3.15 (1H, d, J=11.5Hz), 3.07-2.78 (4H, m) , 2.71 (1H, d, J = 10.3Hz), 2.34-2.26 (1H, m), 1.90 (1H, dd, J = 12.7, 8.3Hz), 1.46 (9H, s).

[Reference Example 215]

(1S, 5R)-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derivative Autoisomer B)

[Formula 331]

(1S,5R)-3-Benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derived from isomer B ) (305 mg, 806 μmol) was dissolved in tetrahydrofuran (6 ml). 20% Palladium hydroxide-carbon (50% wet) (100 mg) was added, and the resulting mixture was stirred under hydrogen atmosphere for 1 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Under ice-cooling, 1M sodium hydroxide solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 196 mg of the title compound as a colorless syrup.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 4.82 (1H, brs), 4.58-4.39 (2H, m), 3.16 (1H, d, J = 11.2Hz), 3.06 (1H, dd, J = 11.1, 5.2Hz), 2.85 (2H, dd, J = 19.3, 11.7Hz), 2.65-2.53 (1H, m), 2.27-1.86 (3H, m), 1.44 (9H, s).

[Example 49]

7-[(1S,5R)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro -1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (derivative Born from isomer A)

[Formula 332]

Triethylamine (143 μl, 1.03 mmol) and 6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro -4-oxoquinoline- ₃ -carboxylic acid-BF chelate (309 mg, 855 μmol) was added to (1S,5R)-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-nitrogen Heterobicyclo[3.2.0]heptane (derived from isomer A) (209 mg, 855 μmol) in sulfolane (3 ml). The resulting mixture was stirred at 40°C for 87 hours. Ethanol (20 ml), water (2 ml) and triethylamine (0.5 ml) were added to the reaction solution, and the mixture was heated under reflux for 2 hr. After evaporation of the solvent under reduced pressure, the resulting residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water 3 times and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol=99:1→9:1). The obtained oil (1.02 g) was dissolved in concentrated hydrochloric acid (5 ml) under ice-cooling, and the resulting solution was stirred at room temperature for 15 minutes. The reaction solution was washed 5 times with chloroform, and then the aqueous layer was adjusted to pH 11 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by PTLC (using the lower layer of chloroform:methanol:water=7:3:1 as a developing solvent), and then the obtained fraction was concentrated under reduced pressure. The resulting residue was recrystallized from ethanol to obtain 120 mg of the title compound as a white solid.

mp: 122-125°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.47 (1H, brs), 7.74 (1H, d, J = 13.4Hz), 5.00 (1H, d, J = 64.5Hz), 4.70-4.49 (2H, m), 4.09-4.01(1H, m), 3.75-3.54(6H, m), 3.14(1H, d, J=10.5Hz), 3.02-2.89(1H, m), 2.65(1H, t, J= 7.8Hz), 2.16 (1H, t, J = 11.8Hz), 2.00 (1H, dd, J = 12.7, 7.8Hz), 1.67-1.41 (2H, m).

Anal _{. Calcd} . for _{C21H22F3N3O4-2.5H2O :} C _, 52.28; H _, 5.64; N, 8.71. Found: C, 52.03; H, 5.50; N, 8.47.

IR (KBr) v: 3404, 2963, 1731, 1619, 1579, 1541, 1452, 1392, 1360, 1320, 1293, 1270, 1053 ^{cm -1} .

[Example 50]

7-[(1S,5R)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro -1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (derivative Born from isomer B)

[Formula 333]

Triethylamine (135 μl, 967 μmol) and 6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methoxy-1,4-dihydro- 4-Oxoquinoline-3-carboxylic acid-BF ₂ chelate (291 mg, 806 μmol) was added to (1S,5R)-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-aza Bicyclo[3.2.0]heptane (derived from isomer B) (196 mg, 806 μmol) in sulfolane (2 ml). The resulting mixture was stirred at 40°C for 111 hours. Ethanol (10 ml), water (1 ml) and triethylamine (0.5 ml) were added to the reaction solution, and the mixture was heated under reflux for 1 hr. After evaporation of the solvent under reduced pressure, the resulting residue was extracted with 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with water 3 times and with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform:methanol=99:1→9:1). The obtained oil (515 mg) was dissolved in concentrated hydrochloric acid (5 ml) under ice-cooling, and the solution was stirred at room temperature for 15 minutes. The reaction solution was washed 5 times with chloroform, and then the aqueous layer was adjusted to pH 11 with saturated sodium hydroxide solution. The alkaline solution was adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by PTLC (using the lower layer of chloroform:methanol:water=7:3:1 as a developing solvent), and then the obtained fraction was concentrated under reduced pressure. The resulting residue was recrystallized from ethanol to obtain 125 mg of the title compound as a white solid.

mp: 193-195°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, brs), 7.73 (1H, d, J = 13.7Hz), 4.98 (1H, d, J = 65.2Hz), 4.68-4.48 (2H, m), 4.10-4.04(1H, m), 3.76-3.67(5H, m), 3.58-3.52(1H, m), 3.22(1H, d, J=10.5Hz), 2.46-2.41(1H, m) , 2.40-2.22 (2H, m), 1.96-1.87 (1H, m), 1.69-1.44 (2H, m).

Anal _. Calcd. for _C2iH22F3N3O4 : C, 57.66; H, 5.07; _F , _{13.03 ;} N, 9.61. Found: C, 57.42; H, 5.07; F, 12.98; N, 9.53.

IR(KBr) v: 3393, 3086, 3063, 3034, 2954, 2930, 2897, 2872, 1720, 1621, 1514, 1452, 1395, 1365, 1344, 1318, 1288, 1273, 1186, 1123, 1108, 1060, 1038, 1020 cm ^-1 .

[Example 51]

7-[(1S,5R)-1-amino-6-fluoromethyl-3-azabicyclo[3.2.0]heptane-3-yl]-6-fluoro -1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (derivative Autoisomer A)

[Formula 334]

Under argon atmosphere, (1S,5R)-1-(tert-butoxycarbonylamino)-6-fluoromethyl-3-azabicyclo[3.2.0]heptane (derived from isomer A) ( 157mg, 643μmol), 7-bromo-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquine Phyloline-3-carboxylic acid ethyl ester (226mg, 643μmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (273mg, 438μmol), tris(dibenzylidene A solution of acetone) and dipalladium(0) (134 mg, 146 μmol) and cesium carbonate (381 mg, 1.17 mmol) in dioxane (5.00 ml) was stirred at room temperature for 30 minutes and then at 100° C. for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate and chloroform. Then, the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=7:1→ethyl acetate).

1N Sodium hydroxide solution (1.21 ml) was added to the obtained ethanol (5 ml) solution of light yellow foam at 0°C, and the mixture was stirred at room temperature for 30 hr. A 10% citric acid solution was added to the reaction solution at 0°C, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure.

The obtained residue was dissolved in concentrated hydrochloric acid (5 ml) at 0°C. The mixture was stirred for 15 minutes, then washed 5 times with chloroform. The aqueous layer was adjusted to pH 12 at 0°C with saturated sodium hydroxide solution, then adjusted to pH 7.4 with hydrochloric acid, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure. The residue was purified by PTLC (using the lower layer of chloroform:methanol:water=7:3:1 as developing solvent). Then, the resulting fraction was recrystallized from ethanol to obtain 28.5 mg of the title compound as a white solid.

mp: 130-133°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.46 (1H, d, J = 3.2Hz), 7.73 (1H, d, J = 13.8Hz), 5.01 (1H, d, J = 64.2Hz), 4.78 -4.46(2H, m), 4.13-4.06(1H, m), 3.91-3.84(1H, m), 3.51(1H, d, J=9.6Hz), 3.34(1H, d, J=11.0Hz), 2.99-2.87 (2H, m), 2.71-2.64 (4H, m), 2.24-2.12 (2H, m), 1.66-1.55 (1H, m), 1.29-1.16 (1H, m).

_Anal. Calcd _. for C21H22F3N3O3-2.25H2O- _0.25 IPA _: C, _{54.77 ;} H, 6.02; F, 11.95; N, 8.81. Found values: C, 54.82, H, 5.71; F, 11.84; N, 8.85.

IR (KBr) v: 3414, 2970, 1723, 1616, 1580, 1546, 1508, 1458, 1434, 1394, 1363, 1320, 1103, 1023 ^{cm -1} .

[Reference Example 216]

Ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate

[Formula 335]

2,5-Difluoro-4-bromo-3-methylbenzoic acid (10.7g, 42.4mmol) was dissolved in toluene (160ml). Thionyl chloride (5.00ml, 63.9mmol) and dimethylformamide (5.0ml) were added, and the mixture was heated to reflux for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (300ml). Ethyl 3-dimethylaminoacrylate (7.30ml, 50.9mmol) and triethylamine (7.60ml, 54.5mmol) were added, and the mixture was heated to reflux for 3 hours. The solvent was evaporated under reduced pressure, dichloromethane and water were added to the residue, and the layers were separated. Then, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=2:1→1:1→1:2) to obtain the title compound (11.35 g) as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 7.81-7.74 (1H, m), 7.27-7.16 (1H, m), 4.00 (2H, q, J=7.1Hz), 3.31 (3H, br s), 2.89 ( 3H, br s), 2.35 (3H, d, J = 2.9 Hz), 0.97 (3H, t, J = 7.1 Hz).

[Reference Example 217]

7-Bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester

[Formula 336]

Ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-dimethylaminoacrylate (11.4 g, 30.2 mmol) was dissolved in dichloromethane (200 ml). (1R,2S)-2-Fluorocyclopropylamine tosylate (8.24 g, 33.3 mmol) was added and the resulting mixture was cooled to -25°C. At -25°C, triethylamine (6.60ml, 47.4mmol) was added dropwise to the reaction solution, and the resulting mixture was stirred at -15°C for 1 hour and then at 0°C for 2.5 hours. The solvent was evaporated under reduced pressure, ethyl acetate and water were added to the residue, and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to afford the aminoacrylate as a yellow oil. The resulting aminoacrylate was dissolved in N,N-dimethylformamide (350ml). Cesium carbonate (19.8 g, 60.9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, ethyl acetate and water were added to the residue, and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=9:1→1:1→1:2) to obtain the title compound (2.98 g) as a colorless powder.

¹ H-NMR (CDCl ₃ ) δ: 8.56 (1H, d, J = 3.2Hz), 8.06 (1H, d, J = 8.1Hz), 4.98-4.73 (1H, m), 4.40 (2H, q, J = 7.1 Hz), 3.91-3.82 (1H, m), 2.85 (3H, s), 1.61-1.22 (2H, m), 1.41 (3H, t, J = 7.1 Hz).

[Reference Example 218]

7-[(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3- Base]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester

[Formula 337]

Under argon atmosphere, (1S, 5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane (318mg, 1.21mmol), 7-bromo -6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (426mg, 1.10 mmol), 1,1'-bis(diphenylphosphino)ferrocene (183mg, 0.331mmol), tris(dibenzylideneacetone)dipalladium(0) (101mg, 0.110mmol) and cesium carbonate ( A mixture of 718mg, 2.20mmol) in dioxane (5.51ml) was stirred at room temperature for 30 minutes and at 100°C for 11 hours. The mixture was diluted with water and extracted with ethyl acetate and chloroform (3x). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane=10:90→50:50→67:33→ethyl acetate) to obtain 436 mg of the title compound as a pale yellow foam.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.54 (1H, d, J = 2.9Hz), 7.96 (1H, d, J = 12.9Hz), 4.99 (1H, brs), 4.94-4.72 (1H, m ), 4.39(2H, q, J=7.1Hz), 3.91-3.79(2H, m), 3.62(2H, s), 3.49-3.41(1H, m), 2.91-2.76(1H, m), 2.62( 3H, s), 2.42-2.12 (4H, m), 1.45 (9H, s), 1.61-1.43 (1H, m), 1.41 (3H, t, J=7.1Hz), 1.34-1.21 (1H, m) .

MS (ESI) m/z: 568 (M+H) ⁺ .

[Reference Example 219]

7-[(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3- Base]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 338]

At 0°C, to 7-[(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3-yl]-6- Fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid ethyl ester (436mg, 0.769mmol) To the ethanol (5 ml) solution was added 1 mol/L aqueous sodium hydroxide solution (0.845 ml), and the mixture was stirred at room temperature for 13 hours. To the mixture was further added 1 mol/L aqueous sodium hydroxide solution (0.845 ml) at 0°C, and the mixture was stirred at room temperature for 4 hours. A 10% aqueous citric acid solution was added to the mixture, and ethanol was distilled off under reduced pressure. The residue was diluted with water and extracted with dichloromethane (3x). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane=1:3→1:1→2:1→ethyl acetate) to obtain 342 mg of the title compound as a colorless foam.

¹ H-NMR (CDCl ₃ ) δ: 14.98 (1H, s), 8.78 (1H, d, J=2.9Hz), 7.95 (1H, d, J=12.7Hz), 5.03-4.77 (2H, m), 4.02-3.87(2H, m), 3.77-3.64(2H, m), 3.57-3.49(1H, m), 2.98-2.83(1H, m), 2.66(3H, s), 2.43-2.12(4H, m ), 1.70-1.53 (1H, m), 1.46 (9H, s), 1.40-1.26 (1H, m).

MS (ESI) m/z: 540 (M+H) ⁺ .

[Example 52]

7-[(1S,5R)-1-amino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro -1-[(1R,2S)-2-(fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 339]

At 0°C, 7-[(1S,5R)-1-tert-butoxycarbonylamino-6,6-difluoro-3-azabicyclo[3.3.0]octane-3-yl]-6- Fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (414mg, 0.767mmol) was dissolved in concentrated hydrochloric acid (4 ml), and the resulting mixture was stirred at 0°C for 1 hour. The resulting aqueous solution was washed with chloroform (3x). The resulting mixture was basified to pH 12 with saturated aqueous sodium hydroxide solution at 0°C and then neutralized to pH 7.4. The solution was extracted with chloroform (5x). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 219 mg of the title compound as a white solid.

Melting point: 211-212°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.52-8.46 (1H, m), 7.79-7.67 (1H, m), 5.12-4.88 (1H, m), 4.18-4.05 (1H, m), 3.91 -3.79(1H, m), 3.68-3.55(1H, m), 3.52-3.40(1H, m), 3.36-3.25(1H, m), 2.71-2.58(4H, m), 2.45-2.28(2H, m), 2.24-2.12 (1H, m), 1.97-1.85 (1H, m), 1.69-1.54 (1H, m), 1.38-1.17 (1H, m).

Anal _{. Calcd} . _{for C21H21F4N3O3-0.2H2O} : C, _56.93 ; H, 4.87; N, _9.49 ; F, 17.15. Found: C, 56.91, H, 4.83; N, 9.47; F, 17.55.

MS (ESI) m/z: 440 (M+H) ⁺ .

IR(ATR) v: 3391, 3061, 2962, 2871, 1714, 1615, 1510, 1460, 1434, 1356, 1336, 1301, 1235, 1207, 1177, 1157, 1140, 1075, 1061, 1045, ^1015cm-1 .

[Reference Example 220]

(3S)-4-Chloro-3-(3-hydroxy-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester

[Formula 340]

Under nitrogen atmosphere, at -78°C, to (3S)-3-[3-(tert-butyldimethylsilyloxy)prop-1-yl]-5-oxo-1-[(1R )-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (960mg, 2.08mmol) in THF (15ml) solution was added 1.0M THF solution of bis(trimethylsilyl)amide lithium (2.29 ml, 2.29 mmol), and the mixture was stirred for 30 minutes. Then, N-chlorosuccinimide (333 mg, 2.50 mmol) was added, and the mixture was stirred at -60°C for 1 hour and then at 0°C for 10 minutes. To the mixture were added saturated aqueous ammonium chloride and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To this residue in THF (20ml) were added acetic acid (0.24ml, 4.16mmol) and 1.0M tetrabutylammonium fluoride in THF (4.16ml, 4.16mmol) at 0°C, and the mixture was stirred at room temperature 16 hours. To the mixture were added 10% aqueous citric acid and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate/hexane=1:1→1:2) to obtain 506 mg of the title compound as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 7.34-7.26 (5H, m), 5.49-5.40 (1H, m), 4.75 (1H, s), 3.68-3.61 (2H, m), 3.39-3.34 (2H, m), 3.24(0.75H, d, J=10.0Hz), 3.14(0.25H, d, J=10.9Hz), 1.95-1.80(2H, m), 1.68-1.40(2H, m), 1.52(3H , d, J=7.1 Hz), 1.28 (9H, s).

[Reference Example 221]

(1S,5R)-5-Chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-yl tert-butyl formate

[Formula 341]

At 0°C, to (3S)-4-chloro-3-(3-hydroxypropan-1-yl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3- To a solution of tert-butyl formate (500mg, 1.31mmol) in dichloromethane (10ml) was added carbon tetrabromide (434mg, 1.31mmol) and triphenylphosphine (344mg, 1.31mmol). After the mixture was stirred at room temperature for 2 hours, carbon tetrabromide (143 mg, 0.431 mmol) and triphenylphosphine (114 mg, 0.434 mmol) were added to the resulting mixture. After stirring for 2 hours, carbon tetrabromide (72 mg, 0.216 mmol) and triphenylphosphine (57 mg, 0.217 mmol) were added, and the mixture was stirred for 16 hours. The solvent was distilled off under reduced pressure. The residue was purified by short silica gel flash column chromatography (15% ethyl acetate/hexanes) to give a colorless oil. Under nitrogen atmosphere, at -78 ℃, to the THF (12ml) solution of this oily substance, add 1.0M THF solution (1.46ml, 1.46mmol) of bis(trimethylsilyl)amide lithium, and the reaction mixture is heated at 2 The temperature was raised to 0°C within hours. To the mixture were added saturated aqueous ammonium chloride and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (15% ethyl acetate/hexane) to afford 337 mg of the title compound as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.54 (1H, q, J = 7.1Hz), 3.51 (1H, d, J = 10.7Hz), 3.02 (1H, d, J =10.7Hz), 2.76-2.71(1H, m), 2.52-2.45(1H, m), 2.38-2.30(1H, m), 2.02-1.96(1H, m), 1.74-1.60(2H, m), 1.53 (3H, d, J = 7.1 Hz), 1.45 (9H, s).

[Reference Example 222]

(1S,5R)-5-Chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1-yl formic acid

[Formula 342]

At room temperature, (1S, 5R)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1- A mixture of tert-butyl carbamate (332mg, 0.912mmol) and trifluoroacetic acid (2ml) in dichloromethane (4ml) was stirred for 14.5 hours. The solvent was distilled off under reduced pressure. Diethyl ether (3 ml) was added to the residue, and the precipitate was collected by filtration to obtain 245 mg of the title compound as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m), 5.50 (1H, q, J = 7.1Hz), 3.53 (1H, d, J = 10.7Hz), 3.07 (1H, d, J =10.8Hz), 2.78-2.73(1H, m), 2.63-2.56(1H, m), 2.41-2.33(1H, m), 2.05-2.01(1H, m), 1.79-1.63(2H, m), 1.54 (3H, d, J = 7.1 Hz).

[Reference Example 223]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-nitrogen Heterobicyclo[3.3.0]octane

[Formula 343]

At 80°C, (1S,5R)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane-1- A solution of carboxylic acid (239mg, 0.777mmol), triethylamine (0.215ml, 1.55mmol) and diphenoxyphosphoryl azide (0.184ml, 0.855mmol) in toluene (6ml) was stirred for 30 minutes. The solvent was distilled off under reduced pressure. To a solution of the residue in 1,4-dioxane (5 ml) was added 6N aqueous hydrochloric acid (5 ml). The mixture was stirred at 50°C for 5 hours. The solvent was distilled off under reduced pressure. To the residue was added 1N aqueous sodium hydroxide solution. The solution was extracted twice with CHCl ₃ , the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A mixture of the residue and di-tert-butyl dicarbonate (847 mg, 3.89 mmol) was stirred at 50 °C for 3 hours, and the mixture was purified by flash column chromatography on silica gel (15% ethyl acetate/hexane) to give 222 mg of the title compound as Colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m), 5.50 (1H, q, J=6.9Hz), 5.25 (1H, brs), 3.66 (1H, brd, J=10.0Hz), 2.96(1H, d, J=6.8Hz), 2.76-2.69(1H, m), 2.55-2.51(1H, m), 2.18-2.08(1H, m), 1.98-1.84(2H, m), 1.51( 3H, d, J = 7.1 Hz), 1.65-1.50 (1H, m), 1.40 (9H, s).

[Reference Example 224]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-3-[(1R)-1-phenylethyl]-3-azabicyclo [3.3.0] Octane

[Formula 344]

Under nitrogen atmosphere, at room temperature, to (1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-4-oxo-3-[(1R)-1-phenylethyl] - To a solution of 3-azabicyclo[3.3.0]octane (217mg, 0.573mmol) in THF (10ml) was added a 1.0M solution of borane-THF complex in THF (1.72ml, 1.72mmol). After stirring for 14 hours, a 1.0M solution of borane-THF complex in THF (0.86ml, 0.86mmol) was added. The mixture was warmed to 50°C and stirred for 18 hours. A 1.0M solution of borane-THF complex in THF (0.86ml, 0.86mmol) was added to the mixture again. The mixture was stirred at 50°C for 24 hours. After cooling to 0°C, water (1 ml), EtOH (9 ml) and triethylamine (1 ml) were added to the mixture. The mixture was warmed to 80°C and stirred for 2 hours. The solvent was distilled off under reduced pressure. To the residue were added saturated aqueous ammonium chloride and ethyl acetate. The separated organic layer was washed with water and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (10% ethyl acetate/hexane) to obtain 67.3 mg of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 7.29-7.19 (5H, m), 5.53 (1H, brs), 3.22 (1H, q, J=6.8Hz), 3.07 (1H, brd, J=8.8Hz), 2.93(1H, brd, J=8.7Hz), 2.82-2.71(1H, m), 2.64-2.57(1H, m), 2.27-2.15(2H, m), 2.09-2.06(2H, m), 1.74- 1.67 (2H, m), 1.55 (9H, s), 1.31 (3H, d, J=6.6Hz).

[Reference Example 225]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-3-azabicyclo[3.3.0]octane

[Formula 345]

Under a hydrogen atmosphere, (1R, 5R)-1-(tert-butoxycarbonylamino)-5-chloro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3. 0] A mixture of octane (63.0mg, 0.173mmol), 10% Pd-C (50wt%, M, 32mg) in methanol (6ml) was stirred at room temperature for 4 hours and then at 40°C for 19 hours. After removing the catalyst by filtration, the filtrate was distilled off under reduced pressure.

MS (ESI) m/z: 261 (M+H) ⁺ .

[Example 53]

7-[(1R,5R)-1-amino-5-chloro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 346]

(1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-3-azabicyclo[3.3.0]octane (45.0mg, 0.173mmol), 6,7-difluoro-1 -[(1R,2S)-2-fluorocyclopropane]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-difluoroboron complex (62.3mg, 0.173 mmol) and triethylamine (0.0598ml, 0.433mmol) in dimethylsulfoxide (3ml) was stirred at 45°C for 45 hours. Water (1 ml), EtOH (9 ml) and triethylamine (1 ml) were added to the mixture. The mixture was stirred at 80°C for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To the residue were added 10% aqueous citric acid and ethyl acetate. The separated organic layer was washed with _H2O and brine. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by TLC (5% MeOH/ _CHCl3 ) to afford 48.0 mg of the N-Boc protected compound as a yellow oil. To the oil was added hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. The mixture was basified to pH 12 with aqueous sodium hydroxide solution, then neutralized to pH 7.8 at 0°C. The solution was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dried under reduced pressure to obtain 33.9 mg of the title compound as a pale yellow solid.

Melting point: 161-163°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, s), 7.70 (1H, d, J=14.2Hz), 5.07-4.85 (1H, m), 4.19-4.08 (2H, m), 3.92(1H, d, J=11.8Hz), 3.76-3.63(5H, m), 2.48-2.41(1H, m), 2.30-2.25(1H, m), 2.08-1.87(4H, m), 1.70- 1.51 (2H, m), 1.19 (1.8H, t, J=7.2Hz).

Anal _. Calcd _. for _{C21H22ClF4N3O3-0.6EtOH} : C, _55.38 ; H, 5.36; N, _8.73 ; F, 7.89; Cl, 7.36. Found: C, 55.24, H, 4.91; N, 8.85; F, 8.27; Cl, 6.92.

MS (ESI) m/z: 454 (M+H) ⁺ .

IR(ATR) v: 3384, 3075, 2880, 1728, 1621, 1513, 1453, 1360, 1318, 1188, 1136, 1120, 1103, 1056 ^{cm -1} .

[Example 54]

7-[6-Amino-8-azatricyclo[4.3.0.0 ^{1, 3} ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane -1-yl]-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7-position: derivative, derived from optical Isomer A)

[Formula 347]

To tris(dibenzylideneacetone)dipalladium(0) (332mg, 0.363mmol) and 4,5-bis(diphenyl)phosphino-9,9-dimethylxanthene (462mg, 0.798mmol) Add 7-bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-bis to a solution of 1,4-dioxane (9.06ml) Hydrogen-4-oxoquinoline-3-carboxylic acid ethyl ester (350mg, 0.906mmol), 6-tert-butoxycarbonylamino-8-azatricyclo[ ^4.3.0.01,3 ]nonane (216mg, 0.906 mmol) and cesium carbonate (355 mg, 1.09 mmol), the mixture was stirred at 90° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (80ml) and extracted with ethyl acetate (90ml). The organic layer was washed with saturated aqueous sodium chloride (80 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2) to obtain a pale yellow solid. To a solution of this solid in ethanol (3.32 ml) in an ice bath was added 1 mol/L aqueous sodium hydroxide solution (1.50 ml), and the mixture was stirred at room temperature for 14 hours. To the reaction solution in an ice bath was added 1 mol/L hydrochloric acid aqueous solution (1.50 ml), and the organic layer was concentrated under reduced pressure. The aqueous solution was diluted with water (30ml) and extracted with ethyl acetate (40ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2) to obtain a pale yellow solid. The obtained solid was dissolved in concentrated hydrochloric acid (1.0 ml) in an ice bath, and the aqueous solution was washed with chloroform (25 ml×3). Saturated sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12.0, and the alkaline aqueous solution was adjusted to pH 7.4 with hydrochloric acid. The solution was extracted with chloroform (120ml×1, 80ml×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford the title compound 68.1 mg (18%) as a pale yellow solid.

mp: 145-149°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.43 (1H, d, J = 3.2Hz), 7.70 (1H, d, J = 14.2Hz), 5.12-4.92 (1H, m), 4.29 (1H, d, J=9.2Hz), 4.12-4.07(1H, m), 3.91-3.88(1H, m), 3.24(1H, d, J=9.6Hz), 3.08(1H, d, J=9.2Hz), 2.54(3H, s), 2.08-1.97(1H, m), 1.92-1.87(1H, m), 1.79-1.74(1H, m), 1.65-1.55(1H, m), 1.32-1.19(3H, m ), 0.84-0.76 (2H, m).

Anal _. Calcd. for _{C22H23F2N3O3-1.5H2O} : _C , _59.72 ; _H , 5.92; F, _8.59 ; N, 9.50. Found: C, 59.72; H, 5.65; F, 59.08; N, 9.47.

MS (ESI) m/z: 416 (M+H) ⁺ .

IR (ATR): 2939, 2867, 1719, 1612, 1542, 1507, 1460, 1428, 1354, 1314, 1284, 1184, 1136, 1024, 967, 921, 884, ^{806 cm -1} .

[Example 55]

7-[6-Amino-8-azatricyclo[4.3.0.0 ^{1, 3} ]Nonan-8-yl]-1-[(1R, 2S)-2-fluorocyclopropane-1- Base]-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (position 7: derivative, derived from optical isomerism Body A)

[Formula 348]

To a solution of 6-tert-butoxycarbonylamino-8-azatricyclo[4.3.0.0 ^1,3 ]nonane (290 mg, 1.22 mmol) in dimethyl sulfoxide (2.42 ml) was added under nitrogen atmosphere Triethylamine (0.507ml, 3.63mmol) and 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline -3-Formic acid (337mg, 1.21mmol), the mixture was stirred at 70°C for 13 days. The reaction solution was diluted with ethyl acetate and washed with 10% aqueous citric acid (50 ml), water (60 ml) and saturated aqueous sodium chloride (60 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2→95:5) to obtain a pale yellow solid. In an ice bath, the solid was dissolved in concentrated hydrochloric acid (1.0 ml), and the aqueous solution was washed with chloroform (30 ml×5). A saturated aqueous sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12.0, and the alkaline aqueous solution was adjusted to pH 7.4 with hydrochloric acid. The solution was extracted with chloroform (80ml×4) and 10% methanol-chloroform (80ml×1, 50ml×1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford the title compound 138 mg (29%) as a pale yellow solid.

mp: >254°C (decomposition).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.42 (1H, d, J = 3.9Hz), 8.00 (1H, d, J = 9.3Hz), 7.14 (1H, d, J = 9.0Hz), 5.13 -4.94(1H, m), 4.32(1H, d, J=10.0Hz), 4.10-4.04(1H, m), 3.73(1H, d, J=10.3Hz), 3.23(1H, d, J=10.0 Hz), 3.00(1H, d, J=10.3Hz), 2.46(3H, s), 2.04-1.92(2H, m), 1.79-1.73(1H, m), 1.66-1.55(1H, m), 1.35 -1.17 (3H, m), 0.86-0.77 (2H, m).

_{Anal . Calcd} . for _{C22H24FN3O3-0.25H2O} : C, _65.74 ; H, 6.14; F, 4.73; N, 10.45. Found: C, 65.84; H, 6.28; F, 5.00; N, 10.41.

MS (ESI) m/z: 398 (M+H) ⁺ .

IR(ATR): 3376, 3030, 2989, 2929, 2858, 1703, 1614, 1547, 1510, 1450, 1430, 1387, 1354, 1337, 1313, 1295, 1266, 1230, 1189, 1177, 1153, 1138, 1090 , 1079, 1054, 1022, 998, 990, ^{923cm -1} .

[Example 56]

7-{(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.2.0]heptane-3-yl}-6-fluoro -1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

[Formula 349]

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (414 mg, 0.452 mmol) and 4,5-bis(diphenyl)phosphino-9,9-dimethylxanthene ( 522mg, 0.902mmol) in 1,4-dioxane (20.0ml) was added 7-bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl- 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (1.28g, 3.31mmol), (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3- Azabicyclo[3.2.0]heptane (693mg, 3.01mmol) and cesium carbonate (1.96g, 6.02mmol), the mixture was stirred at 95°C for 14 hours. The reaction mixture was diluted with water (100ml) and extracted with ethyl acetate (100ml x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate; 100:0→95:5→90:10→75:25→5:95→0:100) to give a pale yellow solid. To a solution of this solid in ethanol (15.9 ml) in an ice bath was added 1 mol/L aqueous sodium hydroxide solution (5.98 ml), and the mixture was stirred at room temperature for 13 hours. To the reaction solution in the ice bath was added 1 mol/L hydrochloric acid aqueous solution (5.98 ml), and the organic layer was concentrated under reduced pressure. The aqueous solution was diluted with water (80ml) and extracted with ethyl acetate (100ml x 1, 80ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99:1→98:2→97:3→96:4→95:5→94:6→93:7) to give a pale yellow solid . The obtained solid was dissolved in concentrated hydrochloric acid (3.0 ml) in an ice bath, and the aqueous solution was washed with chloroform (40 ml×4). Add saturated sodium hydroxide solution to the aqueous layer to adjust the pH to 12.0, and adjust the alkaline aqueous solution to pH 7.4 with hydrochloric acid. The resulting solution was extracted with chloroform (250ml×4). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from ethanol to afford 690 mg (56%) of the title compound as a pale yellow solid.

mp: >272°C (decomposition).

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.49 (1H, d, J = 2.2Hz), 7.70 (1H, dd, J = 13.2, 4.2Hz), 5.08-4.88 (1H, m), 4.12- 4.06(1H, m), 3.69-3.56(2H, m), 3.42-3.39(1H, m), 3.21-3.18(1H, m), 2.64(3H, d, J=5.1Hz), 2.54-2.39( 1H, m), 2.31-2.20 (1H, m), 2.12-1.93 (2H, m), 1.66-1.56 (1H, m), 1.32-1.19 (1H, m).

Anal _. Calcd. _{for C20H20F3N3O3} : C, 58.96; H, 4.95; _F , _13.99 ; N, 10.31. Found: C, 58.76; H, 4.88; F, 14.11; N, 10.28.

MS (ESI) m/z: 408 (M+H) ⁺ .

IR(ATR): 3089, 2980, 2936, 2862, 2837, 1719, 1614, 1544, 1506, 1474, 1454, 1432, 1350, 1318, 1268, 1231, 1213, 1181, 1159, 1140, 1093, 1058, 1047 , 1021, 1009, 977, 962, 930, 898, 864, 837, 805cm ^-1 .

[Example 57]

7-[6-Amino-8-azatricyclo[4.3.0.0 ^{1, 3} ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane -1-yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methanesulfonate

[Formula 350]

To 7-[6-amino-8-azatricyclo[4.3.0.0 ^1,3 ]nonan-8-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane-1 -yl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.24g, 4.82mmol) in ethanol (48.2ml) was added methanesulfonic acid (0.316 ml, 4.87mmol), and the mixture was stirred at room temperature for 15 hours. To the reaction solution was added water (5 ml), and the resulting mixture was concentrated under reduced pressure. To the residue was added 2-propanol (20 ml), and the mixture was stirred at room temperature for 15 hours. The precipitated solid was collected by filtration. The solid was washed with excess 2-propanol to afford 2.41 g (95%) of the title compound as a pale yellow solid.

mp: 202-204°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.39 (1H, d, J = 2.9Hz), 7.64 (1H, d, J = 14.4Hz), 5.09-4.93 (1H, m), 4.21 (1H, dd, J = 10.0, 2.7Hz), 3.97 (1H, dt, J = 10.0, 4.6Hz), 3.72 (1H, dd, J = 10.6, 2.7Hz), 3.53 (3H, s), 3.39 (1H, d , J = 10.3Hz), 3.18 (1H, d, J = 10.3Hz), 2.83 (3H, s), 1.99-1.85 (2H, m), 1.73 (1H, dd, J = 12.2, 8.5Hz), 1.56 -1.46 (1H, m), 1.39-1.23 (2H, m), 1.17-1.13 (1H, m), 0.79-0.74 (2H, m).

_{Anal. Calcd} . for _{C22H23F2N3O4.CH4O3S.0.5H2O :} C, _51.49 ; H, _{5.26 ;} F, _7.08 ; N, 7.83; S, 5.98. Found: C, 51.21; H, 5.20; F, 7.44; N, 7.82; S, 6.00.

MS (ESI) m/z: 432 (M+H) ⁺ .

IR (ATR): 3412, 2944, 2878, 1694, 1617, 1597, 1536, 1513, 1437, 1361, 1330, 1315, 1297, 1273, 1219, 1167, 1135, 1109, 1040, 952, 925, 883, 805cm ^-1 .

[Example 58]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropane]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid methanesulfonate

[Formula 351]

To 7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R,2S)-2 -Fluorocyclopropane]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (4.50g, 10.7mmol) in ethanol (90ml) suspension was added methanesulfonic acid (0.695ml , 10.7mmol), the mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (20ml) and evaporated under reduced pressure. The residue was purified by slurrying in 2-propanol to give 4.96 g of the title compound as a pale yellow powder.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.48 (1H, d, J = 2.9Hz), 7.72 (1H, d, J = 13.7Hz), 5.11-4.86 (1H, m), 4.15-4.07 ( 1H, m), 3.93-3.81 (1H, m), 3.60-3.31 (3H, m), 2.82 (3H, s), .62 (3H, s), 2.16-1.98 (3H, m), 1.92-1.55 (4H, m), 1.33-1.19 (1H, m).

MS (FAB); m/z: 422 (M+H) ⁺ .

_{Anal. Calcd} . for _{C21H22F3N3O3.CH3SO3H.1.75H2O : C} , 48.13 _; H, _{5.42 ;} F, 10.38; N, 7.65; S, 5.84. Found: C, 47.81; H, 5.09; F, 10.43; N, 7.63; S, 5.75.

IR (ATR) v: 3442, 2871, 1709, 1615, 1509, 1432, 1370, 1319, 1265, 1161, 1038, 971, 929, 892, 853, 806 cm ^-1 .

[Reference Example 226]

(3aS)-1-Hydroxy-6-oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrole-3a-carba tert-butyl acid

[Formula 352]

(3aS, 7aS)-1-oxo-2-[(R)-1-phenylethyl]-1,2,3,7a-tetrahydropyrano[3,4-c]pyrrole-3a - A mixture of tert-butyl formate (4.0 g, 11.6 mmol), N-methylmorpholine-N-oxide (2.95 g, 22.0 mmol) and osmium tetroxide (catalytic amount) was dissolved in tert-butanol (20 ml) and water (10ml), and stirred at room temperature for 3 days. The reaction mixture was diluted with AcOEt and 10% aqueous sodium thiosulfate was added. The layers were separated and the aqueous layer was extracted with AcOEt. The combined extracts were washed with saturated aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a dark brown oil (4.4 g). The crude product (2.6g) was dissolved in tetrahydrofuran (60ml) and water (30ml), and sodium periodate (2.6g) was added. The reaction mixture was stirred at room temperature for 18 hours, diluted with AcOEt and water. The layers were separated and the aqueous layer was extracted with AcOEt. The combined extracts were washed with saturated aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was dissolved in ethanol and tetrahydrofuran (20ml; 17:3), and 1N aqueous NaOH solution (5.2ml) was added dropwise at 0°C. The mixture was stirred at room temperature for 3 hours, then additional 1N aqueous NaOH (2.2 ml) was added and the reaction mixture was stirred for a further 1 hour. After removing the solvent in vacuo, the resulting residue was partitioned between AcOEt and water, and the aqueous layer was extracted. The combined extracts were washed with saturated aqueous NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel, eluting with 50% AcOEt in hexanes, to afford the title compound (1.10 g) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.25 (5H, m), 5.71 (1H, d, J=7.3Hz), 5.66-5.44 (1.2H, m), 4.96 (0.2H, d, J=7.3Hz), 4.49(0.8H, d, J=9.6Hz), 4.25(0.2H, d, J=9.6Hz), 4.00(0.2H, d, J=9.2Hz), 3.90(0.8H, d, J = 9.2 Hz), 3.64 (0.8 H, d, J = 7.3 Hz), 3.38-3.24 (3 H, m), 1.54-1.38 (12 H, m).

MS (ESI) m/z: 348 (M+H) ⁺ .

[Reference Example 227]

(3S)-3,4-bis(hydroxymethyl)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidine-3-carboxylate tert-butyl

[Formula 353]

To (3aS)-1-hydroxy-6-oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester (350mg, 1.01mmol ) in THF and ethanol (10ml; 4:1) was added portionwise to a cooled solution (-20°C) of sodium borohydride (38.0mg, 1.00mmol), and the mixture was stirred at the same temperature for 5.5 hours. The reaction mixture was concentrated in vacuo, dissolved in AcOEt and water. The layers were separated and the aqueous layer was extracted with AcOEt. _The combined extracts were washed with brine, dried ( _Na2SO4 ) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 90% AcOEt in hexanes, to give the title compound (153 mg) as a colorless oil.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.25 (5H, m), 5.50 (1H, q, J=7.0Hz), 4.19-3.80 (4H, m), 3.40-3.05 (5H, m) , 1.52 (3H, d, J = 7.0 Hz), 1.40 (9H, s).

MS (ESI) m/z: 350 (M+H) ⁺ .

[Reference Example 228]

(3aS)-6-Oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrole-3a-carboxylic acid tert-butyl ester

[Formula 354]

To (3S)-3,4-di(hydroxymethyl)-5-oxo-1-[(R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (710mg, 2.03mmol) To a cooled (0° C.) solution of triphenylphosphine (450 mg, 2.64 mmol) in tetrahydrofuran (10 ml), 40% diethyl azodicarboxylate in toluene (1.06 ml, 2.33 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 40% AcOEt in hexanes to give the title compound (435 mg) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.39-7.25 (5H, m), 5.48 (1H, q, J = 7.2Hz), 4.32-4.26 (1H, m), 4.01 (1H, d, J = 9.6Hz), 3.97-3.91(1H, m), 3.85(1H, d, J=9.6Hz), 3.43(1H, d, J=10.1Hz), 3.37-3.32(1H, m), 3.26(1H, d, J = 10.1 Hz), 1.54 (3H, d, J = 6.9 Hz), 1.38 (9H, br s).

MS (ESI) m/z: 332 (M+H) ⁺ .

[Reference Example 229]

[(3aS)-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrol-3a-yl]tert-butylcarbamate ester

[Formula 355]

To [(3aS)-6-oxo-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrol-3a-yl]carbamate tert-butyl ester (820mg, 2.47mmol ) in dichloromethane (8ml) was added trifluoroacetic acid (8ml), and the mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and pumped dry to give a white solid (680mg).

At 0°C, 1,1'-carbonylbis-1H-imidazole (480mg, 2.94mmol) was added to a solution of the crude product (540mg) in acetonitrile (10ml), and the mixture was stirred at the same temperature for 1 hour, then warmed up to room temperature. Ammonia gas was bubbled through the reaction mixture for 30 minutes and the solvent was concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a white solid (536 mg).

To a suspension of white solid (536mg) in tert-butanol (20ml) was added lead tetraacetate (1.73g, 3.90mmol) and the mixture was heated to 100°C for 5 hours. The reaction mixture was allowed to cool to room temperature, diluted with diethyl ether (200ml) and sodium bicarbonate (3g) was added. After stirring for 30 minutes, the precipitate was filtered off. The filtrate was concentrated in vacuo, the residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product (620 mg, white solid) was obtained.

Trifluoroacetic acid (6ml) was added to a solution of the crude product (200mg) in dichloromethane (6ml) and the reaction mixture was stirred for 1 hour before the solvent was removed in vacuo and pumped dry. The resulting product was used in the next step.

To a solution of this product in toluene (6 ml) was slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65% in toluene, 690 μL, 2.3 mmol), and the resulting mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then 5N aqueous NaOH was added and stirred for 1 hour. The layers were separated and the aqueous layer was extracted with toluene. _The combined extracts were washed with brine, dried ( _Na2SO4 ) and concentrated in vacuo. The crude product (540 mg) was used without purification.

Di-tert-butyl dicarbonate (589mg) was added to a solution of the crude product in dichloromethane (6ml), the mixture was stirred for 18 hours and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with 30% AcOEt in hexanes to give the title compound (150 mg) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.31-7.21 (5H, m), 5.00 (1H, s), 4.09-3.78 (3H, m), 3.53 (1H, dd, J=8.7, 4.6Hz) , 3.27 (1H, q, J = 6.7Hz), 2.78-2.65 (3H, m), 2.50-2.36 (2H, m), 1.42 (9H, s), 1.33 (3H, d, J = 6.4Hz).

MS (ESI) m/z: 333 (M+H) ⁺ .

[Reference Example 230]

(3aS)-(tetrahydrofuro[3,4-c]pyrrol-3a-yl)carbamate tert-butyl ester

[Formula 356]

Dissolve tert-butyl [(3aS)-5-[(R)-1-phenylethyl]tetrahydrofuro[3,4-c]pyrrol-3a-yl]carbamate (355 mg, 1.06 mmol) in dioxin Alkane (10 ml) and added 20% palladium hydroxide catalyst (20 wt.% palladium on carbon, wet; catalytic amount). The mixture was stirred vigorously at 40° C. for 24 hours under a hydrogen atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with 1N aqueous NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude title compound (243 mg) as a colorless syrup.

MS (ESI) m/z: 229 (M+H) ⁺ .

[Example 59]

7-[(3aS)-3a-aminotetrahydrofuro[3,4-c]pyrrol-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclo Propyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 357]

To 6,7-difluoro-1-[(2S,1R)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-di In a solution of fluoroboron complex (426mg, 1.18mmol) in dimethylsulfoxide (6ml), add (S)-(tetrahydro-2-oxa-5-aziridine[c]cyclopenta Dien-3a-yl) tert-butyl carbamate (270mg, 1.18mmol) and triethylamine (0.50ml, 3.54mmol), the resulting mixture was stirred at 40°C for 17 hours. The reaction solution was concentrated in vacuo, and the concentrate was dissolved in a mixed solution (150 ml) of ethanol and water (9:1). After adding triethylamine (5 ml), the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in AcOEt (100ml×2), and washed with 10% aqueous citric acid (100ml) and brine (100ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification by silica gel column chromatography (3% MeOH in _CHCl3 ), the resulting solid was dissolved in concentrated hydrochloric acid (5ml) in an ice bath, and the aqueous solution was washed with chloroform (50ml x 3). Add 10 mol/L sodium hydroxide aqueous solution to the water layer to adjust the pH to 12.0, and adjust the alkaline aqueous solution to pH 7.4 with hydrochloric acid. The solution was extracted with chloroform (100ml×6), the combined extracts were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative chromatography and further purified by recrystallization from ethanol, then dried under reduced pressure to give the title compound (220 mg) as pale yellow crystals.

mp: 201-202°C.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 8.76 (1H, d, J = 1.4Hz), 7.87 (1H, d, J = 12.8Hz), 4.92-4.71 (1H, m), 4.27 (1H, dd , J=9.2, 7.3Hz), 3.93-3.57 (11H, m), 2.57-2.49 (1H, m), 1.68-1.47 (2H, m).

Anal _. Calcd. for _{C20H21F2N3O5 - H2O} : C, 54.67; H, 5.28; N _, 9.56; _F , 8.65. Found: C, 54.52; H, 5.18; N, 9.58; F, 8.73.

MS (ESI) m/z: 422 (M+H) ⁺ .

IR(ATR) v: 3301, 2974, 2847, 1722, 1614, 1580, 1516, 1447, 1403, 1378, 1365, 1355, 1340, 1316, 1289, 1265 ^{cm -1} .

[Example 60]

7-[(1R, 5S)-1-amino-5-fluoro-3-azabicyclo[3.3.0]octane-3-yl]-6-fluoro-1-[(1R,2S)-2- Fluorocyclopropane]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid

[Formula 358]

Add tris(dibenzylideneacetone)dipalladium(0) (7.75g, 8.46mmol), 4,5-bis(diphenyl)phosphino-9,9-dimethylxanthene (14.7g, 25.4 mmol), 7-bromo-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid Ethyl ester (14.2g, 36.8mmol) and (1R,5S)-1-(tert-butoxycarbonylamino)-5-fluoro-3-azabicyclo[3.3.0]octane (6.90g, 28.2mmol) Cesium carbonate (18.4 g, 56.5 mmol) was added to a solution of 1,4-dioxane (345 ml), and the resulting mixture was stirred at 110° C. for 23 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (400ml) and extracted with ethyl acetate (600ml x 1, 250ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol; 100:0→99.5:0.5→99.25:0.75→99:1) to obtain a solid. To a solution of this solid in ethanol (273 ml) was added 1 mol/L aqueous sodium hydroxide solution (68.2 ml) in an ice bath, and the mixture was stirred at room temperature for 1 hr. To the reaction solution were added ethanol (327 ml) and 1 mol/L sodium hydroxide aqueous solution (27.3 ml), and the mixture was stirred at room temperature for 13 hours. To the reaction solution was added 1 mol/L hydrochloric acid aqueous solution (95.5 ml) in an ice bath, and the organic layer was concentrated under reduced pressure. The aqueous solution was diluted with water (150ml) and extracted with chloroform (250ml x 1, 150ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate; 100:0→2:1→1:1→1:1.5→1:1.7→1:1.85→1:2→1:5→1: 9→0:100), a pale yellow solid was obtained. The solid was dissolved in concentrated hydrochloric acid (30ml) in an ice bath, and the aqueous solution was washed with chloroform (100ml x 5). A saturated sodium hydroxide solution was added to the aqueous layer to adjust the pH to 12.0. Water (1.8 L) was added to the solution, and the basic aqueous solution was adjusted to pH 7.4 with hydrochloric acid. The solution was extracted with chloroform (1.5 l x 1, 800 ml x 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from 2-propanol/methanol=10/1 to obtain 6.14 g (52%) of the title compound as a pale yellow solid. All spectroscopic data for this compound proved to be in good agreement with those of Example 17.

[Reference Example 231]

(3aS)-6-oxo-5-[(R)-1-phenylethyl]-5,6-dihydro-4H-furo[3,4-c]pyrrole-3a-carba tert-butyl acid

[Formula 359]

Add (3aS)-(tetrahydrofuro[3,4-c]pyrrol-3a-yl)carboxylic acid tert-butyl ester (8.80 g, 25.0 mmol) and triethylamine (7.8 ml) in dichloromethane ( 75ml) solution was added dropwise methanesulfonyl chloride (3.13ml, 40.0mmol), the mixture was stirred at the same temperature for 1.5 hours, and then triethylamine (7.8ml) was added again. The reaction mixture was heated to 40°C and stirred for 5 days. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with a mixed solution of AcOEt, hexane and triethylamine (40:60:0.5) to give the title compound (2.56 g, white solid).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.25 (5H, m), 7.08 (1H, s), 5.48 (1H, q, J=6.9Hz), 5.03 (1H, d, J=9.6Hz ), 4.25 (1H, d, J = 9.6Hz), 3.43 (1H, d, J = 10.1Hz), 3.26 (1H, d, J = 10.1Hz), 1.38 (3H, d, J = 6.9Hz), 1.30 (9H, s).

MS (ESI) m/z: 330 (M+H) ⁺ .

[Reference Example 232]

(S)-6-Oxo-5-[(R)-1-phenylethyl]tetrahydro-2-oxa-5-azacyclo[c]pentacyclopentadiene tert-butylene-3a-carboxylate

[Formula 360]

At -10°C, diiodomethane (1.79ml, 22.3mmol) was added dropwise to a solution of diethylzinc (1M in hexane, 22.3ml) in dichloromethane (75ml), and the mixture was stirred at the same temperature 15 minutes at -10°C, add (S)-6-oxo-5-[(R)-1-phenylethyl]-5,6-dihydro-4H-furo[3,4-c ] pyrrole-3a-carboxylate tert-butyl dichloromethane solution, the resulting compound was stirred at room temperature for 8 hours. The reaction mixture was quenched with 10% aqueous citric acid. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 30% AcOEt in hexanes, to give the title compound (1.96 g) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.38-7.25 (5H, m), 5.54 (1H, q, J = 7.0Hz), 4.45 (1H, d, J = 9.2Hz), 4.24 (1H, dd , J=5.5, 2.8Hz), 4.14 (1H, d, J=9.2Hz), 3.51 (1H, d, J=10.1Hz), 3.40 (1H, d, J=10.1Hz), 1.73-1.67 (1H , m), 1.58-1.53 (4H, m), 1.33 (9H, s).

MS (ESI) m/z: 344 (M+H) ⁺ .

[Reference Example 233]

[(S)-5-[(R)-1-Phenylethyl]tetrahydro-2-oxa-5-aziridine[c]pentadiene-3a- base] tert-butyl carbamate

[Formula 361]

To (S)-6-oxo-5-[(R)-1-phenylethyl]tetrahydro-2-oxa-5-aziridine[c]pentadiene-3a- To a solution of tert-butyl formate (880 mg, 2.56 mmol) in dichloromethane (7 ml) was added trifluoroacetic acid (8 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give a white solid (800 mg).

At -0°C, 1,1'-carbonylbis-1H-imidazole (677mg, 4.18mmol) was added to a solution of white solid (800mg) in acetonitrile (15ml), and the mixture was stirred at the same temperature for 1 hour, then Let it warm up to room temperature. Ammonia gas was bubbled through the reaction mixture for 30 minutes and the solvent was concentrated in vacuo. The resulting residue was dissolved in dichloromethane, washed with 1N HCl, saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give a white solid (750 mg).

To a suspension of white solid (120mg) in tert-butanol (5ml) was added lead tetraacetate (558mg, 1.26mmol) and the resulting mixture was heated to 100°C for 5 hours. The reaction mixture was allowed to cool to room temperature, diluted with ether (50ml) and sodium bicarbonate (1g) added. After stirring for 30 minutes, the solid was filtered off. The filtrate was removed in vacuo, the residue was dissolved in dichloromethane, washed with saturated aqueous NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was used without further purification.

Trifluoroacetic acid (6ml) was added to a solution of the crude product in dichloromethane (5ml) and the reaction mixture was stirred for 1 hour before the solvent was removed in vacuo and pumped dry. The resulting product was used in the next step.

To a solution of this product in toluene (4 ml) was slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65% in toluene, 600 μL, 2.0 mmol), and the resulting mixture was heated to 60° C. for 1 hour. The reaction mixture was cooled to room temperature and 5N aqueous NaOH was added, then stirred for 1 hour. The layers were separated and the aqueous layer was extracted with toluene. _The combined extracts were washed with brine, dried ( _Na2SO4 ) and concentrated in vacuo. The crude product was used without further purification.

Di-tert-butyl dicarbonate (163mg) was added to a solution of the crude product in dichloromethane (6ml), the mixture was stirred for 18 hours and the solvent was removed in vacuo. The residue was purified by silica gel chromatography eluting with 25% AcOEt in hexanes to give the title compound (140 mg) as a white solid.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.36-7.19 (5H, m), 4.92 (1H, s), 4.20 (1H, d, J=9.6Hz), 3.98-3.85 (2H, m), 3.43 (1H, q, J = 6.6Hz), 2.99 (1H, d, J = 8.7Hz), 2.81-2.62 (3H, m), 1.40 (9H, s), 1.35 (3H, d, J = 6.6Hz) , 1.19 (1H, d, J=6.4Hz), 0.91 (1H, t, J=5.7Hz).

MS (ESI) m/z: 345 (M+H) ⁺ .

[Reference Example 234]

(S)-tert-butyl(tetrahydro-2-oxa-5-azirido[c]pentalen-3a-yl)carbamate

[Formula 362]

[(S)-5-[(R)-1-phenylethyl]tetrahydro-2-oxa-5-aziridine[c]pentalen-3a-yl]carbamate The tert-butyl ester (480 mg, 1.39 mmol) was dissolved in dioxane (10 mL) and 20% palladium hydroxide catalyst (20 wt. % palladium on carbon, wet; catalytic amount) was added. The mixture was stirred vigorously under hydrogen atmosphere at room temperature for 3 days. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with 1N aqueous NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude title compound (280 mg, white solid).

MS (ESI) m/z: 241 (M+H) ⁺ .

[Example 61]

7-[(3aS)-3a-Amino-5-aza-oxa-tetrahydrocyclopentadien-5-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid

[Formula 363]

To 6,7-difluoro-1-[(2S,1R)-2-fluorocyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid-di Add (S)-(tetrahydro-2-oxa-5-aziridine[c]pentacyclopentadiene to a solution of fluoroboron complex (361mg, 1.00mmol) in dimethyl sulfoxide (5ml) En-3a-yl) tert-butyl carbamate (250mg, 1.08mmol) and triethylamine (0.50ml, 3.54mmol), the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated in vacuo, and the concentrate was dissolved in a mixed solution (150 ml) of ethanol and water (9:1). After adding triethylamine (5 ml), the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was dissolved in AcOEt (100ml×2), and washed with 10% aqueous citric acid (100ml) and brine (100ml). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After purification by silica gel chromatography (5% MeOH in CHCl ₃ ), the residue was dissolved in concentrated hydrochloric acid (5 ml) in an ice bath, and the aqueous solution was washed with chloroform (50 ml×3). Add 10 mol/L sodium hydroxide aqueous solution to the water layer to adjust the pH to 12.0, and adjust the alkaline aqueous solution to pH 7.4 with hydrochloric acid. The solution was extracted with chloroform (100ml×6), the combined extracts were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative chromatography and further purified by recrystallization from ethanol, followed by drying under reduced pressure to give the title compound (135 mg) as pale yellow needles.

mp: 189-191°C.

¹ H-NMR (400MHz, 0.1N NaOD) δ: 8.42 (1H, d, J = 2.8Hz), 7.71 (1H, d, J = 13.8Hz), 5.13-4.89 (1H, m), 4.17-4.01 ( 4H, m), 3.94 (1H, dd, J=10.5, 2.3Hz), 3.67 (3H, s), 3.64-3.47 (3H, m), 1.63-1.37 (3H, m), 1.02 (1H, dd, J = 7.8, 5.5 Hz).

Anal _. Calcd _. for _{C21H21F2N3O5-1.25H2O} : C _{, 55.32} ; H, 5.20; N, 9.22 _; F, 8.33. Found: C, 55.48; H, 5.12; N, 9.00; F, 8.61.

MS (ESI) m/z: 434 (M+H) ⁺ .

IR (ATR) v: 3358, 3076, 2941, 2879, 1721, 1620, 1513, 1437, 1367, 1323, 1274 cm ^-1 .

[Test Example 1]

The antibacterial activity of the compounds of the present invention was determined according to the standard method prescribed by the Japanese Society of Chemotherapy. The results are shown in MIC (μg/ml) (Table 2).

In order to compare with the MIC values of the compounds of the present invention, Table 2 also shows the 7-[3-(R)-(1-aminocyclopropyl)pyrrolidin-1-yl]-8- Cyano-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (control drug 1: following formula) , MIC values of levofloxacin (LVFX), ciprofloxacin (CPFX) and moxifloxacin (MXFX).

Compounds specifically exemplified in the "Description of the Related Art" section of EP-A-343524 are represented by the following formula:

[Formula 364]

One of two optical isomers with its 7-position substituent. The inventors of the present invention have synthesized the compound represented by the following formula:

[Formula 365]

It has (1S,5R)-1-amino-3-azabicyclo[3.3.0]octan-3-yl, which is a highly reactive isomer of its 7-position substituent. It has been confirmed that the compound represented by the formula 365 is positive for the induction of micronuclei after intravenous administration in the mouse bone marrow micronucleus assay. That is, the compound is considered genotoxic. In addition, the compound was also found to be positive for phototoxicity after intravenous administration in a mouse phototoxicity test. On the other hand, the compound described in Example 11 as a representative compound of the present invention was found to be negative in the above two tests. That is, the compound is considered to be weakly genotoxic and non-phototoxic, and therefore quite safe as a human drug.

Claims (46)

1. one kind is compound, its salt or the hydrate of representative with following formula (I),

R wherein ¹Represent hydrogen atom, have the alkyl of 1-6 carbon atom, have the cycloalkyl of 3-6 carbon atom, perhaps derived from the substituted carbonyl of amino acid, dipeptides or tripeptides; Described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, cyano group, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;

R ²Represent hydrogen atom, have the alkyl of 1-6 carbon atom or have the cycloalkyl of 3-6 carbon atom, described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, have the alkylthio of 1-6 carbon atom and have the alkoxyl group of 1-6 carbon atom, and described cycloalkyl can have one or more following substituting groups that are selected from: alkyl, amino, hydroxyl and halogen atom with 1-6 carbon atom;

R ³And R ⁴The independent alkyl of representing hydrogen atom or having 1-6 carbon atom, described alkyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom;

R ⁵Represent hydrogen atom, halogen atom, alkyl with 1-6 carbon atom, alkoxyl group with 1-6 carbon atom, thiazolinyl with 2-6 carbon atom, alkynyl with 2-6 carbon atom, have 3-6 carbon atom and can have substituent cycloalkyl, have 6-10 carbon atom and can have substituent aryl and maybe can have substituent heteroaryl, described alkyl, thiazolinyl and alkynyl can be straight or brancheds, described alkyl can have one or more following substituting groups that are selected from: hydroxyl, amino, halogen atom, alkylthio and alkoxyl group with 1-6 carbon atom with 1-6 carbon atom, and described thiazolinyl can have one or more following substituting groups that are selected from: halogen atom and the alkoxyl group with 1-6 carbon atom;

R ⁶And R ⁷The carbon atom that is connected with them is combined together to form 4-7 unit ring texture, described ring texture representative forms the part-structure that condenses ring-type (dicyclo) structure with pyrrolidine ring, the first ring texture of described 4-7 can contain two keys also can contain Sauerstoffatom or the sulphur atom composed atom as ring

R ⁵Can be methylene radical, its can with R ⁶Be combined together to form 3 yuan and condense the ring-type structure division, and this condenses ring texture and can be positioned at the described other parts that condense ring-type (dicyclo) structure, and the described ring that forms as mentioned above can be positioned at the described other parts that condense ring-type (dicyclo) structure, and described 4-7 unit ring texture can have one or more following substituting groups that are selected from: have 1-6 carbon atom and also can have substituent alkyl, have 1-6 carbon atom and can have substituent alkoxyl group, have 2-6 carbon atom and can have substituent thiazolinyl, have 2-6 carbon atom and can have substituent alkynyl, have 3-6 carbon atom and can have substituent cycloalkyl, can have substituent outer methylene radical, can have substituent spirane base, have 6-10 carbon atom and can have substituent aryl, can have substituent heteroaryl, have 1-6 carbon atom and can have substituent Alkoximino, halogen atom, hydroxyl, cyano group and oxyimino; Perhaps have 2-5 carbon atom polymethylene chain can in conjunction with and form spiro system; With

The Q representative is the part-structure of representative with following formula (II):

R wherein ⁸Representative have 1-6 carbon atom alkyl, have 2-6 carbon atom thiazolinyl, have alkyl that the halogen of 1-6 carbon atom replaces, have 3-6 carbon atom also can have substituent cycloalkyl, can have substituent halogen replacement phenyl, can have substituent halogen replacement heteroaryl, have the alkoxyl group of 1-6 carbon atom or have the alkylamino of 1-6 carbon atom;

R ⁹Represent hydrogen atom or have the alkylthio of 1-6 carbon atom, perhaps R ⁹And R ⁸The atom that links to each other with them is combined together to form ring texture, and described ring texture can contain the composed atom of sulphur atom as ring, and the alkyl of halogen replacement that can have the alkyl that contains 1-6 carbon atom or contain 1-6 carbon atom is as substituting group;

R ¹⁰Represent hydrogen atom, phenyl, acetoxy-methyl, valeryl oxygen ylmethyl, ethoxy carbonyl, choline base, dimethyl aminoethyl, 5-indanyl, phthalidyl, 5-alkyl-2-oxo butyl, have 1-6 carbon atom alkyl, have the alkoxy methyl of 2-7 carbon atom or by the alkylidene group with 1-6 carbon atom and phenyl and the phenylalkyl that forms;

R ¹¹Represent hydrogen atom, amino, hydroxyl, thiol group, halogenated methyl or have the alkyl of 1-6 carbon atom, described amino can have one or two and be selected from following substituting group: formyl radical, have the alkyl of 1-6 carbon atom and have the acyl group of 2-5 carbon atom;

X ¹Represent halogen atom or hydrogen atom;

A ¹Represent nitrogen-atoms or be the part-structure of representative with following formula (III):

X wherein ²The methyl or the halogenated methoxy that represent hydrogen atom, have the alkyl of 1-6 carbon atom, the alkoxyl group with 1-6 carbon atom, cyano group, halogen atom, halogen replace, perhaps X ²And R ⁸Be combined together to form ring texture with their precursor skeleton connection portion, described ring texture can contain Sauerstoffatom, nitrogen-atoms or the sulphur atom composed atom as ring, and can be had 1-6 carbon atom and can have substituent alkyl replacement; With

A ²And A ³Represent nitrogen-atoms or carbon atom separately, and A ¹, A ², A ³, R ⁸And A ²With A ³The carbon atom that is connected is represented following part-structure together:

＞C＝C(-A ¹＝)-N(-R ⁸)-

Or following part-structure:

＞N-C(-A ¹＝)＝C(-R ⁸)-。

2. the compound of claim 1, its salt or hydrate are that the compound of representative is to be the compound of representative with the following formula with formula (I) wherein:

Or be the compound of representative with the following formula:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷With Q such as claim 1 definition.

3. the compound or its salt of claim 1 or its hydrate are that the compound of representative is to be the compound of representative with the following formula with formula (I) wherein:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷With Q such as claim 1 definition.

4. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) are the structure of representative:

Or be the structure of representative with the following formula:

R wherein ⁸, R ⁹, R ¹⁰, R ¹¹, X ¹And A ¹Such as claim 1 definition.

5. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, be that the Q of representative has with the following formula with formula (II) are the structure of representative:

R wherein ⁸, R ⁹, R ¹⁰, R ¹¹, X ¹And A ¹Such as claim 1 definition.

6. claim 1,2 or 3 compound, its salt or hydrate, wherein in formula (I), R ¹And R ²The hydrogen atom of respectively doing for oneself.

7. claim 1,2 or 3 compound, its salt or hydrate, wherein in formula (I), R ¹And R ²In one be hydrogen atom, another is to be selected from following substituting group: methyl, ethyl, sec.-propyl, fluoro ethyl, cyano ethyl, cyclopropyl and cyclobutyl.

8. each compound, its salt or hydrate among the claim 1-7, wherein in formula (I), R ³And R ⁴The hydrogen atom of respectively doing for oneself.

9. each compound, its salt or hydrate among the claim 1-8, wherein in formula (I), R ⁵Be hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, sec.-propyl, cyclopropyl, methyl fluoride, fluoro ethyl, trifluoromethyl, methoxymethyl, vinyl, ethynyl, methoxyl group, Ben Ji Huo oxazole-2-base.

10. each compound, its salt or hydrate among the claim 1-9 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them the formed ring texture that combines is 4 yuan of rings, and it can be replaced by one or more substituting groups.

11. each compound, its salt or hydrate among the claim 1-9 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, it can be replaced by one or more substituting groups.

12. each compound, its salt or hydrate in claim 1-9 and 11 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them the formed ring texture that combines is to contain two keys as 5 yuan of rings or 6 yuan of rings of forming structure, and it can be replaced by one or more substituting groups.

13. each compound, its salt or hydrate among claim 1-9 and the 11-12 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them the formed ring texture that combines is to contain Sauerstoffatom 5 yuan of composed atom rings or 6 yuan of rings as ring.

14. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the cis-condensed-bicyclic structure of representative:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷With Q such as claim 1 definition.

15. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them the formed ring texture that combines is 5 yuan of rings or 6 yuan of rings and condenses with pyrrolidine ring that to form with the following formula be the trans-condensed-bicyclic structure of representative:

R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷With Q such as claim 1 definition.

16. each compound, its salt or hydrate among claim 1-9 and the 11-13 are wherein in formula (I), by R ⁶And R ⁷The carbon atom that is connected with them combine formed ring texture be 5 yuan the ring or 6 yuan of rings, R ⁵And R ⁶Be combined together to form two key part-structures, the gained ring texture is representative with the following formula:

R wherein ¹, R ², R ³, R ⁴, R ⁷As above define with Q.

17. each compound, its salt or hydrate among the claim 1-16 are among the part-structure Q of representative with formula (II) in formula (I) wherein, X ¹Be hydrogen atom or fluorine atom.

18. each compound, its salt or hydrate among the claim 1-17 are among the part-structure Q of representative with formula (II) in formula (I) wherein, X ¹Be fluorine atom.

19. each compound, its salt or hydrate among the claim 1-18 are among the part-structure Q of representative with formula (II) in formula (I) wherein, A ¹Be nitrogen-atoms.

20. each compound, its salt or hydrate among the claim 1-18 are among the part-structure Q of representative with formula (II) in formula (I) wherein, A ¹For being the part-structure of representative with formula (III).

21. each compound, its salt or hydrate among the claim 1-18, wherein in formula (III), X ²Be methyl, ethyl, methoxyl group, difluoro-methoxy, cyano group or chlorine atom.

22. each compound, its salt or hydrate among the claim 1-18, wherein in formula (III), X ²Be methyl or methoxy.

23. each compound, its salt or hydrate among the claim 1-22 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ⁸Be 1,2-is suitable-the 2-halogenated cyclopropyl.

24. each compound, its salt or hydrate among the claim 1-22 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ⁸Single 1 for stereochemistry, 2-is suitable-the 2-halogenated cyclopropyl.

25. the compound of claim 24, its salt or hydrate are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ⁸1,2-is suitable-the 2-halogenated cyclopropyl be (1R, 2S)-the 2-halogenated cyclopropyl.

26. the compound of claim 25, its salt or hydrate are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ⁸(1R, 2S)-the 2-halogenated cyclopropyl be (1R, 2S)-2-fluorine cyclopropyl.

27. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, Q is for being the compound of representative with the following formula:

R wherein ⁹, R ¹⁰, R ¹¹And X ¹Such as claim 1 definition, Y ⁰Be methyl or methyl fluoride.

28. each compound, its salt or hydrate among the claim 1-27 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ⁹Be hydrogen atom.

29. the compound of claim 1, its salt or hydrate are being in the compound of representative with formula (I) wherein, Q is to be the compound of representative with following formula (IV):

R wherein ¹⁰And X ¹Such as claim 1 definition, Y ⁰Be methyl or methyl fluoride.

30. the compound or its salt of claim 29 or its hydrate, wherein in formula (IV), Y ⁰Be methyl.

31. each compound, its salt or hydrate among the claim 1-30 are among the part-structure Q of representative with formula (II) in formula (I) wherein, R ¹⁰Be hydrogen atom.

32. each compound, its salt or hydrate among the claim 1-31 are that the compound of representative is a stereochemistry simplification compound with formula (I) wherein.

33. the compound of claim 1, its salt or hydrate, wherein in formula (I), Q has following structure:

(1) 7-carboxyl-9-cyclopropyl-3-fluoro-6 (H)-6-oxo pyridine [1,2-a] pyrimidine-4-base also;

(2) 3-carboxyl-1-cyclopropyl-7-fluoro-9-methyl-4 (H)-4-oxo quinolizine-8-base;

(3) 5-carboxyl-9-fluoro-2,3-dihydro-3-(R)-methyl-6 (H)-6-oxo pyrans is [2,3,4-ij] quinolizine-10-base also;

(4) 1-(6-amino-3,5-difluoro pyridine-2-yl)-8-chloro-3-carboxyl-6-fluoro-1,4-dihydro-4-quinoline-7-base;

(5) 1-(6-amino-3,5-difluoro pyridine-2-yl)-3-carboxyl-6-fluoro-1,4-dihydro-8-methyl-4-quinoline-7-base;

(6) 6-carboxyl-9-fluoro-3-(R)-methyl fluoride-2,3-dihydro-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;

(7) 6-carboxyl-9-fluoro-2,3-dihydro-3-(S)-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;

(8) 8-amino-6-carboxyl-9-fluoro-2,3-dihydro-3-(S)-methyl-7 (H)-7-oxo pyridine is [1,2,3-de] [1,4] benzoxazine-10-base also;

(9) 3-carboxyl-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-Oxoquinoline-7-base;

(10) 3-carboxyl-8-chloro-1-cyclopropyl-1,4-dihydro-4-Oxoquinoline-7-base;

(11) 3-carboxyl-8-cyano group-1-cyclopropyl-6-fluoro-1,4-dihydro-4-Oxoquinoline-7-base;

(12) 3-carboxyl-8-cyano group-1-cyclopropyl-1,4-dihydro-4-Oxoquinoline-7-base;

(13) 3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;

(14) 3-carboxyl-1-cyclopropyl-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;

(15) 3-carboxyl-1-cyclopropyl-6-fluoro-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;

(16) 3-carboxyl-1-cyclopropyl-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;

(17) 3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;

(18) 3-carboxyl-1-cyclopropyl-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;

(19) 5-amino-3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;

(20) 5-amino-3-carboxyl-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;

(21) 3-carboxyl-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;

(22) 3-carboxyl-8-chloro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;

(23) 3-carboxyl-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;

(24) 3-carboxyl-8-cyano group-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-7-base;

(25) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;

(26) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base;

(27) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;

(28) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-7-base;

(29) 3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;

(30) 3-carboxyl-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base;

(31) 5-amino-3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-7-base; Or

(32) 5-amino-3-carboxyl-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-7-base.

34. the compound of claim 1, its salt or hydrate, wherein in formula (I), the part-structure that replaces on Q has following structure:

(1) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.2.0] heptane-3-base;

(2) (1S, 5S, 6R)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;

(3) (1S, 5S, 6S)-1-amino-6-fluoro-3-azabicyclo [3.2.0] heptane-3-base;

(4) (1S, 5S)-1-amino-6,6-two fluoro-3-azabicyclo [3.2.0] heptane-3-bases;

(5) (1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;

(6) (1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-base;

(7) (1S, 5R, 6R)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;

(8) (1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-base;

(9) spiral shell [(1S, 5S)-1-amino-3-azabicyclo [3.2.0] heptane-6,1 '-cyclopropane]-the 3-base;

(10) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-base;

(11) (1S, 5S)-1-amino-3-azabicyclo [3.3.0] octane-3-base;

(12) (1R, 5S)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;

(13) (1R, 5R)-1-amino-5-fluoro-3-azabicyclo [3.3.0] octane-3-base;

(14) (1S, 5R, 6S)-1-amino-6-fluoro-3-azabicyclo [3.3.0] octane-3-base;

(15) (1S, 5R)-1-amino-6,6-two fluoro-3-azabicyclo [3.3.0] octane-3-bases;

(16) (1S, 5R, 7S)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;

(17) (1S, 5R, 7R)-1-amino-7-fluoro-3-azabicyclo [3.3.0] octane-3-base;

(18) (1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;

(19) (1S, 5R)-1-amino-7-methyl-3-azabicyclo [3.3.0] suffering-7-alkene-3-base;

(20) (1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;

(21) (1S)-1-amino-6-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-base;

(22) (1R, 5R)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;

(23) (1R, 5S)-1-amino-3-oxa--5-azabicyclo [3.3.0] octane-5-base;

(24) (1R, 5R)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;

(25) (1R, 5S)-1-amino-4-oxa--5-azabicyclo [3.3.0] octane-5-base;

(26) 6-amino-8-aza-tricycle [4.3.0.0 ^1,3] nonane-8-base;

(27) (1S, 5R)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;

(28) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-base;

(29) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-7-alkene-3-base;

(30) (1S, 5S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-8-alkene-3-base;

(31) (1S)-1-amino-3-azabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene-3-base;

(32) (1R, 6S)-1-amino-5-oxa--8-azabicyclo [4.3.0] nonane-8-base;

(33) (1S, 6S)-1-amino-4-oxa--8-azabicyclo [4.3.0] nonane-8-base; Or

(34) (1S, 6S)-1-amino-3-oxa--8-azabicyclo [4.3.0] nonane-8-base.

35. the compound of following formula (I), its salt or hydrate:

(1) 7-[(1S, 5R, 6R)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(2) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(3) 7-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(4) 10-[(1S, 5R, 6S)-1-amino-6-methyl-3-azabicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(5) 7-[(1S, 5R, 6S)-1-amino-6-methyl fluoride-3-azabicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(6) 7-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(7) 10-[(1S, 5R, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(8) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(9) 7-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(10) 10-[(1S, 5S, 6R)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(11) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(12) 7-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(13) 10-[(1S, 5S, 6S)-1-amino-3-azabicyclo-6-fluorine dicyclo [3.2.0] heptane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(14) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(15) 10-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(16) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(17) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(18) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(19) 7-[(1R, 5S)-1-amino-3-azepine-5-fluorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(20) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(21) 7-[(1R, 5S)-1-amino-3-azepine-5-chlorine dicyclo [3.3.0] octane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(22) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(23) 7-[(1S, 5R)-1-amino-3-azabicyclo [3.3.0] suffering-7-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(24) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(25) 7-[(1S)-1-amino-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(26) 7-[(1S)-1-amino-5-methyl-3-azabicyclo [3.3.0] suffering-5-alkene-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(27) 10-[6-amino-8-aza-tricycle [4.3.0.0 ^1,3] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(28) 7-[6-amino-8-aza-tricycle [4.3.0.0 ^1,3] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(29) 7-[6-amino-8-aza-tricycle [4.3.0.0 ^1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(30) 7-[6-amino-8-aza-tricycle [4.3.0.0 ^1,3] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(31) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(32) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(33) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(34) 7-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid;

(35) 10-[(1S, 5S)-1-amino-3-azabicyclo [4.3.0] nonane-3-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid;

(36) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(37) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-8-cyano group-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-formic acid;

(38) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-formic acid;

(39) 7-[(1S, 6S)-1-amino-8-azepine-3-oxabicyclo [4.3.0] nonane-8-yl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-formic acid; Or

(40) 10-[(1S, 6S)-1-amino-8-azepine-3-oxa--dicyclo [4.3.0] nonane-8-yl]-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-formic acid.

36. medicine that comprises among the claim 1-34 each compound, its salt or hydrate as activeconstituents.

37. antibacterials that comprise among the claim 1-34 each compound, its salt or hydrate as activeconstituents.

38. a medicine that is used for the treatment of infection, described pharmaceutical pack contain compound, its salt or hydrate that right requires among the 1-34 each as activeconstituents.

39. a method that is used for the treatment of disease, described method comprise that the compound, its salt or the hydrate that give among the claim 1-34 each are as activeconstituents.

40. a method that is used for the treatment of infection, described method comprise that the compound, its salt or the hydrate that give among the claim 1-34 each are as activeconstituents.

41. a method of producing medicine, described method comprise that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.

42. a method of producing antibacterials, described method comprise that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.

43. a production is used for the treatment of the method for the medicine of infection, described method comprises that the compound, its salt or the hydrate that add among the claim 1-34 each are as activeconstituents.

44. each compound, its salt or the hydrate purposes in producing medicine among the claim 1-34.

45. each compound, its salt or the purposes of hydrate in the production antibacterials among the claim 1-34.

46. each compound, its salt or hydrate are used for the treatment of purposes in the medicine of infection in production among the claim 1-34.

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