# Patent

## Title
Quinolone derivative or salt thereof

## Abstract

A platelet aggregation inhibitor comprising a quinolone derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a novel quinolone derivative or a pharmaceutically acceptable salt thereof useful as a platelet aggregation inhibitor.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 10/562,128 filed Dec. 23, 2005 (allowed), which is a National Stage Application filed under §371 of PCT Application No. PCT/JP2004/010781 filed Jul. 22, 2004. The entire disclosures of the prior applications, application Ser. No. 10/562,128 and PCT/JP2004/010781 are considered part of the disclosure of the accompanying continuation application and are hereby incorporated by reference.


TECHNICAL FIELD
The present invention relates to a platelet aggregation inhibitor and a P2Y12 inhibitor comprising a quinolone derivative or a pharmaceutically acceptable salt thereof as an active component, and a novel quinolone derivative or a pharmaceutically acceptable salt thereof useful as a pharmaceutical agent, particularly a platelet aggregation inhibitor and a P2Y12 inhibitor.
BACKGROUND OF THE INVENTION
Since platelet was discovered in 1842 by Donne, platelet has been considered as one blood component required for hemostasis for a long time. Presently, it is demonstrated that platelet not only just plays a principle role in the hemostatic mechanism but also exerts multi-functionality for example in the establishment of arteriosclerosis having been drawing clinical attention and the involvement in circulatory diseases including thrombotic diseases, cancer metastasis, inflammations, and post-graft rejections, and additionally in immune reactions.
Generally, therapies for blood reperfusion with pharmaceutical agents or physical methods have been done for thrombotic diseases and ischemic diseases. However, it has been found in recent years that phenomena such as the elevation of platelet activation, adhesion and aggregation occur after blood reperfusion, for example via the rupture of vascular tissues including endothelial cells or the deterioration of the balance between fibrinogenolysis and coagulation with pharmaceutical agents themselves. Clinically, such phenomena have drawn attention. It has also been revealed that after reperfusion is established with thrombolysis using for example t-PA, fibrinolysis potency and coagulation potency are activated, leading to the deterioration of the balance between systemic coagulation and fibrinolysis. Clinically, such phenomena induce re-occlusion and cause serious clinical problems (non-patent reference 1).
Meanwhile, PTCA and stenting have spread rapidly for the therapeutic treatment of diseases based on the constrictions of coronary artery and aorta, including for example angina and myocardial infarction, to give certain fruitful results. However, these therapies disadvantageously damage vascular tissues including endothelial cells, so that acute coronary occlusion and restenosis emerging at chronic stage draw serious concerns. Platelet plays an important role in various thrombotic disorders (re-occlusion and the like) after blood reperfusion therapy. Therefore, anti-platelet agents efficacious in these cases are now desired. However, anti-platelet agents in the related art have not yet been verified to be sufficiently effective.
As the prophylactic or therapeutic agents of these circulatory diseases, platelet aggregation inhibitors such as aspirin, indometacin, cilostazol, prostaglandin I2, prostaglandin E1, ticlopidine, and dipyridamole have been used. Recently, GPIIb/IIIa antagonists inhibiting the final stage of platelet aggregation and having a potent platelet aggregation-inhibiting activity has additionally been developed. The application thereof is however limited to intravenous infusion at the acute stage of thrombosis (non-patent reference 2).
It has been elucidated in recent years concerning ticlopidine for use as an anti-platelet agent that an active metabolite thereof can exert its platelet aggregation-inhibiting action by inhibiting P2Y12 as an ADP receptor. Reports have subsequently been issued, telling triazolo[4,5-D]pyrimidine derivative (patent reference 1) and piperidine and/or homopiperazine (patent reference 2 and patent reference 3) as compounds with the P2Y12-inhibiting action.
Anti-microbial compounds represented by the formula (A) have been known as quinolone derivatives (patent reference 4). However, it has never been known that these derivatives have a platelet aggregation-inhibiting action.




(See the official gazette of the patent reference 4 about the symbols in the formula.)

[Non-patent reference 1] Journal of the American College of Cardiology, 1988, Vol. 12, p. 616-623
[Non-patent reference 2] General Clinical Practice (“Sogo Rinsho” in Japanese), 2003, Vol. 52, p. 1516-1521
[Patent reference 1] The pamphlet of International Publication WO 00/34283
[Patent reference 2] The pamphlet of International Publication WO 02/098856
[Patent reference 3] The pamphlet of International Publication WO 03/022214
[Patent reference 4] The pamphlet of International Publication WO 98/23592
DISCLOSURE OF THE INVENTION
In such circumstances, it is strongly desired to develop an anti-platelet agent with a high safety profile with a smaller adverse bleeding effect and with distinct pharmaceutical efficacies. Thus, it is an object of the invention to provide a platelet aggregation inhibitor and a P2Y12 inhibitor having a high pharmacological effect and a good balance between the pharmacological effect and the safety profile, and a novel compound useful as a platelet aggregation inhibitor and a P2Y12 inhibitor having a high pharmacological effect and a good balance between the pharmacological effect and the safety profile.
Thus, the invention has been achieved.
The present inventors made investigations so as to overcome the problems. The inventors found that a quinolone derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof is a compound with a novel skeleton and with an excellent platelet aggregation-inhibiting action and a P2Y12-inhibiting action.
Specifically, the invention relates to a platelet aggregation inhibitor comprising a quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient:




[the symbols in the formula have the following meanings:

X: C—R7 or N;

Y: C—R6 or N;

R11: —H, a lower alkyl which may be substituted, or an amino which may be substituted with a lower alkyl which may be substituted;

R12: —H, or a lower alkyl or an aryl, which respectively may be substituted, provided that R11 and R12 together with the adjacent nitrogen may form a cyclic amino which may be substituted;

R2: a lower alkyl, a cycloalkyl, an aryl or hetero-ring, which respectively may be substituted;

R3: a halogen, a lower alkyl or —O-lower alkyl;

R4: a cycloalkyl or a non-aromatic hetero ring, which respectively may be substituted, or a lower alkyl substituted with a cycloalkyl; provided that in case that R4 represents a non-aromatic hetero ring which may be substituted, a carbon atom composing the ring binds to the adjacent NH;

R5: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N(a lower alkyl)CO-lower alkyl, an amino which may be substituted with a lower alkyl, or a cyclic amino which may be substituted;

R6: —H, a halogen, a lower alkyl or a halogeno-lower alkyl;

R7: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl);

provided that when Y represents C—R6, R2 and R6 together may form a lower alkylene or a lower alkenylene.

In accordance with the invention, the following inventions described in (2) through (21) are provided.
(2) A P2Y12 inhibitor comprising the quinolone derivative of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(3) Use of the quinolone derivative of the formula (I) or a pharmaceutically acceptable salt thereof as a platelet aggregation inhibitor.
(4) Use of the quinolone derivative of the formula (I) or a pharmaceutically acceptable salt thereof as a P2Y12 inhibitor.
(5) Use of the quinolone derivative of the formula (I) or a pharmaceutically acceptable salt thereof so as to produce a platelet aggregation inhibitor.
(6) Use of the quinolone derivative of the formula (I) or a pharmaceutically acceptable salt thereof so as to produce a P2Y12 inhibitor.
(7) A novel quinolone derivative represented by the formula (I-a) or a pharmaceutically acceptable salt thereof:




[the symbols in the formula have the following meanings:

X: C—R7 or N;

Y: C—R6 or N;

R11: —H, a lower alkyl which may be substituted, or an amino which may be substituted with a lower alkyl which may be substituted;

R2: —H, or a lower alkyl or an aryl, which independently may be substituted, provided that R11 and R12 together with the adjacent nitrogen may form a cyclic amino which may be substituted;

R2: a lower alkyl, a cycloalkyl, an aryl or hetero-ring, which respectively may be substituted;

R3: a halogen, a lower alkyl or —O-lower alkyl;

R4: a cycloalkyl or a non-aromatic hetero ring, which respectively may be substituted, or a lower alkyl substituted with a cycloalkyl; provided that in case that R4 represents a non-aromatic hetero ring which may be substituted, a carbon atom composing the ring binds to the adjacent NH;

R5: —H, a halogen, cyano, nitro, a lower alkyl, a halogeno-lower alkyl, a cycloalkyl, an aryl, a hetero ring, —O-lower alkyl, —OH, —NHCO-lower alkyl, —N-a lower alkyl)CO-lower alkyl, an amino which may be substituted with a lower alkyl, or a cyclic amino which may be substituted;

R6: —H, a halogen, a lower alkyl or a halogeno-lower alkyl;

R7: —H, a halogen, a lower alkyl or a halogeno-(lower alkyl);

provided that when Y represents C—R6, R2 and R6 together may form a lower alkylene or a lower alkenylene and provided that 4-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbohydrazide is excluded.

(8) The compound described above in (7), where X is CH.
(9) The compound described above in (8), where R3 is a halogen.
(10) The compound described above in (9), where R4 is a cycloalkyl.
(11) The compound described above in (10), where R5 is —H, —OH or a halogen.
(12) The compound described in (11), where R12 is a lower alkyl respectively substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P):
Group P: —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2; and
Group Q: —F, —OH, —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2 
(13) The compound described in (11), wherein NR11R12 together is a cyclic amino group substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P).
(14) The compound described above in (7), which is

    [2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid,
    (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)butanedioic acid,
    2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl dihydrogen phosphate,
    (2S)-2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic acid,
    {2-[({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3S)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid,
    {2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3R)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid,
    [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-1,1-difluoroethyl]phosphonic acid,
    {2-[({7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino)ethyl}phosphonic acid,
    [2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic acid,
    [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)ethyl]phosphonic acid,
    [2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid,
    (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)pentanedioic acid,
    (2S)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnolin-3-yl]carbonyl}amino)pentanedioic acid or
    [2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, or a pharmaceutically acceptable salt thereof.


(16) The pharmaceutical composition described above in (15), which is a platelet aggregation inhibitor.
(17) The pharmaceutical composition described above in (15), which is a P2Y12 inhibitor.
(18) Use of the compound described above in any of (7) through (14) as a platelet aggregation inhibitor.
(19) Use of the compound described above in any of (7) through (14) as a P2Y12 inhibitor.
(20) Use of the compound described above in any of (7) through (14) for producing a platelet aggregation inhibitor.
(21) Use of the compound described above in any of (7) through (14) for producing a P2Y12 inhibitor.
Furthermore, the invention relates to a method for therapeutically treating circulatory diseases in close relation with thrombosis via platelet aggregation, including administering an effective amount of the quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof to a patient.
An active ingredient or compound in accordance with the invention has a quinolone skeleton where the ring atom at position 2 and/or 8 may be substituted with nitrogen atom and may be condensed together between the bonds at positions 1 and 2, and has a characteristic chemical structure in that the quinolone skeleton has an aminocarbonyl substituent at position 3 and an amino group substituent at position 7. Additionally, the compound of the invention has a pharmacologically characteristic feature of platelet aggregation-inhibiting action.
The invention is now described in more detail hereinbelow.
In the present specification, the term “lower” means a linear or branched carbon chain with one to 6 carbon atoms, unless otherwise stated.
Therefore, the term “lower alkyl” means C1-6 alkyl and specifically includes for example methyl, ethyl, propyl, butyl, pentyl or hexyl, or structural isomers thereof such as isopropyl or tert-butyl. Preferably, the lower alkyl is C1-5 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and 3-pentyl.
The term “lower alkenyl” means C2-6 alkyl with one or more double bonds at an appropriate position and specifically includes for example ethenyl, propenyl, butenyl, pentenyl, hexenyl and butadienyl. Preferably, the lower alkenyl is C2-3 alkenyl, such as ethenyl, 1-propenyl, 2-propenyl and 3-propenyl.
The term “lower alkynyl” means C2-6 alkyl with one or more triple bonds at an appropriate position.
The term “lower alkylene” means a divalent group prepared by eliminating one hydrogen atom at an appropriate position in “lower alkyl” and specifically includes for example methylene, methylmethylene, ethylene, trimethylene, propylene and butylene. Preferably, the lower alkylene is methylene, ethylene and trimethylene.
The term “lower alkenylene” means a divalent group prepared by eliminating one hydrogen atom at an appropriate position in “lower alkenyl” and specifically includes for example vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, and 3-butenylene. Preferably, the lower alkenylene is vinylene, 1-propenylene and 2-propenylene.
The term “lower alkylidene” means a group with a free atomic valence composing a part of the double bond, as prepared after one hydrogen elimination from a carbon atom with a binding ability in the “lower alkyl”.
The term “cycloalkyl” means a monovalent group of non-aromatic C3-8 hydrocarbon ring and may form a crosslinked ring or spiro ring or may partially form an unsaturated bond. Specifically, the cycloalkyl includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclohexenyl, cyclooctandienyl, adamantyl and norbornyl and preferably includes cyclopentyl or cyclohexyl.
The term “aryl” means a monovalent group of monocyclic to tricyclic aromatic C6-14 hydrocarbon ring and specifically includes for example phenyl and naphthyl. Preferably, the aryl is phenyl.
The term “non-aromatic hetero ring” means a monovalent group of a three- to ten-membered ring, preferably a five- to seven-membered ring with hetero atoms such as nitrogen, oxygen and sulfur, which may partially have an unsaturated bond and may be condensed with an aryl or aromatic hetero ring and specifically includes for example pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morphonyl, thiomorphonyl, pyrazolidinyl, dihydropyrrolyl, tetrahydropyranyl, tetrahydrofuryl, dioxanyl, tetrahydrothiopyranyl, and tetrahydrothienyl. Preferably, the non-aromatic hetero ring is pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morphonyl, thiomorphonyl, tetrahydropyranyl, dioxanyl and tetrahydrothiopyranyl.
The term “hetero ring” is the generic name of the term “non-aromatic hetero ring” including the term “aromatic hetero ring”. The term “aromatic hetero ring” means a monovalent group of an aromatic hetero ring containing one to four aromatic hetero atoms which may be the same or different and is selected from the group of nitrogen, oxygen and sulfur and being satisfactorily condensed with benzene ring and specifically includes for example pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, furazanyl, pyridyl, pyranyl, thiopyranyl, pyridazinyl, pyrimidinyl, pyrazyl, indolyl, isoindolyl, indolidinyl, benzofuryl, benzothienyl, benzoimidazolyl, indazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzoxadiazonyl, quinolyl, isoquinolyl, chromenyl, benzothiopyranyl, phthalazinyl, naphthlidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzodioxolyl, benzodioxynyl, benzodioxepinyl, and carbazolyl. Nitrogen atom and/or sulfur atom composing these rings may be oxidized. Further, these rings may be partially saturated. Preferably, the monovalent group is pyridyl, furyl, thienyl, indolyl, indazolyl or benzotriazolyl.
The term “halogen” means a monovalent halogen atom group, and specifically includes for example fluoro, chloro, bromo and iodo and preferably includes fluoro and chloro.
The term “halogeno-lower alkyl group” means a group where one or more appropriate hydrogen atoms in the “lower alkyl group” are substituted with one or more of the “halogen” described above and specifically includes for example trifluoromethyl, and trifluoroethyl. Preferably, the halogeno-lower alkyl group is trifluoromethyl.
The term “cyclic amino” is a monovalent group of a hetero ring with a binding hand to nitrogen atom and may satisfactorily contain oxygen and sulfur as hetero atoms. Specifically, the cyclic amino includes pyrrolidino, piperidino, piperazino, homopiperazino, morpholino, thiomorpholino and 3,4-dihydroisoquinolin-2(1H)-yl. Preferably, the cyclic amino is pyrrolidino, piperidino, piperazino, and 3,4-dihydrosioquinolin-2(1H)-yl.
In the specification, the substituents acceptable as those for the phrase “which may be substituted” satisfactorily include those for routine use in the art as substituents for the individual groups. Additionally, one or more substituents which may be the same or different may exist on the individual groups.
The substituents acceptable for the “aryl which may be substituted” in R12, the “cyclic amino which may be substituted” as represented by R11 and R12 together with adjacent nitrogen; the “cycloalkyl which may be substituted”, the “aryl which may be substituted”, the “non-aromatic hetero ring which may be substituted” and the “aromatic hetero ring which may be substituted” in R2; the “cycloalkyl which may be substituted” and the “non-aromatic hetero ring which may be substituted” in R4; and “the cyclic amino which may be substituted” in R5 include substituents shown below in (a) through (h). Additionally, the substituents acceptable for the “lower alkyl which may be substituted” in R11; the “lower alkyl which may be substituted” in R12; and the “lower alkyl which may be substituted” and the “lower alkenyl which may be substituted” in R2 include groups shown below in a) through (g). Additionally, Rz represents a lower alkyl which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyls, aminos which may be substituted with one or two lower alkyls, —CO2H, —CO2Rz, carbamoyl which may be substituted with one or two lower alkyls, aryls (the aryls may be substituted with halogens), aromatic hetero rings and halogens.
(a) Halogens.
(b) —OH, —O—Rz, —O-aryl, —OCO—Rz, oxo (═O), —OSO3H, —OP(O)(O—Rz)2, —P(O)(O—Rz)2, —OP(O)(OH)(O—Rz), —P(O)(OH)(O—Rz), —OP(O)(OH)2, —P(O)(OH)2.
(c) —SH, —S—Rz, —S-aryl, —SO—R2, —SO-aryl, —SO2—Rz, —SO3H, —SO2-aryl, sulfamoyl which may be substituted with one or two Rz groups.
(d) Amino which may be substituted with one or two Rz groups, —NHCO—Rz, —NHCO-aryl, —NHSO2—Rz, —NHSO2-aryl, nitro and imino (═N—Rz).
(e) —CHO, —CO—Rz, —CO2H, —CO2—Rz, carbamoyl which may be substituted with one or two Rz groups or aryls, —CO-non-aromatic hetero ring (the non-aromatic hetero ring may be substituted with —CO2H or —CO2—Rz), and cyano.
(f) Aryl or cycloalkyl, provided that the aryl or cycloalkyl may be substituted individually with one or more groups selected from the group consisting of —OH, —O-lower alkyls, aminos which may be substituted with one or two lower alkyls, —CO2H, —CO2Rz, carbamoyl which may be substituted with one or two lower alkyls, aryls, aromatic hetero rings, halogens and Rz.

(g) Aromatic hetero ring or non-aromatic hetero ring, provided that these groups may be substituted individually with one or more groups selected from the group consisting of —OH, —O-lower alkyls, oxo (═O), aminos which may be substituted with one or two lower alkyls, —CO2H, —CO2Rz, carbamoyl which may be substituted with one or two lower alkyls, aryls, aromatic hetero rings, halogens and Rz.

(h) Lower alkyl which may be substituted with one or more groups selected from the substituents described above in (a) through (g).

Particularly, individual substituents for the “lower alkyl which may be substituted” and the “aryl which may be substituted” in R12, or substituents for —NR11R12 integrally composing a cyclic amino group are preferably one or more substituents selected from the following Group Q.
Group Q: —F, —OH, —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2.
The phrase “amino group which may be substituted with a lower alkyl group which may be substituted” means an amino group substituted with only one “lower alkyl group which may be substituted” or two such “lower alkyl groups”. The lower alkyl groups for the di-substitution may be the same or different.
In the compound, X is preferably CH.
Further, Y is preferably CH or N, more preferably CH.
Additionally, R11 is preferably —H.
R12 is preferably a lower alkyl group or aryl substituted individually with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P); more preferably methyl, ethyl, propyl or butyl substituted individually with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P)
Herein, the Groups P and Q represent the following groups.
Group P: —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2; and
Group Q: —F, —OH, —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2.
When —NR11R12 integrally represents a cyclic amino group, it is preferably a cyclic amino group substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P).
Additionally, R2 is preferably a lower alkyl, cycloalkyl or non-aromatic hetero ring, which may be individually substituted.
Further, R3 is preferably a halogen, more preferably fluoro.
Still further, R4 is preferably a cycloalkyl, more preferably cyclohexyl.
Furthermore, R5 is preferably —H, —OH or a halogen, more preferably H, —OH or fluoro, and still more preferably —H or —OH.
And further, R6 is preferably —H.
Still further, R7 is preferably —H.
The quinolone derivative represented by the formula (I) or (I-a) may sometimes form a salt. Such salt is encompassed within an active ingredient of the invention or the compound of the invention, as long as the salt is a pharmaceutically acceptable salt. Specifically, the salt includes salts thereof with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts thereof with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; addition salts thereof with inorganic bases such as sodium, potassium, calcium and magnesium and organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, and ammonium salts.
An active ingredient or compound of the invention may sometimes include asymmetric carbon atoms, depending on the substituent type. Therefore, optical isomers based on such carbon atom may exist. These optical isomers in mixture or in isolation are all encompassed within the scope of the invention. Additionally, an active ingredient or compound of the invention may sometimes exist in the forms of tautomeric isomers. These isomers in separation or in mixture are also encompassed within the scope of the invention. Additionally, an active ingredient or compound of the invention after labeling, namely an active ingredient or the compound with one or more atoms therein being substituted with a radioisotope or a non-radioactive isotope is also encompassed within the scope of the invention.
Furthermore, various hydrates of an active ingredient or compound of the invention, various solvates thereof and polymorphic substances thereof are also encompassed within the scope of the invention. It is needless to say that an active ingredient or compound of the invention is not limited to the compounds described below in the Examples but includes all derivatives represented by the formula (I) or (I-a) and all pharmaceutically acceptable salts thereof.
Furthermore, the compound of the invention encompasses compounds to be metabolized into an active ingredient or compound of the invention within a living body, namely so-called prodrugs in their entirety. The groups forming the prodrugs of the compound of the invention include the groups described in Prog. Med. 5: 2157-2161 (1985) and the groups described in “The Development of Pharmaceutical Products (“Iyakuhin-no Kaihatsu” in Japanese)”, Vol. 7, Molecular Design, pp. 163-198, 1990, Hirokawa Shoten.
(Production Processes)
An active ingredient or compound of the invention can be produced through application of various known synthesis processes by utilizing the characteristic based on the basic skeleton thereof or kinds of the substituents. Representative production processes will be enumerated below. Incidentally, in some case, it is effective on the production technology that depending on the kind of a functional group, the functional group is replaced by a protective group, i.e., a group that can be readily converted into the functional group in a state of the starting material or intermediates. Thereafter, if desired, the protective group is removed, thereby enabling to obtain the desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group and an amino group. Examples of the protective group thereof include the protective groups as described in Greene and Wuts, Protective Groups in Organic Synthesis (third edition), and these may be properly used depending on the reaction condition.




(In the formula, R11, R12, R2, R3, R4, R5, R6 and X independently represent the aforementioned groups, while Lv represents a leaving group, depending on the reaction; the same is true hereinbelow.)

(Step A)

This step is a step of producing a compound (1c) via the condensation and cyclization of the compound (1a) with the compound (1b).
The condensation and cyclization at the step can be carried out in the absence of any solvent or in the presence of a solvent with a high boiling point (for example diphenyl ether is preferably used) under heating and under reflux under heating.
(Step B)
This step is a step of producing a compound (1e) via the alkylation of the compound (1c) with the compound (1d).
The leaving group Lv in the compound (1d) at the step may satisfactorily be any leaving group for routine use in alkylation. As such, halogens such as bromo, iodo and chloro; and sulfonyloxy groups such as methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy are preferably used. The method described in J. Med. Chem., 23, 1358-1363, 1980 or a method according to the method can be employed.

(Step C)

The step is a step of producing a compound (1g) by substituting the elimination group in the compound (1e) with the amino group in the compound (1f).
The leaving group Lv in the compound (1e) at the step may be any elimination for routine use in aromatic nucleophilic substitution reaction. As such, preferably, use is made of halogens such as fluoro, chloro and bromo; sulfonyloxy groups such as methanesulfonyloxy, p-toluenesulfonyloxy, and trifluoromethanesulfonyloxy; sulfonyl groups such as lower alkylsulfonyl and arylsulfonyl. In case that sulfonyl is defined as the leaving group Lv at the step C, the compound (1a) with sulfonyl as Lv can be used as the starting material. Otherwise, the compound (1a) with the corresponding sulfanyl as Lv can be used as the starting material. After an appropriate step for example Step B, then, Lv is modified into sulfonyl via an oxidation reaction using for example m-chloroperbenzoic acid, for use in the substitution reaction at the Step C.
The substitution reaction at the step can be carried out in the absence of any solvent or in the presence of solvents inert to the reaction, for example aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran (THF), and dioxane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform; N,N-dimethylformamide (DMF); dimethylsulfoxide (DMSO); esters such as ethyl acetate (EtOAc); acetonitrile; and alcohols such as methanol (MeOH), ethanol (EtOH) and 2-propanol, at ambient temperature and under reflux under heating, using an equimolar amount of the compound (1e) and the compound (1f) or an excess of either one of the compounds. Depending on the compound, the substitution reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
(Step D)
The step is a step of producing the compound (1h) by subjecting the compound (1g) to a hydrolysis reaction.
The hydrolysis reaction of the compound (1g) at the step can be carried out in the presence of acids such as inorganic acids for example mineral acids including for example sulfuric acid, hydrochloric acid and hydrobromic acid and organic acids such as formic acid and acetic acid or in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate or ammonia, under cooling and under reflux under heating in solvents inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, DMF, N,N-dimethylacetamide (DMA), N-methylpyrrolidone, DMSO, pyridine and water. The reaction temperature can be selected, appropriately, depending on the compounds and the reaction reagents.
(Step E)
The step is a step of producing the compound (I-b) of the invention via the amidation of the compound (1h) or a reactive derivative thereof with the compound (1i).
For the amidation at this step, amidation for routine use by a person skilled in the art can be employed. Preference is given to a process using condensing agents such as carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (WSC.HCl), dicyclohexylcarbodiimide, diphenylphosphorylazide, and diethylphosphorylcyanide and a process through a mixed acid anhydride, using isobutyl chloroformate and ethyl chloroformate.
Generally, the step is carried out under cooling, under cooling or at ambient temperature, or at ambient temperature and under reflux under heating in solvents inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, DMF and DMSO, although the details vary depending on the reactive derivative and the condensing agent to be used.
(Step F)
The step is a step of producing the compound (1j) by subjecting the compound (1e) to a hydrolysis reaction according to the Step D.
(Step G)
The step is a step of producing the compound (1h) by substituting the elimination group in the compound (1j) with the amino group in the compound (1f) according to the Step C.
(Step H)
The step is a step of producing the compound (1k) via the amidation of the compound (1j) or a reactive derivative thereof with the compound (1i) according to the Step E.
(Step I)
The step is a step of producing the compound (I-b) of the invention by substituting the elimination group in the compound (1k) with the amino group in the compound (1f) according to the Step C.
(Step J)
The step is a step of producing the compound (1l) via the alkylation of the compound (1a). The alkylation at the step can be carried out by a process according to the Step B or by reductive alkylation. For the reductive alkylation, reductive alkylation processes for routine use by a person skilled in the art can be employed. For example, the method described in “Experimental Lecture Series of Chemistry (“Jikken Kagaku Koza” in Japanese) (the 4th edition)”, Japan Chemical Association, Vol. 20, 1992 (Maruzen) is listed. Generally, the step is preferably carried out using reducing agents such as sodium borohydride and sodium triacetoxyborohydride under cooling, at ambient temperature and under reflux under heating in solvents inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, alcohols, and acetic acid. Depending on the compound, advantageously, the reaction is carried out in the presence of acids such as mineral acids including for example sulfuric acid, hydrochloric acid and hydrobromic acid and organic acids such as formic acid and acetic acid.
(Step K)
The step is a step of producing the compound (1e) via the condensation and cyclization of the compound (1b) and the compound (1l) according to the Step A.




The present process through the Step A is a production process employable in case that the introduction of R2 involves difficulty in the Step B of the first process, depending on the bulkiness of tert-butyl group, adamantyl group and the like. Additionally, the process through the Step B is a production process employable in case that R2 and R6 together form a ring.
(Step A)
The step is a step of producing the compound (2c) via the condensation of the compound (2a) with orthoformate ester and subsequent addition and elimination with the compound (2b).
The condensation with orthoformate ester at the step can be carried out in a solvent capturing alcohols generated from orthoformate ester such as acetic anhydride, or via the reaction with a reagent capturing alcohols generated from orthoformate ester in a solvent inert to the reaction, such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, DMSO, esters such as ethyl acetate (EtOAc), and acetonitrile, at ambient temperature and under reflux under heating.
The addition and elimination reaction subsequent to the condensation can be carried out under cooling, at ambient temperature and under reflux under heating in solvents inert to the reaction, such as alcohols, halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF and DMSO. An excess of the compound (2c) may be used for the reaction. Depending on the compound, advantageously, the step may be carried out in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used) or bases in the form of metal salts (for example potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium tert-butoxide are preferably used).
(Step B)
The step is a step of producing the compound (2c) via the addition and elimination reaction of the compound (2a) with the compound (2d).
The addition and elimination reaction at the step can be carried out in solvents inert to the reaction, for example halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF and DMSO, using an equimolar amount of the compound (2a) and the compound (2d) or an excess of either one of the compounds, under cooling, at ambient temperature and under reflux under heating. Depending on the compound, the addition and elimination reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
(Step C)
The step is a step of producing the compound (1e) via the intramolecular cyclization of the amino group in the compound (2c).
The addition and elimination reaction of the compound (2c) at this step can be carried out under cooling, at ambient temperature and under reflux under heating in solvents inert to the reaction, such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF, and DMSO. Depending on the compound, the addition and elimination reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
The compound (1e) produced at the step is subjected to the process similar to the first process, to produce the inventive compound (I-c).




The process is a production process employable in case that R2 and R6 together form a ring.

(Step A)

The step is a step of producing the compound (2c) via the condensation of the compound (3a) with the compound (3b).
As the leaving group Lv in the compound (3a) at the step, halogens such as chloro and bromo, alkoxy, acyloxy and sulfonyloxy such as p-toluenesulfonyl are preferably used. Additionally, the compound (3b′) instead of the compound (3b) at the step can be used, where the position of the double bond is isomerized.
The condensation reaction at the step can be carried out in solvents inert to the reaction, for example halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF and DMSO at ambient temperature and under reflux under heating, using an equimolar amount of the compound (3a) and the compound (3b) or an excess of either one of the compounds. Depending on the compound, the condensation reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
(Step B)
The step is a step of producing the compound (1e) via the cyclization reaction of the compound (2c).
The intramolecular cyclization reaction at this step can be carried out according to the step C of the second process. So as to promote the reaction smoothly at this step, the step is advantageously carried out in the presence of bases in the form of metal salts, such as sodium hydride.
Depending on the conditions for the step A, the compound (1e) may instantly be obtained from the compound (3a) without the isolation of the compound (2c).
The compound (1e) produced at the step is subjected to the same process as in the first process, to produce the inventive compound (I-d).




The process is a production process of constructing a fused ring after the preliminary introduction of R4NH—.

(Step A)

The step is a step of producing the compound (4a) by substituting the leaving group in the compound (1a) with the amino group in the compound (1f) according to the step C of the first process.
Additionally, the step may be carried out via a substitution reaction using a palladium catalyst (in this case, halogens such as bromo and iodo and trifluoromethanesulfonyloxy are preferably used as the Lv in the compound (1a)), according to the method described in Tetrahedron Lett., 38, 6359-6362, 1997 or a process according to the method.
(Step B)
The step is a step of producing the compound (4b) via the condensation and cyclization reaction of the compound (4a) with the compound (1b) according to the step A of the first process.
(Step C)
The step is a step of producing the compound (4c) via the alkylation reaction of the compound (4b) and the compound (1d) according to the step B of the first process.
(Step D)
The step is a step of producing the compound (1h) by subjecting the compound (4c) to a hydrolysis reaction according to the step D of the first process.
(Step E)
The step is a step of producing the inventive compound (I-e) via the amidation of the compound (1h) or a reactive derivative thereof with the compound (1i) according to the step E of the first process.




The process is a process of producing a compound of the formula (I) or (I-a) where Y is N.

(Step A)

The step is a step of producing the compound (5b) by preparing the compound (5a) into a diazo compound and subsequently adding ethyl cyanoacetate to the resulting diazo compound.
The diazo preparation as the first stage of the step can be carried out in the presence of acids such as hydrochloric acid, sulfuric acid and acetic acid, in solvents inert to the reaction, such as water and alcohol, using an equimolar amount of a reagent for preparing diazo compounds such as sodium nitrite and amyl nitrite and the compound (5a) or an excess of either one of the compounds, under cooling. The addition reaction at the second stage can be carried out in the presence of a base, using an equimolar amount of the diazo compound produced at the first stage and ethyl cyanoacetate or an excess of either one of them under cooling, at ambient temperature and under reflux under heating. As the base, organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used) can be used.
(Step B)
The step is a step of producing the compound (5c) via the alkylation reaction of the compound (5b) and the compound (1d) according to the step B of the first process.
(Step C)
The step is a step of producing the compound (5d) by subjecting the compound (5c) to a hydrolysis reaction according to the step D of the first process.
(Step D)
The step is a step of producing the compound (5e) by subjecting the compound (5d) to acid halogenation and cyclization.
The acid halogenation as the first stage of the step can be carried out in the absence of any solvent or in solvents inert to the reaction, such as aromatic hydrocarbons, ethers, halogenated hydrocarbons, esters such as ethyl acetate, and acetonitrile, using an equimolar amount or an excess of a halogenation agent such as thionyl chloride and oxalyl chloride and the compound (5d) under cooling, at ambient temperature and under reflux under cooling. Depending on the compound, the reaction may sometimes be carried out advantageously by adding a catalytic amount of DMF and the like. The cyclization reaction as the second stage can be carried out by using the acid halide obtained at the first stage and an equimolar amount or an excess of an Lewis acid in the presence of Lewis acids such as aluminum chloride, in the absence of any solvent or in solvents inert to the reaction such as aromatic hydrocarbons, halogenated hydrocarbons, and esters such as ethyl acetate under cooling, at ambient temperature and under reflux under heating.
(Step E)
The step is a step of producing the compound (5f) by substituting the leaving group in the compound (5e) with the amino group in the compound (1f) according to the step C of the first process.
(Step F)
The step is a step of producing the compound (5d) by subjecting the compound (5f) to a hydrolysis reaction according to the step D of the first process.
(Step G)
The step is a step of producing the inventive compound (I-f) via the amidation of the compound (5g) or a reactive derivative thereof and the compound (1i) according to the step E of the first process.




The process is a process of producing the compound of the formula (I) or (I-a) where Y is N.

(Step A)

The step is a step of producing the compound (6a) via the preparation of the compound (2a) into a diazo compound.
The diazo-preparing reaction at this step can be done using an equimolar amount of a diazo-preparing reagent such as sodium azide and p-toluenesulfonyl azide and the compound (2a) or an excess of either one of the compounds in solvents inert to the reaction, for example hydrocarbons such as pentene and hexane, aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, acetonitrile and water, at ambient temperature and under reflux under heating. Depending on the compound, the reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
(Step B)
The step is a step of producing the compound (6b) via the reductive intramolecular cyclization reaction of the compound (6a).
At this step, trialkylphosphine or triarylphosphine can be used as the reducing agent. As the leaving group Lv in the compound (6a), for example, halogens such as fluoro, chloro and bromo, sulfonyloxy such as p-toluenesulfonyl and nitro are used. The use of fluoro is particularly preferable. For this step, the method described in Chem. Pharm. Bull., 36, 1321-1327, 1988 or a method according to the method can be employed.
(Step C)
The step is a step of producing the compound (6c) via the alkylation reaction of the compound (6b) and the compound (1d) according to the step B of the first process.
(Step D)
The step is a step of producing the compound (6d) by substituting the leaving group in the compound (6c) with the amino group in the compound (1f) according to the step C of the first process.
(Step E)
The step is a step of producing the compound (6e) by subjecting the compound (6d) to a hydrolysis reaction according to the step D of the first process.
(Step F)
The step is a step of producing the inventive compound (I-g) via the amidation of the compound (6e) or a reactive derivative thereof and the compound (1i) according to the step E of the first process.




(In the formula, R8 represents a lower alkenyl or a lower alkynyl with an unsaturated bond at position β, such as allyl and propargyl, which may be substituted; R9 and R10 represents H or a lower alkyl group; otherwise, R9 and R10 together may represent a lower alkylidene; and m and n represent 0 to 3.)

The process is a process of producing the compound of the formula (I) or (I-a), where R2 and R6 together form a ring.
(Step A)
The step is a step of producing the compound (7b) via the alkylation reaction of the compound (1c′) and the compound (7a).
The alkylation reaction at this step can be done, using an equimolar amount of the compound (1c′) and the compound (7a) or an excess of either one of the compounds in the absence of any solvent or in solvents inert to the reaction, for example aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, esters such as ethyl acetate, and acetonitrile or in solvents such as alcohol, at ambient temperature and under reflux under heating. Depending on the compound, the substitution reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
(Step B)
The step is a step of producing the compound (7c) via the intramolecular rearrangement reaction of the compound (7b).
The cyclization reaction at this step can be done in the absence of any solvent or in the presence of a solvent with a high boiling point (for example 1,2-dichlorobenzene is preferably used) under heating and under reflux under heating.
(Step C)
The step is a step of producing the inventive compound (1e′) via the intramolecular cyclization reaction of the compound (7c) in case that R8 has an leaving group such as halogens (chloro and bromo are preferably used) and sulfonyloxy(methanesulfonyloxy and p-toluenesulfonyloxy are preferably used) or a triple bond.
The intramolecular cyclization reaction of the compound (7c) at this step can be done in the absence of any solvent or in solvents inert to the reaction, such as halogenated hydrocarbons, ethers, aromatic hydrocarbons, DMF and DMSO, under cooling, at ambient temperature and under reflux under heating. Depending on the compound, the reaction may sometimes be carried out advantageously in the presence of organic bases (for example triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine are preferably used), or bases in the form of metal salts (potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide are preferably used).
Depending on the conditions for the step B, further, the compound (1e′) may sometimes be obtained instantly from the compound (7b) without isolation of the compound (7c).
The compound (1e′) produced at the step is subjected to the same process as the first process, to produce the inventive compound (I-h).
Additionally, some compounds represented by the formula (I) or (I-a) may also be produced from the inventive compounds thus obtained by an appropriate combination of known steps for routine use by a person skilled in the art, such as alkylation, acylation, substitution, oxidation, reduction and hydrolysis.
The inventive compounds thus produced are isolated and purified as they are free or are isolated and purified as salts prepared by general methods. The isolation and purification are done by general chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographic means.
Various isomers can be isolated by general methods, utilizing the difference in physico-chemical properties between the isomers. For example, a racemic mixture can be prepared into an optically pure isomer by a general racemic resolution method including for example preparing a diastereomer salt with a general optically active acid such as tartaric acid and subsequent optical resolution. Additionally, a diastereomer mixture can be separated for example by fractional crystallization or various chromatographic means. Still further, optically active compounds can be produced by using appropriate optically active starting materials.
INDUSTRIAL APPLICABILITY
An active ingredient or compound of the invention has an excellent platelet aggregation-inhibiting action and an excellent P2Y12-inhibiting action. Therefore, an active ingredient or compound of the invention is useful as a pharmaceutical agent, particularly a platelet aggregation inhibitor and a P2Y12 inhibitor. Accordingly, an active ingredient or compound of the invention is useful as a prophylactic and/or therapeutic agent of circulatory diseases in close relation with thrombosis via platelet aggregation, including ischemic disorders for example unstable angina, acute myocardial infarction and secondary onsets thereof, re-occlusion and re-stenosis post-liver artery bypass surgery, post-PTCA or post-stenting, thrombolytic promotion of liver artery and prophylaxis of re-occlusion; cerebral vascular disorders such as transient cerebral ischemia attack (TIA), cerebral stenosis, and subarachnoid hemorrhage (vascular constriction): and peripheral artery diseases such as chronic artery occlusion; as well as an aiding agent during heart surgery or vascular surgery.
The excellent platelet aggregation-inhibiting action of the inventive compound was verified by the following test methods.
(1) Test for Assaying Human Platelet Aggregation-Inhibiting Activity
Blood was withdrawn from healthy human volunteers (adult males), in the presence of a 1/10th volume of sodium citrate, and centrifuged to obtain supernatant platelet-enriched plasma (PRP). The platelet count in PRP was determined with an automatic blood cell counter (MEK-6258; manufactured by NIHON KOHDEN CORPORATION). Then, the platelet count in PRP was adjusted to 3×108/ml with platelet-poor plasma. ADP as a platelet aggregation-inducing agent was a product of MCMEDICAL, Inc. Platelet aggregation was measured using an aggregometer (MCM Hematracer 212; MCMEDICAL, Inc.). Specifically, 80 μl of PRP and 10 μl of a solution of an active ingredient or compound of the invention or a solvent (10% DMSO) were incubated together at 37° C. for one minute, to which 10 μl of ADP (50 μM) was added to induce platelet aggregation. Then, the change of the transmitting light was recorded over 5 minutes. Using the area-under-the curve of platelet aggregation as an indicator, the inhibition ratio was calculated. The results from an active ingredient or compound of the invention at 10 μM (as final concentration) are shown in Table 1.







TABLE 1







Human platelet aggregation-inhibiting action










Test compound
% inhibition







Example 18
92



Example 419
88



Example 429
88



Example 522
86



Example 557
81



Example 583
92



Example 603
81



Example 619
91










(2) Substitution Test of the Binding Between Human P2Y12 and 2-methylthio-ADP (2-MeS-ADP)

After C6-15 cells were inoculated on a DMEM culture medium to 1×106 cells in a 10-cm petri dish for culturing for one day, where 8 μg of a plasmid pEF-BOS-dhfr-human P2Y12 and 0.8 μg of pEF-BOS-neo (Nucleic Acid Res., 18, 5322, 1990) were genetically introduced with a transfection reagent (LipofectAMINE 2000; manufactured by GIBCO BRL).
24 hours after the gene introduction procedure described above, the cells with the gene introduced therein were recovered and suspended in a DMEM culture medium containing 0.6 mg/ml G418 (manufactured by GIBCO BRL), to prepare serial dilutions, which were inoculated on a 10-cm petri dish. Colonies appearing 2 weeks later were individually obtained and defined as C6-15 cell expressing the protein P2Y12, for use in the following experiment (WO 02/36631, Mol. Pharmacol., 60, 432, 2001).
The C6-15 cell expressing the protein P2Y12 was cultured and recovered. After the cell was rinsed with PBS, the cell was suspended in 20 mM Tris-HCl, pH 7.4 containing 5 mmol/l EDTA and a protease inhibitor cocktail set CompleteTM (manufactured by Boehringer Mannheim GmbH) and then homogenized with Polytron. After ultra-centrifugation, the resulting precipitate was suspended in 50 mM Tris-HCl, pH 7.4 containing 1 mM EDTA, 100 mM NaCl and CompleteTM. The resulting suspension was defined as a membrane fraction.
1.5 μl of an active ingredient or compound of the invention and 50 μl of 0.75 nM [3H]-2-MeS-ADP (80 Ci/mmol; manufactured by Amersham Pharmacia Biotech) were added to 100 μl of the P2Y12 protein-expressing C6-15 cell membrane fraction (100 μg/ml) thus prepared, for incubation in 50 mM Tris-HCl, pH 7.4 containing 100 mM NaCl and 50 mM MgCl2, at ambient temperature for one hour. Subsequently, the incubation mixture was recovered onto a glass filter with a cell harvester. Adding a microscintillator onto the glass filter, the radioactivity was assayed with a liquid scintillation counter. At the test, additionally, the radioactivity levels of such cell cultures with no addition of the compound and with addition of 1.5 μl of 100 μM 2-MeS-ADP were assayed as total binding and non-specific binding, respectively. Defining the total binding and the non-specific binding at inhibition ratios of 0% and 100%, respectively, the inhibition ratio (%) of an active ingredient or compound in accordance with the invention was calculated. The results from an active ingredient or the compound of the invention at 30 nM (final concentration) are shown in Table 2.







TABLE 2







Inhibition activity of the binding between P2Y12 and 2-MeS-ADP










Test compounds
% inhibition







Example 18
96



Example 22
75



Example 28
63



Example 178
30



Example 259
52



Example 265
40



Example 279
31



Example 290
74



Example 336
46



Example 406
80



Example 425
93



Example 429
98



Example 463
62



Example 501
95



Example 522
80



Example 532
36



Example 583
80



Example 619
73










A pharmaceutical composition comprising an active ingredient of the invention is prepared into tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, ointments and paps, using carriers and excipients and other additives for general use, for oral or parenteral administration.
The clinical dose of an active ingredient of the invention is appropriately determined, taking account of for example the symptoms, body weight, age and sex of a patient to be administered. Generally, the daily oral dose is generally about 0.0001 to 50 mg/kg, preferably about 0.001 to 10 mg/kg, more preferably about 0.01 to 1 mg/kg, in one portion or in divided portions of 2 to 4. For intravenous administration, appropriately, the daily dose is appropriately about 0.0001 to 1 mg/kg, preferably about 0.0001 to 0.1 mg/kg per body weight, in one portion per day or in divided plural portions per day. The dose varies depending on the variable conditions. Therefore, a sufficient effect may sometimes be obtained at an amount smaller than the ranges of the doses.
As a solid composition for oral administration in accordance with the invention, for example, tablets, powders and granules are used. In such solid composition, one or more active substances are mixed with at least one inactive diluent type, including for example lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and magnesium metasilicate aluminate. The composition may satisfactorily contain additives other than the inactive diluents, for example lubricants such as magnesium stearate, disintegrators such as fibrin calcium glycolate, stabilizers and auxiliary agents for dissolution. If necessary, the tablets and pills may be coated with sugar coatings of sucrose, gelatin, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose phthalate or with films dissolvable in stomach or intestine.
The liquid composition for oral administration contains for example pharmaceutically acceptable emulsifiers, fluids, suspending agents, syrups and elixirs and also contain inactive diluents for general use, including for example distilled water, and ethanol (EtOH). The composition may satisfactorily contain auxiliary agents such as emollients and suspending agents, sweeteners, flavors, aromatic agents and preservatives other than the inactive diluents.
The injections for parenteral administration contain sterile, aqueous or non-aqueous fluids, suspending agents and emulsifiers. The aqueous fluids and the suspending agents include for example distilled water for injections and physiological saline. The non-aqueous fluids and suspending agents include for example propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as EtOH, polysorbate 80. Such composition further may contain preservatives, emollients, emulsifiers, dispersants, stabilizers and auxiliary agents for dissolution. These are sterilized by for example filtration through bacteria-deposit filters, blending of sterilizing agents or irradiation. These may also be used in a form of a sterile solid composition, which is preliminarily dissolved in sterile water or sterile solvents for injections.


BEST MODE FOR CARRYING OUT THE INVENTION
The invention is now specifically described in the following Examples but is never limited to these Examples. Herein, the starting material compounds for use in the Examples include novel substances. The processes from such starting material compounds are described in Reference Examples.
The symbols in the Tables represent the following meanings (the same is true hereinbelow).
Rf: Number of Reference Example
Ex: Number of Example
(In case that only the number of Example is described in the column Ex, the compound is in the free form; in case that a diagonal line (/) and HCl are added after the number of Example, the compound is in the form of hydrochloride salt.)
Data: Physical data [Sal: Salt (no description of Sal indicates free form; in case that for example HCl is added, the compound is in the form of hydrochloride salt.)]
R, R1, R2, R3, R4, A: substituent groups in general formulas (Me: methyl; Et: ethyl; nPr: n-propyl; iPr: isopropyl; iBu: isobutyl; sBu: sec-butyl; tBu: tert-butyl; nPen: n-pentyl; cPr: cyclopropyl; cBu: cyclobutyl; cPen: cyclopentyl; cHex: cyclohexyl; cHep: cycloheptyl; cOct: cyclooctyl; Ph: phenyl; Py: pyridyl; fur: furyl; the: thienyl; Bn: benzyl; btria: benzotriazolyl; bimid: benzoimidazolyl; pyrr: pyrrolidinyl; pipe: piperidinyl; pipa: piperazinyl; mor: morpholinyl; THF: tetrahydrofuranyl; THP: tetrahydropyranyl; THSP: tetrahydrothiopyranyl; 2-thiq: 3,4-dihydroisoquinolin-2(1H)-yl; Boc: tert-butyloxycarbonyl; Ac: acetyl; Bz: benzoyl; tri: tri; di: di. The number before a substituent group expresses the position substituted. Accordingly, for example, 4-EtO2C-1-pipe represents 4-ethoxycarbonylpiperidin-1-yl and 2-the-(CH2)2—NH— represents 2-(thiophen-2-yl)ethylamino.) Syn: production process (a numerical figure indicates the use of a corresponding starting material for production, like a compound of Example with the numerical figure; when two or more numbers are written, the production is done, using numbered production processes sequentially from the preceding numbers.)
Reference Example 1
3-Bromo-4-fluorobenzoic acid was dissolved in toluene, to which tert-butanol, triethylamine and diphenylphosphorylazide were sequentially added to stir at 100° C. for 20 hours, to obtain tert-butyl(3-bromo-4-fluorophenyl)carbamate.
FAB-MS (Neg): 288, 290 (M+−1)
Reference Example 2
The compound of Reference Example 1 was dissolved in toluene, to which aniline, cesium carbonate, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, and tris(dibenzylidene acetone)dipalladium were sequentially added for stirring at 110° C. for 2 days, to obtain tert-butyl(3-anilino-4-fluorophenyl)carbamate. The resulting compound was dissolved in EtOAc, to which 4M HCl-EtOAc solution was added for stirring at ambient temperature for one day, to obtain 4-fluoro-N3-phenylbenzene-1,3-diamine.
FAB-MS (Pos): 203 (M++1)
Reference Example 3
Diethyl ethoxymethylenemalonate was added to 3,4-difluoroaniline at ambient temperature and the mixture was stirred at 130° C. for 17 hours. After diphenyl ether was additionally added to the reaction mixture, stirring was done at 260° C. for one hour. A solid obtained by leaving the reaction mixture to stand for cooling to ambient temperature was filtered, to obtain ethyl 6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
In the same manner as in the process of Reference Example 3, Reference Examples 4 through 10 in Table 3 were produced using the respective corresponding starting materials.







TABLE 3













 












Rf
R1
R2
R3
R4
Data















3
H
F
F
H
FAB-MS(Pos); 254(M+ + 1)


4
H
Br
F
H
FAB-MS(Pos); 314, 316(M+ + 1)


5
H
F
Ph-NH—
H
FAB-MS(Pos); 327(M+ + 1)


6
H
H
F
H
FAB-MS(Pos); 236(M+ + 1)


7
H
F
F
F
FAB-MS(Pos); 272(M+ + 1)


8
H
Cl
F
H
FAB-MS(Pos); 270(M+ + 1)


9
H
Me
F
H
FAB-MS(Pos); 250(M+ + 1)


10
F
F
F
H
FAB-MS(Pos); 272(M+ + 1)









Reference Example 11
Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate produced according to Organic Preparations and Procedures International, 29, 231-234, 1997 was dissolved in acetic anhydride, to which ethyl orthoformate was added at ambient temperature, for stirring at 150° C. for one hour. The resulting mixture was concentrated under reduced pressure. The resulting residue was dissolved in EtOH, to which cyclopentylamine was added under ice cooling, for stirring at ambient temperature for one hour. The resulting mixture was concentrated under reduced pressure. The resulting residue was dissolved in 1,4-dioxane, to which 60% sodium hydride was added at ambient temperature, for stirring at 80° C. for 4 hours and subsequent concentration under reduced pressure. Then, aqueous hydrochloric acid solution was added to the resulting concentrate for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in acetic acid, to which aqueous 6 M HCl was added at ambient temperature for stirring at 120° C. for 5.5 hours, to obtain 1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
In the same manner as in the process of Reference Example 11, Reference Examples 12 through 28 as shown in Table 4 were produced using the respective corresponding starting materials.







TABLE 4













 









Rf
R
Data





11
cPen
FAB-MS(Pos); 294(M+ + 1)


12
iPr
FAB-MS(Pos); 268(M+ + 1)


13
Ph
FAB-MS(Pos); 302(M+ + 1)


14
cHex
FAB-MS(Pos); 308(M+ + 1)


15
cBu
FAB-MS(Pos); 280(M+ + 1)


16
sBu
FAB-MS(Pos); 282(M+ + 1)


 


17




FAB-MS(Pos); 320(M+ + 1)


 


18
(Et)2CH—
FAB-MS(Pos); 296(M+ + 1)


19
iPr-CH(Me)-
FAB-MS(Pos); 296(M+ + 1)


20
nPr-CH(Me)-
FAB-MS(Pos); 296(M+ + 1)


21
CF3CH2—
FAB-MS(Pos); 308(M+ + 1)


22
t-Bu-CH(Me)-
FAB-MS(Pos); 310(M+ + 1)


23
nPr-CH(Et)-
FAB-MS(Pos); 310(M+ + 1)


24
iBu
FAB-MS(Pos); 282(M+ + 1)


25
cPr
FAB-MS(Pos); 266(M+ + 1)


26
iBu-CH(Me)-
FAB-MS(Pos); 310(M+ + 1)


27
(nPr)2CH—
FAB-MS(Pos); 324(M+ + 1)


28
4,4-diMe-cHex
FAB-MS(Pos); 336(M+ + 1)









Reference Example 29
The compound of Reference Example 5 was suspended in DMF, to which potassium carbonate and ethyl iodide were sequentially added under ice cooling, for stirring at ambient temperature for 4 days, to obtain ethyl 7-anilino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate. The compound was suspended in aqueous 1M NaOH, for stirring at 100° C. for one hour, to obtain 7-anilino-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos): 327 (M++1)
Reference Example 30
The compound of Reference Example 3 was suspended in DMF, to which potassium carbonate and ethyl iodide were sequentially added under ice cooling, for stirring at ambient temperature for 24 hours and subsequent chloroform extraction. The resulting extract was concentrated under reduced pressure. The resulting residue was suspended in acetic acid, to which aqueous 6M HCl was added at ambient temperature for stirring at 120° C. for 4 hours, to obtain 6,7-difluoro-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
In the same manner as in the process of Reference Example 30, Reference Examples 31 through 39 as shown in Table 5 were produced using the respective corresponding starting materials.







TABLE 5







 








 











Rf
R1
R2
R
Data














30
F
H
Et
FAB-MS(Pos); 254(M+ + 1)


31
F
H
Me
FAB-MS(Pos); 240(M+ + 1)


32
F
H
Bn
FAB-MS(Pos); 316(M+ + 1)


33
F
H
4-MeO-Bn
FAB-MS(Pos); 346(M+ + 1)


34
F
H
allyl
FAB-MS(Pos); 266(M+ + 1)


35
H
H
Et
FAB-MS(Pos); 236(M+ + 1)


36
Br
H
Et
FAB-MS(Pos); 314, 316(M+ + 1)


37
F
F
Et
FAB-MS(Pos); 272(M+ + 1)


38
Cl
H
Et
FAB-MS(Pos); 270(M+ + 1)


39
Me
H
Et
FAB-MS(Pos); 250(M+ + 1)









Reference Example 40
The compound of Reference Example 30 was suspended in DMSO, to which cyclohexylamine was added at ambient temperature, for stirring at 80° C. for 2 hours and subsequent recrystallization in aqueous 80% acetic acid solution, to obtain 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.50 (m, 7H), 1.60-1.70 (m, 1H), 1.72-1.82 (m, 2H), 1.90-2.00 (m, 2H), 3.55-3.67 (m, 1H), 4.53 (q, J=7.4 Hz, 2H), 6.65 (dd, J=2.2, 8.1 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 7.79 (d, J=11.3 Hz, 1H), 8.83 (s, 1H), 15.78 (s, 1H)
In the same manner as in the process of Reference Example 40, Reference Examples 41 through 87 as shown in Tables 6 and 7 were produced using the respective corresponding starting materials.







TABLE 6







 








 










Rf
R1
R2
Data













40
Et
cHex
FAB-MS(Pos); 333(M+ + 1)


41
Et
iPr
FAB-MS(Pos); 293(M+ + 1)


42
Et
tBu
FAB-MS(Pos); 307(M+ + 1)


43
Et
4-THP
FAB-MS(Pos); 335(M+ + 1)


44
Et
cPen
FAB-MS(Pos); 319(M+ + 1)


45
Et
1-Boc-4-pipe
FAB-MS(Pos); 434(M+ + 1)


46
Et
Ph
FAB-MS(Pos); 327(M+ + 1)


47
Et
cHep
FAB-MS(Pos); 347(M+ + 1)


48
Et
cOct
FAB-MS(Pos); 361(M+ + 1)


49
Et
1-Me-cHex
FAB-MS(Pos); 347(M+ + 1)


50
Et
4-THSP
FAB-MS(Pos); 351(M+ + 1)


51
Et
4-Me-cHex
FAB-MS(Pos); 347(M+ + 1)


52
Et
4,4-diF-cHex
FAB-MS(Pos); 369(M+ + 1)


53
cPen
4-THSP
FAB-MS(Pos); 391(M+ + 1)


54
cPen
4,4-diF-cHex
FAB-MS(Pos); 409(M+ + 1)


55
cPen
3-THP
FAB-MS(Pos); 375(M+ + 1)
















TABLE 7







 








 












Rf
R1
R2
R3
R
Data















56
H
F
H
Me
FAB-MS(Pos);







319(M+ + 1)


57
H
F
H
iPr
FAB-MS(Pos);







347(M+ + 1)


58
H
F
H
Bn
FAB-MS(Pos);







395(M+ + 1)


59
H
F
H
cPen
FAB-MS(Pos);







373(M+ + 1)


60
H
F
H
4-MeO-Bn
FAB-MS(Pos);







425(M+ + 1)


61
H
F
H
Ph
FAB-MS(Pos);







381(M+ + 1)


62
H
F
H
cHex
FAB-MS(Pos);







387(M+ + 1)


63
H
F
H
allyl
FAB-MS(Pos);







345(M+ + 1)


64
H
H
H
Et
FAB-MS(Pos);







315(M+ + 1)


65
H
Br
H
Et
FAB-MS(Pos);







393, 395







(M+ + 1)


66
H
F
F
Et
FAB-MS(Pos);







351(M+ + 1)


67
H
Cl
H
Et
FAB-MS(Pos);







349(M+ + 1)


68
H
Me
H
Et
FAB-MS(Pos);







329(M+ + 1)


69
H
F
H
cBu
FAB-MS(Pos);







359(M+ + 1)


70
H
F
H
sBu
FAB-MS(Pos);







361(M+ + 1)


 


71
H
F
H




FAB-MS(Pos); 399(M+ + 1)


 


72
H
F
H
(Et)2CH—
FAB-MS(Pos);







375(M+ + 1)


73
H
F
H
iPr—CH(Me)—
FAB-MS(Pos);







375(M+ + 1)


74
H
F
H
nPr—CH(Me)—
FAB-MS(Pos);







375(M+ + 1)


75
H
F
H
CF3CH2—
FAB-MS(Pos);







387(M+ + 1)


76
H
F
H
t-Bu-CH(Me)—
FAB-MS(Pos);







389(M+ + 1)


77
H
F
H
nPr—CH(Et)—
FAB-MS(Pos);







389(M+ + 1)


78
H
F
H
iBu
FAB-MS(Pos);







361(M+ + 1)


79
H
F
H
cPr
FAB-MS(Pos);







345(M+ + 1)


80
H
F
H
iBu-CH(Et)—
FAB-MS(Pos);







389(M+ + 1)


81
H
F
H
(nPr)2CH—
FAB-MS(Pos);







403(M+ + 1)


82
H
F
H
4,4-diMe-cHex
FAB-MS(Pos);







415(M+ + 1)


83
H
F
H
(FCH2)2CH—
FAB-MS(Pos);







383(M+ + 1)


84
H
F
H
H2C═C(CH2F)—
FAB-MS(Pos);







363(M+ + 1)


85
NHMe
F
H
Et
ESI-MS(Pos);







362(M+ + 1)


86
NH(cHex)
F
H
Et
FAB-MS(Pos);







430(M+ + 1)


87
NH2
F
H
Et
FAB-MS(Pos);







348(M+ + 1)









Reference Example 88
The compound of Reference Example 10 was dissolved in DMF, to which potassium carbonate and ethyl iodide were sequentially added under ice cooling, for stirring at ambient temperature for 2 days, to obtain ethyl 1-ethyl-5,6,7-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
In the same manner as in the process of Reference Example 88, Reference Examples 89 through 91 as shown in Table 8 were produced using the respective corresponding starting materials.







TABLE 8







 








 










Rf
R1
R
Data













88
F
Et
FAB-MS(Pos); 300(M+ + 1)


89
H
(1,3-dioxolan-2-yl)-CH2—
FAB-MS(Pos); 340(M+ + 1)


90
H
tBuO2CCH2—
FAB-MS(Pos); 368(M+ + 1)


91
H
tBuO2CCH(Me)—
FAB-MS(Pos); 382(M+ + 1)









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







TABLE 9







 








 











Rf
R1
R
A
Data














92
F
Et
CH
FAB-MS(Pos);






379(M+ + 1)


94
H
(1,3-dioxolan-2-yl)-CH2—
CH
FAB-MS(Pos);






419(M+ + 1)


95
H
tBuO2CCH2—
CH
FAB-MS(Pos);






447(M+ + 1)


96
OMe
Et
CH
ESI-MS(Pos);






392(M+ + 1)


97
H
tBuO2CCH(Me)—
CH
ESI-MS(Pos);






461(M+ + 1)


98
H
cPen
N
FAB-MS(Pos);






402(M+ + 1)


99
F
(Et)2CH—
CH
FAB-MS(Pos);






421(M+ + 1)


100
AcN(Me)—
(Et)2CH—
CH
ESI-MS(Pos);






474(M+ + 1)
















TABLE 10







 








 









Rf
—R1—R2—
Data












101
—(CH2)3—
ESI-MS(Pos); 373(M+ + 1)


102
—C(═CH2)—(CH2)2—
ESI-MS(Pos); 385(M+ + 1)


103
—CH2—C(═CH2)—(CH2)2—
ESI-MS(Pos); 399(M+ + 1)









Reference Example 104
Ethyl 7-(cyclohexylamino)-1′-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 415 (M++1)
Reference Example 105
Ethyl 9-(cyclohexylamino)-8-fluoro-6-oxo-6H-pyrido[1,2-a]quinoline-5-carboxylate
FAB-MS (Pos): 383 (M++1)
Reference Example 106
Ethyl[7-(cyclohexylamino)-6-fluoro-1′-isopropyl-4-oxo-1,4-dihydro-1,8-naphthylidin-3-yl]carboxylate
FAB-MS (Pos): 376 (M++1)
Reference Example 107
Under ice cooling, triethylamine and 2,4,5-trifluorobenzoyl chloride were added to a solution of ethyl 3-(cyclopentylamino)buta-2-enoate in dioxane, for stirring at ambient temperature for 30 minutes and at 65° C. for one hour, to obtain ethyl 3-(cyclopentylamino)-2-(2,4,5-trifluorobenzoyl)buta-2-enoate.
FAB-MS (Pos): 356 (M++1)
Reference Example 108
60% sodium hydride was added to a solution of the compound of Reference Example 107 in dioxane, for stirring at 70° C. for 2 hours, to obtain ethyl 1-cyclopentyl-6,7-difluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 336 (M++1)
Reference Example 109
Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate was dissolved in acetic anhydride, to which ethyl orthoformate was added at ambient temperature, for stirring at 140° C. for 12 hours and subsequent concentration under reduced pressure. The resulting residue was dissolved in EtOH, to which triethylamine and EtOH solution of tetrahydrofuran-3-amine hydrochloride was added under ice cooling, for stirring under ice cooling for 30 minutes and at ambient temperature for one hour. Water was then added for ethyl acetate extraction. The resulting extract was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. 60% sodium hydride was added to a suspension of the resulting residue in 1,4-dioxane, for stirring at 80° C. for 1.5 hours, to obtain ethyl 6,7-difluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-carboxylate. The product was suspended in DMSO, to which cyclohexylamine was added, for stirring at 100° C. for 22 hours, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-4-oxo-1-(tetrahydrofuran-3-yl)-1,4-dihydroquinoline-3-carboxylate.
In the same manner as in the process of Reference Example 109, Reference Examples 110 through 125 as shown in Table 11 were produced using the respective corresponding starting materials (In Reference Examples 123 and 124, the hydroxyl group in the corresponding starting materials was protected with tert-butyldimethylsilyl group).







TABLE 11







 








 









Rf
R
Data












109
3-THF
FAB-MS(Pos); 403(M+ + 1)


110
2,2-diMe-1,3-dioxan-5-yl
FAB-MS(Pos); 447(M+ + 1)


111
(3R)-3-THF
FAB-MS(Pos); 403(M+ + 1)


112
(3S)-3-THF
FAB-MS(Pos); 403(M+ + 1)


113
cyclopent-3-en-1-yl
FAB-MS(Pos); 399(M+ + 1)


114
oxetan-3-yl
FAB-MS(Pos); 389(M+ + 1)


115
4-THP
FAB-MS(Pos); 417(M+ + 1)


 


116




FAB-MS(Pos); 427(M+ + 1)


 


117
1-Boc-3-pyrr
FAB-MS(Pos); 502(M+ + 1)


118
1-Boc-4-pipe
FAB-MS(Pos); 516(M+ + 1)


119
1-Boc-azetidin-3-yl
FAB-MS(Pos); 488(M+ + 1)


120
tBu
FAB-MS(Pos); 389(M+ + 1)


121
MeO(CH2)2—
FAB-MS(Pos); 391(M+ + 1)


122
CF3CH(Me)—
FAB-MS(Pos); 429(M+ + 1)


 


123




FAB-MS(Pos); 489(M+ + 1)


 


124
HO(CH2)3—
ESI-MS(Neg); 389(M+ − 1)


125
3-methylcyclopent-3-en-1yl
FAB-MS(Pos); 413(M+ + 1)









Reference Example 126
Palladium-carbon was added to a solution of the compound of Reference Example 105 in trifluoroacetic acid, for stirring under hydrogen pressure for 12 hours, to obtain ethyl 9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylate.
FAB-MS (Pos): 387 (M++1)
Reference Example 127
The compound of Reference Example 95 was dissolved in methylene chloride, to which trifluoroacetic acid was added, for stirring at ambient temperature for 24 hours, to obtain [7-(cyclohexylamino)-3-(ethoxycarbonyl)-6-fluoro-4-oxoquinolin-1(4H)-yl]acetic acid trifluoroacetate.
FAB-MS (Pos): 391 (M++1)
In the same manner as in the process of Reference Example 127, Reference Example 128 was produced using the corresponding starting material.
Reference Example 128
2-[7-(Cyclohexylamino)-3-(ethoxycarbonyl)-6-fluoro-4-oxoquinolin-1(4H)-yl]propionic acid
ESI-MS (Pos): 405 (M++1)
Reference Example 129
The compound of Reference Example 127 was dissolved in THF, to which 1,1′-carbonyldiimidazole was added under ice cooling, for stirring under ice cooling for one hour. Then water was added to the mixture, to which sodium borohydride was added, for stirring at ambient temperature for 4 hours, to obtain 7-(cyclohexylamino)-6-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 377 (M++1)
In the same manner as in the process of Reference Example 129, Reference Example 130 was produced using the corresponding starting material.
Reference Example 130
Ethyl 7-(cyclohexylamino)-6-fluoro-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos): 391 (M++1)
Reference Example 131
The compound of Reference Example 129 was dissolved in methylene chloride, to which pyridinium p-toluenesulfonate and dihydropyrane were sequentially added under ice cooling, for stirring at ambient temperature for 3 days, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-4-oxo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 461 (M++1)
Reference Example 132
The compound of Reference Example 127 was dissolved in THF, to which 1,1′-carbonylbis-1H-imidazole was added under ice cooling, for stirring at ambient temperature for 2.5 hours. An aqueous methylamine solution was added to the resulting reaction mixture under ice cooling, for stirring at ambient temperature for one hour, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-(methylamino)-2-oxoethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 404 (M++1)
In the same manner as in the process of Reference Example 132, Reference Examples 133 through 134 were produced using the respective corresponding starting materials.
Reference Example 133
Ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 473 (M++1)
Reference Example 134
Ethyl 7-(cyclohexylamino)-6-fluoro-1-(2-morpholin-4-yl-2-oxoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 460 (M++1)
Reference Example 135
An aqueous 70% acetic acid solution was added to the compound of Reference Example 110, for stirring at 80° C. for 18 hours, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 407 (M++1)
Reference Example 136
The compound of Reference Example 135 was dissolved in DMF, to which methyl iodide and silver oxide were added for stirring at ambient temperature for 51 hours, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-methoxy-1-(methoxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 435 (M++1)
Reference Example 137
The compound of Reference Example 129 was dissolved in methylene chloride, to which triethylamine and methanesulfonyl chloride were added under ice cooling, for stirring at ambient temperature for 2 hours, to obtain a mesyl compound. The mesyl compound was dissolved in DMF, to which sodium azide was added for stirring at ambient temperature for 5 hours, to obtain an azide compound. The azide compound was dissolved in THF, to which triphenylphosphine was added, for stirring at 50° C. for one hour. Water was then added for stirring overnight at 80° C. Pyridine and acetic anhydride were added to the resulting reaction mixture, for stirring at ambient temperature for 3 hours, to obtain ethyl 1-[2-(acetylamino)ethyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 418 (M++1)
In the same manner as in the process of Reference Example 137, Reference Examples 138 through 140 were produced using the respective corresponding starting materials.
Reference Example 138
Ethyl 1-[2-(acetylamino)propyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos): 432 (M++1)
Reference Example 139
Ethyl 1-{2-(acetylamino)-1-[(acetylamino)methyl]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 489 (M++1)
Reference Example 140
Ethyl 1-[2-(acetylamino)-1-methylethyl]-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos): 432 (M++1)
Reference Example 141
The compound of Reference Example 117 was suspended in EtOAc, to which 4M HCl-EtOAc solution was added under ice cooling, for stirring as it was for one hour, overnight at ambient temperature and overnight at 50° C. Insoluble materials therein were filtered and dried. The dried materials were suspended in methylene chloride, to which sodium acetate, formaldehyde solution (36%) and sodium triacetoxyborohydride were added under ice cooling, for stirring for 45 minutes as the mixture remained as it was, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 416 (M++1)
In the same manner as in the process of Reference Example 141, Reference Examples 142 and 143 were produced using the respective corresponding starting materials.
Reference Example 142
Ethyl 7-(cyclohexylamino)-6-fluoro-1-(1-methylpiperidin-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 430 (M++1)
Reference Example 143
Ethyl 7-(cyclohexylamino)-6-fluoro-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 402 (M++1)
Reference Example 144
5-Methoxy-3,4-dihydro-2H-pyrrole and triethylamine were added to ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate, for stirring at 60° C. for 4 days, to obtain ethyl 3-oxo-2-pyrrolidin-2-ylidene-3-(2,4,5-trifluorophenyl)propanoate.
ESI-MS (Pos): 314 (M++1)
Reference Example 145
60% sodium hydride was added to a dioxane solution of the compound of Reference Example 144, for stirring at ambient temperature for one hour, to obtain ethyl 7,8-difluoro-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate.
ESI-MS (Pos): 294 (M++1)
Reference Example 146
Diethylaminosulfur trifluoride was added to a methylene chloride solution of the compound of Reference Example 130 in at −78° C. Then, the mixture was gradually warmed to ambient temperature over 2 hours, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-(2-fluoro-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 393 (M++1)
Reference Example 147
To a methylene chloride solution of the compound of Reference Example 130 were added triethylamine and methanesulfonyl chloride at 0° C., for stirring as it was for one hour, to obtain a mesyl compound. The mesyl compound was dissolved in THF, to which potassium tert-butoxide was added for stirring at ambient temperature for 3 hours, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-isopropenyl-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 373 (M++1)
Reference Example 148
Sodium hydride and methyl iodide were added to a DMF solution of the compound of Reference Example 137 at 0° C., for stirring for 5 hours, to obtain ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 446 (M++1)
In the same manner as in the process of Reference Example 148, Reference Examples 149 was produced using the corresponding starting material.
Reference Example 149
Ethyl 1-{2-[acetyl(methyl)amino]-1-methylethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
ESI-MS (Pos): 446 (M++1)
Reference Example 150
Palladium-carbon and conc. hydrochloric acid were added to a EtOH solution of the compound of Reference Example 102, for stirring under hydrogen atmosphere for 12 hours, to obtain ethyl 8-(cyclohexylamino)-7-fluoro-1-methyl-5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylate.
ESI-MS (Pos): 387 (M++1)
In the same manner as in the process of Reference Example 150, Reference Examples 151 was produced using the corresponding starting material.
Reference Example 151
Ethyl 9-(cyclohexylamino)-8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-4-carboxylate
ESI-MS (Pos): 401 (M++1)
Reference Example 152
Potassium carbonate and iodocyclopentane were added to a DMF solution of ethyl 6,7-difluoro-4-hydroxycinnoline-3-carboxylate, for stirring at 80° C. for 40 minutes, to obtain ethyl 1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate.
FAB-MS (Pos): 323 (M++1)
In the same manner as in the process of Reference Example 152, Reference Examples 153 was produced using the corresponding starting material.
Reference Example 153
Ethyl 1-(1-ethylpropyl)-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate
FAB-MS (Pos): 325 (M+1)
Reference Examples 154 and 155
Ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate was dissolved in acetic anhydride, to which ethyl orthoformate was added at ambient temperature, for stirring at 140° C. for 3 hours and subsequent concentration under reduced pressure. The resulting residue was dissolved in EtOH, to which [2-fluoro-1-(fluoromethyl)ethyl]amine hydrochloride and triethylamine were added under ice cooling, for stirring at ambient temperature for 30 minutes and subsequent concentration under reduced pressure. Water was added to the resulting residue, for ethyl acetate extraction. The resulting organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in acetonitrile, to which potassium carbonate was added at ambient temperature, for stirring at 50° C. for 15 hours and additional stirring at 80° C. for 7 hours, to obtain ethyl 6,7-difluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (Reference Example 154) and ethyl 6,7-difluoro-1-[1-(fluoromethyl)vinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (Reference Example 155).
Reference Example 154
FAB-MS (Pos): 332 (M++1)
Reference Example 155
FAB-MS (Pos): 312 (M++1)
Reference Example 156
3-Pentanone, acetic acid and sodium triacetoxyborohydride were added to a 1,2-dichloroethane solution of 3,4,5-trifluoroaniline, for stirring at ambient temperature for 14 hours, to obtain N-(1-ethylpropyl)-3,4,5-trifluoroaniline.
EI-MS (Pos): 217 (M++1)
Reference Example 157
Diethyl(ethoxymethylene)malonate was added to the compound of Reference Example 156, for stirring at 130° C. for 20 hours, to obtain diethyl{[(1-ethylpropyl)(3,4,5-trifluorophenyl)amino]methylene}malonate.
FAB-MS (Pos): 388 (M++a)
Reference Example 158
Polyphosphoric acid was added to the compound of Reference Example 157, for stirring at 130° C. for 30 minutes, to obtain ethyl 1-(1-ethylpropyl)-5,6,7-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 342 (M++1)
Reference Example 159
The compound of Reference Example 88 was added to a toluene suspension of lithium methoxide, for stirring at ambient temperature for 3 days, to obtain ethyl 1-ethyl-6,7-difluoro-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 312 (M++1)
In the same manner as in the process of Reference Example 159, Reference Example 160 was produced using the corresponding starting material.
Reference Example 160
5-(Benzyloxy)-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
ESI-MS (Pos): 481 (M++1)
Reference Example 161
An aqueous solution of methylamine was added to a toluene suspension of the compound of Reference Example 88, for stirring at 70° C. for 20 hours, to obtain ethyl 1-ethyl-6,7-difluoro-5-(methylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
ESI-MS (Pos): 311 (M++1)
In the same manner as in the process of Reference Example 161, Reference Example 162 was produced using the corresponding starting material.
Reference Example 162
Ethyl 5-(benzylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate
FAB-MS (Pos): 387 (M++1)
Reference Example 163
3-Methylcyclopent-3-ene-1-carboxylic acid was dissolved in toluene, to which tert-butanol, triethylamine and diphenylphosphorylazide were sequentially added for stirring at 90° C. for 3 days, to obtain tert-butyl(3-methylcyclopent-3-en-1-yl)carbamate.
NMR (CDCl3) 6; 1.44 (s, 9H), 1.71 (brs, 3H), 2.02-2.18 (m, 2H), 2.58-2.77 (m, 2H), 4.27 (brs, 1H), 4.69 (brs, 1H), 5.25 (brs, 1H)
Reference Example 164
The compound of Reference Example 163 was dissolved in methylene chloride, to which trifluoroacetic acid was added, for stirring at ambient temperature for 4 hours, to obtain 3-methylcyclopent-3-ene-1-amine trifluoroacetate. Ethyl 3-(2-chloro-4,5-difluorophenyl)-3-oxopropanoate was dissolved in acetic anhydride, to which ethyl orthoformate was added, for stirring at 150° C. for 2 hours and subsequent concentration under reduced pressure. The resulting residue was dissolved in EtOH, to which triethylamine and 3-methylcyclopent-3-ene-1-amine trifluoroacetate were sequentially added under ice cooling, for stirring under ice cooling for 18 hours, to obtain ethyl 2-(2-chloro-4,5-difluorobenzoyl)-3-[(3-methylcyclopenta-3-en-1-yl)amino]acrylate. The resulting compound was dissolved in 1,4-dioxane, to which sodium hydride was added, for stirring at 50° C. for 3 hours, to obtain ethyl 6,7-difluoro-1-(3-methylcyclopenta-3-en-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 334 (M+1)
Reference Example 165
The compound of Reference Example 162 was dissolved in EtOH-acetic acid, to which palladium-carbon (10%) was added, for stirring under hydrogen atmosphere for 3 hours, to obtain ethyl 5-amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 297 (M++1)
Reference Example 166
3-Pentanone and p-toluenesulfonic acid monohydrate were added to a benzene solution of ethyl 7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate, for stirring under reflux under heating for 34 hours, to obtain ethyl 7-(cyclohexylamino)-1-(2,2-diethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate.
FAB-MS (Pos): 475 (M++1)
Reference Example 167
The compound of Reference Example 92 was dissolved in EtOH-THF, to which 2M aqueous NaOH was added, for stirring at ambient temperature for 12 hours, to obtain 7-(cyclohexylamino)-1-ethyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
In the same manner as in the process of Reference Example 167, Reference Examples 168 through 214 as shown in Tables 12 through 15 were produced using the respective corresponding starting materials.







TABLE 12







 








 










Rf
R1
R
Data













167
F
Et
FAB-MS(Pos);





351(M+ + 1)


168
H
(1,3-dioxolan-2-yl)-CH2—
FAB-MS(Pos);





391(M+ + 1)


169
H
2,2-diMe-1,3-dioxan-5-yl
FAB-MS(Pos);





419(M+ + 1)


170
H
3-THF
FAB-MS(Pos);





375(M+ + 1)


171
H
(3R)-3-THF
FAB-MS(Pos);





375(M+ + 1)


172
H
(3S)-3-THF
FAB-MS(Pos);





375(M+ + 1)


173
H
cyclopent-3-en-1-yl
FAB-MS(Pos);





371(M+ + 1)


174
H
oxetan-3-yl
FAB-MS(Pos);





361(M+ + 1)


175
H
4-THP
FAB-MS(Pos);





389(M+ + 1)


 


176
H




FAB-MS(Pos); 399(M+ + 1)


 


177
H
1-Boc-3-pyrr
FAB-MS(Pos);





474(M+ + 1)


178
H
1-Boc-4-pipe
FAB-MS(Pos);





488(M+ + 1)


179
H
tBu
FAB-MS(Pos);





361(M+ + 1)


180
H
MeO(CH2)2—
FAB-MS(Pos);





363(M+ + 1)


181
H
CF3CH(Me)CH—
FAB-MS(Pos);





401(M+ + 1)


 


182
H




FAB-MS(Pos); 461(M+ + 1)


 


183
H
2-THP-O—(CH2)2—
FAB-MS(Pos);





433(M+ + 1)


184
H
MeNH(CO)CH2—
ESI-MS(Pos);





376(M+ + 1)


185
H
(4-Me-1-pipe)(CO)CH2—
ESI-MS(Pos);





445(M+ + 1)


186
H
(4-mor)(CO)CH2—
FAB-MS(Pos);





432(M+ + 1)


187
H
(MeOCH2)2CH—
FAB-MS(Pos);





407(M+ + 1)


188
H
AcNH(CH2)2—
FAB-MS(Pos);





390(M+ + 1)


189
H
AcNH(CH2)3—
FAB-MS(Pos);





404(M+ + 1)


190
H
(AcNHCH2)2CH—
FAB-MS(Pos);





461(M+ + 1)


191
H
1-Me-3-pyrr
FAB-MS(Pos);





388(M+ + 1)


192
H
1-Me-4-pipe
FAB-MS(Pos);





402(M+ + 1)


193
H
1-Me-azetidin-3-yl
FAB-MS(Pos);





374(M+ + 1)


194
OMe
Et
ESI-MS(Pos);





363(M+ + 1)


195
H
FCH2CH(Me)—
FAB-MS(Pos);





365(M+ + 1)


196
H
isopropenyl
FAB-MS(Pos);





345(M+ + 1)


197
H
AcNHCH2CH(Me)—
FAB-MS(Pos);





404(M+ + 1)


198
H
AcN(Me)(CH2)2—
FAB-MS(Pos);





418(M+ + 1)


199
H
AcN(Me)CH2CH(Me)—
FAB-MS(Pos);





418(M+ + 1)


200
NH(cHex)
Et
FAB-MS(Pos);





351(M+ + 1)


201
NHMe
Et
ESI-MS(Pos);





283(M+ + 1)


202
H
3-methylcyclopent-3-en-1yl
FAB-MS (Pos);





385(M+ + 1)


203
H
2-THP-OCH2CH(Me)—
FAB-MS(Pos);





447(M+ + 1)


204
H
2,2-diethyl-1,3-dioxan-5-yl
FAB-MS (Pos);





447(M+ + 1)


205
F
(Et)2CH—
FAB-MS(Pos);





393(M+ + 1)


206
AcN(Me)—
(Et)2CH—
ESI-MS(Pos);





446(M+ + 1)
















TABLE 13







 








 









Rf
R1
Data





207
NH2
FAB-MS(Pos); 269(M+ + 1)


208
NHMe
ESI-MS(Pos); 283(M+ + 1)


209
NH(cHex)
FAB-MS(Pos); 351(M+ + 1)
















TABLE 14













 










Rf
R1
R2
Data













210
H
H
FAB-MS(Pos); 345(M+ + 1)


211
Me
H
FAB-MS(Pos); 359(M+ + 1)









212
CH2═
FAB-MS(Pos); 357(M+ + 1)
















TABLE 15







 








 









Rf
R
Data












213
cPen
FAB-MS(Pos); 374(M+ + 1)


214
(Et)2CH—
FAB-MS (Pos); 376(M+ + 1)









Reference Example 215
Aqueous LiOH was added to a EtOH-THF solution of the compound of Reference Example 15104, for stirring at 60° C. for 24 hours and at 80° C. for 24 hours, to obtain 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos): 387 (M++1)
In the same manner as in the process of Reference Example 215, Reference Examples 216 through 220 were produced using the respective corresponding starting materials.
Reference Example 216
9-(Cyclohexylamino)-8-fluoro-6-oxo-6H-pyrido[1,2-a]quinoline-5-carboxylic acid
FAB-MS (Pos): 355 (M++1)
Reference Example 217
Ethyl[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydro-1,8-naphthylidin-3-yl]carboxylic acid
FAB-MS (Pos): 348 (M++1)
Reference Example 218
Ethyl 9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic acid
FAB-MS (Neg): 357 (M+−1)
Reference Example 219
9-(Cyclohexylamino)-8-fluoro-2-methylene-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoquinoline-5-carboxylic acid
FAB-MS (Pos): 371 (M++1)
Reference Example 220
9-(Cyclohexylamino)-8-fluoro-2-methyl-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic acid
FAB-MS (Pos): 373 (M++1)
Reference Example 221
An aqueous solution of sodium nitrate was added dropwise to an aqueous hydrochloric acid solution of 3,4-difluoroaniline under ice cooling, for stirring at the same temperature for 1.5 hours. The resulting reaction mixture was added dropwise to an aqueous EtOH solution of ethyl cyanoacetate and sodium acetate as prepared in a separate reaction flask, for stirring at ambient temperature for 2 hours, to obtain ethyl cyano[(3,4-difluorophenyl)diazenyl]acetate.
FAB-MS (Pos): 254 (M++1)
Reference Example 222
The compound of Reference Example 221 was suspended in acetonitrile, to which ethyl iodide and potassium carbonate were added for stirring at 50° C. for 7 days, to obtain ethyl 2-cyano[(3,4-difluorophenyl)(ethyl)hydrazono]acetate.
FAB-MS (Pos): 282 (M++1)
Reference Example 223
The compound of Reference Example 222 was suspended in EtOH, to which aqueous NaOH was added under ice cooling, for stirring at ambient temperature for 2 hours, to obtain 2-cyano[(3,4-difluorophenyl)(ethyl)hydrazono]acetic acid.
FAB-MS (Pos): 254 (M++1)
Reference Example 224
The compound of Reference Example 223 was suspended in toluene, to which thionyl chloride was added, for stirring at 90° C. for 1.5 hours and subsequent concentration under reduced pressure. The resulting residue was azeotropically evaporated with toluene. Hexane was added to the residue and the resulting solid was filtered. The solid was dissolved in dichloroethane, to which aluminium chloride was added for stirring at 55° C. for 24 hours and reflux for another 23 hours, to obtain 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carbonitrile.
FAB-MS (Pos): 236 (M++1)
Reference Example 225
The compound of Reference Example 224 was dissolved in DMSO, to which cyclohexylamine was added, for stirring at 80° C. for 3 hours, to obtain 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnoline-3-carbonitrile.
FAB-MS (Pos): 315 (M++1)
Reference Example 226
The compound of Reference Example 225 was dissolved in acetic acid, to which aqueous HCl was added, for stirring at 120° C. for 2 days, to obtain 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid.
FAB-MS (Pos): 334 (M++1)
Reference Example 227
DMF and N-chlorosuccinimide were added to the compound of Reference Example 40, for stirring at 100° C. for 14 hours, to obtain 8-chloro-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos): 367 (M++1)
Reference Example 228
Cyclohexylamine was added to a DMSO solution of the compound of Reference Example 153, for stirring at 80° C. for 14 hours. After the reaction mixture was cooled to ambient temperature, water and saturated aqueous ammonium chloride were added for chloroform extraction. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in ethanol, to which aqueous 1N sodium hydroxide solution was added, for stirring at ambient temperature for 2 hours, to obtain 7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylic acid.
FAB-MS (Pos): 376 (M++1)
Reference Example 229
Water and conc. hydrochloric acid were added to an acetic acid solution of the compound of Reference Example 154, for stirring at 100° C. for 5 hours, to obtain 6,7-difluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos): 304 (M++1)
In the same manner as in the process of Reference Example 229, Reference Example 230 was produced using the corresponding starting material.
Reference Example 230
6,7-Difluoro-1-[1-(fluoromethyl)vinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
FAB-MS (Pos): 284 (M++1)
Reference Example 231
The compound of Reference Example 130 was dissolved in methylene chloride, to which pyridinium p-toluenesulfonate and dihydropyrane were sequentially added for overnight stirring at ambient temperature, to obtain ethyl 7-(cyclohexylamino)-6-fluoro-1-[1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate. The resulting compound was suspended in EtOH-THF, to which 1M aqueous NaOH was added for overnight stirring, to obtain 7-(cyclohexylamino)-6-fluoro-1-[1-methyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
FAB-MS (Pos): 447 (M++1)
Reference Example 232
The compound of Reference Example 40 was suspended in DMF, to which 1,1′-carbonylbis-1H-imidazole was added at ambient temperature, for stirring at 100° C. for 24 hours, to obtain 7-(cyclohexylamino)-1-ethyl-6-fluoro-3-(1H-imidazol-1-ylcarbonyl)quinolin-4(1H)-one.
NMR (CDCl3) δ; 1.25-1.53 (m, 5H), 1.59 (t, J=7.6 Hz, 3H), 1.65-1.76 (m, 1H), 1.80-1.90 (m, 2H), 2.05-2.15 (m, 2H), 3.34-3.45 (m, 1H), 4.22 (q, J=7.6 Hz, 2H), 4.57-4.66 (m, 1H), 6.44 (d, J=6.4 Hz, 1H), 7.04-7.05 (m, 1H), 7.51-7.53 (m, 1H), 7.99 (d, J=12.0 Hz, 1H), 8.12 (s, 1H), 8.15-8.16 (m, 1H).
Reference Example 233
By the same method described below in Example 16, tert-butyl{[(6,7-difluoro-1-ethyl-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetate was obtained from the compound of Reference Example 30.
FAB-MS (Pos): 367 (M+1)
In the same manner as in Reference Example 233, Reference Example 234 was produced using the corresponding starting material.
Reference Example 234
Ethyl{[(5-amino-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetate
FAB-MS (Pos): 354 (M++1)
Reference Example 235
Acetic anhydride was added to the compound of Reference Example 234, for stirring at 120° C. for 4 hours, to obtain ethyl({[5-(acetylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
FAB-MS (Pos): 396 (M++1)
In the same manner as in Reference Example 235, Reference Example 236 was produced using the corresponding starting material.
Reference Example 236
Ethyl[5-(acetylmethylamino)-1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinolin-3-yl]carboxylic acid
ESI-MS (Pos): 395 (M++1)
Reference Example 237
(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl)phosphonic acid was suspended in benzene, to which benzyl N,N′-dicyclohexylimide carbamate was added, for stirring under reflux conditions for 4 hours, to obtain dibenzyl(2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl)phosphonate.
FAB-MS (Pos): 528 (M++1)
Reference Example 238
The compound of Reference Example 237 was dissolved in DMF, to which diisopropylethylamine was added, for stirring at ambient temperature for 2 days, to obtain dibenzyl(2-aminoethyl)phosphonate. Further, oxalic acid was added to the resulting phosphonate, to obtain dibenzyl(2-aminoethyl)phosphonate oxalate.
FAB-MS (Pos): 306 (M++1)
Reference Example 239
Hydrazine monohydrate was added to a methylene chloride solution of diethyl[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,1-difluoroethyl]phosphonate, for stirring at ambient temperature for one hour, to obtain diethyl(2-amino-1,1-difluoroethyl)phosphonate.
ESI-MS (Pos): 218 (M++1)
Reference Example 240
Diethyl pyridin-3-ylphosphonate was dissolved in EtOH-acetic acid, to which platinum oxide was added, for stirring under 3.4 kgf/cm2 hydrogen for 120 hours, to obtain diethyl piperidin-3-ylphosphonate.
ESI-MS (Pos): 222 (M++1)
In the same manner as in the process of Reference Example 240, Reference Example 241 was produced using the corresponding starting material.
Reference Example 241
Diethyl(piperidin-2-ylmethyl)phosphonate
FAB-MS (Pos): 236 (M++1)
Reference Example 242
Palladium-carbon (10%) was added to a solution of benzyl((3aRS,4SR,6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate in EtOH, for stirring overnight under hydrogen atmosphere, to obtain (3aRS,4SR,6RS,6aRS)-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyltetrahydro-3 aH-cyclopenta[d][1,3]dioxol-4-amine.
FAB-MS (Pos): 288 (M++1)
Reference Example 243
Platinum oxide and conc.HCl were added to a solution of diethyl(1-cyano-2-phenylethyl)phosphonate in EtOH, for overnight stirring under hydrogen atmosphere, to obtain diethyl[2-amino-1-(cyclohexylmethyl)ethyl]phosphonate.
FAB-MS (Pos): 278 (M++1)
Example 1
400 mg of the compound of Reference Example 59 was suspended in 5.0 ml of DMF, to which 350 mg of 1,1′-carbonylbis-1H-imidazole was added at ambient temperature, for stirring at 100° C. for 20 hours. 0.2 ml of triethylamine and 180 mg of glycine ethyl ester hydrochloride were added sequentially to the resulting reaction mixture under ice cooling, for stirring at ambient temperature for another 5 hours. The reaction mixture was concentrated under reduced pressure, to which water was added for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from EtOH, to obtain 408 mg of ethyl({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 2
300 mg of the compound of Reference Example 232 was dissolved in 5.0 ml of DMF, to which 0.2 ml of triethylamine and 120 mg of glycine ethyl ester hydrochloride were added sequentially to the resulting reaction mixture under ice cooling, for stirring at ambient temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, to which water was added for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from EtOH, to obtain 219 mg of ethyl({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 3
The compound of Reference Example 232 was dissolved in 3.0 ml of DMF, to which 150 mg of O-trimesylsilylhydroxylamine was added under ice cooling, for stirring at 50° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, to which 5.0 ml of MeOH was added. Subsequently, 4.0 ml of aqueous 1M HCl was added under ice cooling, for stirring at ambient temperature for 2 hours and at 50° C. for 2.5 hours. The resulting mixture was left to stand for cooling to ambient temperature, to obtain the resulting solid, which was then washed with EtOAc and then recrystallized from aqueous 80% acetic acid, to obtain 141 mg of 7-(cyclohexylamino)-1-ethyl-6-fluoro-N-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxamide.
Example 4
300 mg of the compound of Example 56 was suspended in 5.0 ml of EtOH, to which 1.0 ml of aqueous 3M HCl was added under ice cooling, for stirring at 50° C. for 22 hours. The reaction mixture was concentrated under reduced pressure, to which water was added. The resulting mixture was neutralized with aqueous 1M NaOH, for 10% MeOH-chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with EtOH, to obtain 230 mg of 7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-N-[(1RS,2RS,3RS,4SR)-2,3,4-trihydroxycyclopentyl]-1,4-dihydroquinoline-3-carboxamide.
Example 5
360 mg of the compound of Example 51 was dissolved in 5.0 ml of methylene chloride, to which 2.0 ml of trifluoroacetic acid was added under ice cooling, for stirring at ambient temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, to which water was added for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed from diisopropyl ether, to obtain 282 mg of (4S)-4-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-5-[4-(ethoxycarbonyl)piperazin-1-yl]-5-oxopentanoic acid.
Example 6
300 mg of the compound of Example 1 was suspended in 5.0 ml of EtOH, to which 0.8 ml of aqueous 1M NaOH was added under ice cooling, for stirring at ambient temperature for 25 hours. Water was added to the reaction mixture, which was neutralized with aqueous 1M HCl. The resulting solid was filtered and washed with EtOH, to obtain 263 mg of ({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetic acid.
Example 7
2.23 ml of bromotrimethylsilane (TMSBr) was gradually added to a solution of 1.106 g of the compound of Example 44 in 20 ml of chloroform under ice cooling, for stirring under ice cooling for 30 minutes and then at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, to which 15 ml of MeOH was added. Again, the resulting mixture was concentrated under reduced pressure, to which ether and a small amount of MeOH were added. The generated insoluble materials were filtered and recovered. 10 ml of aqueous 1M NaOH, MeOH and water were added to the insoluble materials, to filter off the insoluble matters. The precipitate resulting from the addition of 1 ml of aqueous 1M HCl to the filtrate was filtered. The precipitate was washed with 80% EtOH, to obtain 841 mg of [2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid.
Example 8
250 mg of the compound of Example 374 was suspended in 2.0 ml of EtOAc, to which 2.0 ml of 4M HCl-EtOAc solution was added under ice cooling, for stirring at ambient temperature for 4 days. The generated solid was filtered and washed with EtOAc, to obtain 210 mg of ({[1-ethyl-6-fluoro-4-oxo-(7-piperidin-4-ylamino)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate hydrochloride.
Example 9
300 mg of the compound of Example 163 was suspended in 5.0 ml of THF, to which 200 mg of 1,1′-carbonylbis-1H-imidazole was added under ice cooling, for stirring at ambient temperature for 17 hours. 1.0 ml of aqueous 28% ammonia was added to the resulting reaction mixture under ice cooling, for stirring at ambient temperature for another 1.5 hours. The reaction mixture was concentrated under reduced pressure, to which water was added for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The resulting solid was recrystallized from EtOH, to obtain 214 mg of N-(4-amino-4-oxobutyl)-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-carboxamide.
Example 10
210 mg of the compound of Example 161 was suspended in 5.0 ml of DMF, to which 0.1 ml of ethoxycarbonylpiperazine, 130 mg of WSC.HCl and 100 mg of 1-hydroxybenzotriazole were added sequentially to the resulting reaction mixture under ice cooling, for stirring at ambient temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, to which water was added for chloroform extraction. The resulting organic layer was washed sequentially with aqueous saturated NaHCO3 and aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The resulting solid was washed with EtOH, to obtain 228 mg of ethyl 4-[({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetyl]piperazine-1-carboxylate.
Example 11
530 mg of the compound of Example 196 was suspended in a mixed solvent of 10 ml of acetone and 3.0 ml of water, to which 0.30 g of N-methylmorpholine-N-oxide and 2.0 ml of OsO4 (2.5 wt % in BuOH) were sequentially added at ambient temperature, for stirring at ambient temperature for one week. Water was added to the reaction mixture, to which 2.0 g of sodium thiosulfate was added at ambient temperature, for overnight stirring at ambient temperature. Insoluble matters in the reaction mixture were filtered off, while the resulting filtrate was concentrated under reduced pressure. The resulting solid was washed with water, to obtain 190 mg of ethyl({[7-(cyclohexylamino)-1-(2,3-dihydroxypropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 12
423 mg of the compound of Example 72 was suspended in 5 ml of chloroform and 5 ml of MeOH, to which 126 mg of LiOH.H2O was added, for stirring at ambient temperature for 30 minutes. 1.17 g of methyl-1-bromo-1-deoxy-2,3,4-tri-o-acetyl-α-D-glucopyranoside uronate was added to the reaction mixture, for stirring at ambient temperature for one hour. Further, 126 mg of LiOH.H2O and 1.17 g of methyl-1-bromo-1-deoxy-2,3,4-tri-o-acetyl-α-D-glucopyranoside uronate were added, for stirring at ambient temperature for 6 hours. 15 ml of water, 5 ml of MeOH and 1.0 g of sodium carbonate were added to the reaction mixture, for stirring at ambient temperature for 1.5 hours. Additionally, 30 ml of water, 220 ml of MeOH and 1.0 g of sodium carbonate were added, for stirring at ambient temperature for 30 minutes. The resulting mixture was neutralized with acetic acid and stirred at ambient temperature for 12 hours. After the resulting insoluble matters were filtered off, water was added to the resulting filtrate, which was then washed with chloroform. The resulting aqueous solution was concentrated under reduced pressure. The residue was purified by ODS column chromatography, to obtain 168 mg of 3-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)phenyl β-D-glucopyranoside uronic acid.
Example 13
0.20 g of the compound of Reference Example 233 was dissolved in 5.0 ml of DMSO, to which 2.0 ml of cyclohexylmethylamine was added at ambient temperature, for stirring at 80° C. for 19 hours. Water was added to the resulting reaction mixture, for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, to obtain 0.23 g of tert-butyl[({7-[(cyclohexylmethyl)amino]-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetate.
0.23 g of the tert-butyl ester compound was dissolved in 5.0 ml of methylene chloride, to which 2.0 ml of trifluoroacetic acid was added under ice cooling, for stirring at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, to which water was added. The generated solid was filtered, to obtain 102 mg of [({7-[(cyclohexylmethyl)amino]-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetic acid.
Example 14
89 mg of sodium acetate, 55 μl of formaldehyde solution (37%), and 177 mg of sodium triacetoxyborohydride were added to a suspension of 253 mg of the compound of Example 210 in 10 ml of THF, for stirring at ambient temperature for 3 hours. Aqueous saturated NaHCO3 was added for chloroform extraction. The resulting extract was washed with aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 146 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(1-methylpyrrolidin-3-yl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 15
0.45 g of the compound of Example 412 was dissolved in 10 ml of methylene chloride, to which 1.0 ml of bromotrimethylsilane was added under ice cooling, for stirring at ambient temperature for 3 days. The resulting reaction mixture was concentrated under reduced pressure, to which MeOH was added, for stirring at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, to which EtOH was added, to filter the solid, to obtain 344 mg of [2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid hydrobromide.
Example 16
The compound of Reference Example 75 was suspended in 20 ml, to which 149 μl of triethylamine and 177 μl of isobutyl chloroformate were added under ice cooling. After the mixture was stirred as it was for one hour, 149 μl of triethylamine and 138 mg of glycine ethyl ester hydrochloride were added, for stirring at ambient temperature for 12 hours. Aqueous saturated NH4Cl was added for chloroform extraction. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and washed with EtOAc, to obtain 227 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 17
0.51 g of the compound of Example 200 was dissolved in 5.0 ml of methylene chloride, to which 0.5 ml of triethylamine and 0.2 ml of methanesulfonyl chloride were added sequentially under ice cooling, for stirring under ice cooling for 30 minutes. Water was added to the resulting solution for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, to obtain a mesyl compound. The resulting mesyl compound was dissolved in 10 ml of DMF, to which 0.10 g of sodium azide was added under ice cooling, for stirring at ambient temperature for 20 hours. Water was added to the resulting reaction mixture for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, to obtain an azide compound. The resulting azide compound was dissolved in 10 ml of THF, to which 0.40 g of triphenylphosphine was added at ambient temperature, for stirring at 50° C. for one hour. 2.0 ml of water was added to the resulting reaction mixture for stirring at 80° C. for 3.5 hours. The reaction mixture was left to stand for cooling, to which 0.30 g of di-tert-butyl dicarbonate was added under ice cooling, for stirring at ambient temperature for 27 hours. Water was added to the reaction mixture, for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 494 mg of ethyl{[(1-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)carbonyl]amino}acetate.
Example 18
407 mg of the compound of Example 589 was dissolved in 5 ml of MeOH, to which 30 mg of palladium-carbon (10%) was added, for stirring under hydrogen atmosphere for 3 hours. After 1.15 ml of aqueous 1M NaOH was added to the reaction mixture, the resulting insoluble matters were filtered off through Celite. Aqueous 1.15 ml of 1M HCl was added to the filtrate and the resulting precipitate was filtered and washed with water, to obtain 220 mg of [2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid.
Example 19
415 mg of the compound of Example 200 was suspended in 5 ml of methylene chloride, to which 400 μl of triethylamine and 111 μl of methanesulfonyl chloride were added under ice cooling, for stirring at ambient temperature for 10 minutes. Water and aqueous saturated sodium chloride were added to the reaction mixture, for chloroform extraction. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in 5 ml of DMF, to which 948 μl of piperidine was added, for stirring at 70° C. for 23 hours. The reaction mixture was cooled to ambient temperature, to which water was added for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 202 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(2-piperidin-1-ylethyl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 20
149 mg of the compound of Example 31 was suspended in 5 ml of chloroform, to which 75 μl of triethylamine was added under ice cooling. Then 30 μl of acetyl chloride was added. After overnight stirring at ambient temperature, water was added for chloroform extraction and the resulting extract was washed with aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 167 mg of ethyl({[1-(1-acetylpyrrolidin-3-yl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 21
734 mg of the compound of Example 200 was suspended in 10 ml of methylene chloride, to which 708 μl of triethylamine and 197 μl of methanesulfonyl chloride were added under ice cooling, for stirring at ambient temperature for 15 minutes. Water and aqueous saturated sodium chloride were added to the reaction mixture, for chloroform extraction. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in 10 ml of DMSO, to which 100 mg of sodium cyanide was added, for stirring at 70° C. for 24 hours. Water and saturated aqueous sodium chloride were added to the reaction mixture for chloroform extraction. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 354 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 22
Aqueous 70% acetic acid was added to 146 mg of the compound of Example 18, for stirring at, 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and azeotropically evaporated with EtOH. The resulting residue was crystallized from EtOH-water, to obtain 96 mg of ethyl{2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid.
Example 23
374 mg of methyl(2R)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-3-pyridin-3-ylpropanoate was suspended in 4 ml of EtOAc, to which 2 ml of 0.5M HCl EtOAc solution was added, for stirring for 30 minutes. Subsequently, the resulting precipitate was filtered, to obtain 156 mg of methyl(2R)-2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-3-pyridin-3-ylpropanoate hydrochloride.
Example 24
0.5 ml of aqueous 2M NaOH was added to 11 mg of the compound of Example 44, for stirring at 100° C. for 30 minutes. 0.1 ml of 2-propanol was added, for stirring at 100° C. for 12 hours, to which 1.1 ml of aqueous 1M HCl was added. The generated precipitate was filtered and washed with diethyl ether, to obtain 7 mg of ethyl hydrogen [2-({[7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonate.
Example 25
148 mg of the compound of Example 31 was suspended in 5 ml of acetonitrile, to which 67 mg of potassium carbonate, 46 μl of benzyl bromide and 5 ml of DMF were added for overnight stirring. Water was added, for chloroform extraction and rinsing with aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 174 mg of Ethyl({[1-(1-benzylpyrrolidin-3-yl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 26
183 mg of the compound of Example 220 was suspended in 20 ml of chloroform, to which 1.35 ml of bromotrimethylsilane was added under ice cooling, for stirring at ambient temperature for 24 hours. 1.35 ml of bromotrimethylsilane was added, for stirring for 3 days, to which EtOH was added. After the solvent was distilled off under reduced pressure, water and aqueous saturated NaHCO3 were added to filter insoluble materials. Aqueous saturated NaHCO3 was added to the insoluble materials, for chloroform extraction. The resulting extract was washed with aqueous 1M HCl, aqueous saturated NaHCO3 and aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 54 mg of ethyl[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(1RS,2SR,3RS,4SR)-2,3,4-trihydroxycyclopentyl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetate.
Example 27
10 ml of acetonitrile, 720 μl of 1,8-diazabicyclo[5.4.0]-7-undecene and 575 μl of chloromethyl pivalate were added to 743 mg of the compound of Example 15, 226 mg of tetrabutylammonium hydrogensulfate and 102 mg of sodium iodide, for stirring at 75° C. for 65 hours. Water was added, for EtOAc extraction. The resulting extract was washed with water, saturated aqueous NaHCO3, and aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography and washed with diethyl ether, to obtain 378 mg of his {[(2,2-dimethylpropanoyl)oxy]methyl}[2-({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonate.
Example 28
273 mg of the compound of Example 544 was suspended in 10 ml of THF, to which 1.2 ml of aqueous 1M LiOH was added for stirring at ambient temperature for 2 days, at 50° C. for 3 hours and at 60° C. for 20 hours. After the solvent was distilled off under reduced pressure, aqueous 1M HCl was added and the generated precipitate was filtered, to obtain 270 mg of 2-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)-2-methylpropionic acid.
Example 29
148 mg of the compound of Example 31 was suspended in 5 ml of chloroform, to which 75 μl of triethylamine was added. The resulting mixture was cooled to −45° C., to which 32 μl of methanesulfonyl chloride was added. The mixture was gradually warmed and stirred overnight at ambient temperature. Then, water was added to the resulting mixture, for chloroform extraction and washing with aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 138 mg of ethyl[({7-(cyclohexylamino)-6-fluoro-1-[1-(methylsulfonyl)pyrrolidin-3-yl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetate.
Example 30
0.40 g of the compound of Example 17 was suspended in 5.0 ml of EtOH, to which 1.1 ml of aqueous 1M NaOH was added under ice cooling, for stirring at ambient temperature for 25 hours. The resulting reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in 20 ml of water, to which 3.0 ml of conc. hydrochloric acid was added under ice cooling, for stirring at 50° C. for 6 hours. The mixture was left to stand for cooling to ambient temperature. The generated solid was filtered, to obtain 0.15 g of ({[1-(2-aminoethyl)-7-(cyclohexylamino)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetic acid hydrochloride.
Example 31
Aqueous saturated NaHCO3, water and EtOH were added to 1 g of the compound of Example 210, for chloroform extraction. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, to obtain 750 mg of ethyl({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 32
2 ml of aqueous 6M HCl was added to 50 mg of the compound of Example 241, for stirring at 80° C. for 1.5 hours. 2 ml of aqueous 6M HCl was added to the resulting mixture, for stirring at 80° C. for one hour. After the solvent was distilled off under reduced pressure, water was added to the resulting residue, to filter insoluble materials. The materials were recrystallization from EtOH, to obtain 18 mg of [({7-(cyclohexylamino)-6-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]acetic acid was obtained.
Example 33
52 mg of the compound of Example 348 was suspended in 1 ml of DMSO, to which 46 μl of triethylamine and 165 μl of a THF solution of 2.0 M dimethylamine were added, for stirring at 100° C. for 24 hours. Water was added and the generated precipitate was filtered. The precipitate was dissolved in ethyl acetate, and washed with water, saturated NH4Claq and aqueous saturated sodium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography, to obtain 43 mg of ethyl({[7-(cyclohexylamino)-5-(dimethylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
Example 34
53 mg of the compound of Reference Example 235 was dissolved in 1.5 ml of DMSO, to which 31 μl of cyclohexylamine was added at ambient temperature, for stirring at 80° C. for 13 hours and at 100° C. for 10 hours. Water was added to the reaction mixture, and the generated precipitate was filtered and washed with water. The precipitate was purified by silica gel chromatography, to obtain 51 mg of ethyl({[5-(acetylamino)-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)acetate.
The structures and physical data of the compounds of the Examples are shown below in Tables 16 through 41.







TABLE 16







 








 










Ex
Syn
R
Data













2
2
EtO2CCH2—NH—
FAB-MS(Pos); 418(M+ + 1)


3
3
HO—NH—
FAB-MS(Pos); 348(M+ + 1)


4
4
(1RS,2SR,3RS,4SR)-2,3,4-triHO-cPen—NH—
FAB-MS(Pos); 448(M+ + 1)


 


5
5




FAB-MS(Pos); 602(M+ + 1)


 


7
7
(HO)2(O)P—(CH2)2—NH—
FAB-MS(Pos); 440(M+ + 1)


9
9
H2NOC(CH2)3—NH—
FAB-MS(Pos); 417(M+ + 1)


10
10
(4-EtO2C-1-pipe)-COCH2—NH—
FAB-MS(Pos); 530(M+ + 1)


 


12
12




FAB-MS(Pos); 600(M+ + 1)


 


24
24
(HO)(EtO)(O)P—(CH2)2NH—
FAB-MS(Pos); 468(M+ + 1)


35
1
H2N—
FAB-MS(Pos); 332(M+ + 1)


36
1
MeNH—
FAB-MS(Pos); 346(M+ + 1)


37
1
Me2N—
FAB-MS(Pos); 360(M+ + 1)


38
1
BocHNNH—
FAB-MS(Pos); 447(M+ + 1)


39
1
Ph—NH—
FAB-MS(Pos); 408(M+ + 1)


40
1
H2NC(═NH)—NH—
FAB-MS(Pos); 374(M+ + 1),





Sal: HCl


41
1
tBuO—NH—
FAB-MS(Pos); 404(M+ + 1)


42
1
2-MeO2C-1-pyrr
FAB-MS(Pos); 444(M+ + 1)


43
1
Me2NOCCH(tBuO2C(CH2)2)—NH—
FAB-MS(Pos); 545(M+ + 1)


44
1
(EtO)2(O)P(CH2)2—NH—
FAB-MS(Pos); 496(M+ + 1)


45
1
1-btria-O(CH2)3—NH—
FAB-MS(Pos); 507(M+ + 1)


46
1
1-btria-O(CH2)2—NH—
FAB-MS(Pos); 493(M+ + 1)


47
1
(S)-H2NOCCH(MeO2C(CH2)2)—NH−
FAB-MS(Pos); 475(M+ + 1)


48
1
(S)-Ph—CH2CH(CO2Me)—NH—
FAB-MS(Pos); 494(M+ + 1)


49
1
(R)-Ph—CH2CH(CO2Me)—NH—
FAB-MS(Pos); 494(M+ + 1)


50
1
HOCH2—CH(CO2Me)—NH—
FAB-MS(Pos); 434(M+ + 1)


 


51
1




FAB-MS(Pos); 658(M+ + 1)


 


52
2
(S)-H2NOCCH(iBu)-NH—
FAB-MS(Pos); 445(M+ + 1)


53
2
HO(CH2)2—NH—
FAB-MS(Pos); 376(M+ + 1)
















TABLE 17







 








 










Ex
Syn
R
Data













54
2
EtO2C(CH2)2—NH—
FAB-MS(Pos);





432(M+ + 1)


55
2
EtO2C(CH2)3—NH—
FAB-MS(Pos);





446(M+ + 1)


 


56
2




FAB-MS(Pos); 488(M+ + 1)


 


57
2
1-Me2N-cHex-(CH2)2—NH—
FAB-MS(Pos);





485(M+ + 1)


58
2
4-EtO2C—Ph—NH—
FAB-MS(Pos);





480(M+ + 1)


 


59
2




FAB-MS(Pos); 502(M+ + 1)


 


60
2
(1R,2S)-2-Ph-cPr—NH—
FAB-MS(Pos);





448(M+ + 1)


61
2
(3R)-3-(2-bimid)-1-pipe
FAB-MS(Pos);





516(M+ + 1)


62
2
(3S)-3-(2-bimid)-1-pipe
FAB-MS(Pos);





516(M+ + 1)


63
2
(1R,2S)-2-(3,4-diF-Ph)-cPr—NH-
FAB-MS(Pos);





484(M+ + 1)


64
2
H2NOCCH2—NH—
FAB-MS(Pos);





389(M+ + 1)


65
2
H2NOC(CH2)2—NH—
FAB-MS(Pos);





403(M+ + 1)


66
2
3-EtO2C—Ph—NH—
FAB-MS(Pos);





480(M+ + 1)


67
2
2-EtO2C—Ph—NH—
FAB-MS(Pos);





480(M+ + 1)


68
2
3-H2NOC—Ph—NH—
FAB-MS(Pos);





451(M+ + 1)


 


69
2




FAB-MS(Pos); 532(M+ + 1)


 


70
2
4-EtO2C-1-pipe
FAB-MS(Pos);





472(M+ + 1)


71
2
4-HO—Ph—NH—
FAB-MS(Pos);





424(M+ + 1)


72
2
3-HO—Ph—NH—
FAB-MS(Pos);





424(M+ + 1)


73
2
2-HO—Ph—NH—
FAB-MS(Pos);





424(M+ + 1)


74
2
4-H2NOC-1-pipe
FAB-MS(Pos);





443(M+ + 1)


75
2
HO3S(CH2)2—NH—
FAB-MS(Pos);





440(M+ + 1)


76
2
HO3SO(CH2)2—NH—
FAB-MS(Pos);





456(M+ + 1)


77
2
2-HO-6-O2N—Ph—NH—
FAB-MS(Pos);





469(M+ + 1)


78
2
2-H2N-6-HO—Ph—NH—
FAB-MS(Pos);





439(M+ + 1)
















TABLE 18







 








 










Ex
Syn
R
Data













79
2
6-AcO-2-AcNH—Ph—NH—
FAB-MS(Pos);





523(M+ + 1)


80
2
2-AcNH-3-HO—Ph—NH—
FAB-MS(Pos);





481(M+ + 1)


81
2
2-AcNH-6-HO—Ph—NH—
FAB-MS(Pos);





481(M+ + 1)


82
2
2-BzNH-6-HO—Ph—NH—
FAB-MS(Pos);





543(M+ + 1)


83
2
2-BzNH-3-HO—Ph—NH—
FAB-MS(Pos);





543(M+ + 1)


84
2
6-HO-2-(Ph—HNOC)—Ph—NH—
FAB-MS(Pos);





543(M+ + 1)


85
2
6-HO-2-(Me—HNOC)—Ph—NH—
FAB-MS(Pos);





481(M+ + 1)


86
2
1,3,4-thiadiazol-2-yl-NH—
ESI-MS(Pos);





416(M+ + 1)


87
2
2-MeO—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


88
2
3,4-diMeO—Ph—NH—
ESI-MS(Pos);





468(M+ + 1)


89
2
3-HO-2-Me—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


90
2
4-HO-2-Me—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


91
2
4-HO-3-O2N—Ph—NH—
ESI-MS(Pos);





469(M+ + 1)


92
2
3-Et2NCH2-4-HO—Ph—NH—
ESI-MS(Pos);





509(M+ + 1)


93
2
3-HO-2-Py—NH—
ESI-MS(Pos);





425(M+ + 1)


94
2
2-HOCH2—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


95
2
3-HOCH2—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


96
2
4-HOCH2—Ph—NH—
ESI-MS(Pos);





438(M+ + 1)


97
2
2-HO(CH2)2Ph—NH—
ESI-MS(Pos);





452(M+ + 1)


98
2
indol-5-yl-NH—
ESI-MS(Pos);





447(M+ + 1)


99
2
indazol-5-yl-NH—
ESI-MS(Pos);





448(M+ + 1)


100
2
4-AcNH—Ph—NH—
ESI-MS(Pos);





465(M+ + 1)


101
2
4-(4-mor-CO)—Ph—NH—
ESI-MS(Pos);





521(M+ + 1)


102
2
3-Ac—Ph—NH—
ESI-MS(Pos);





450(M+ + 1)


103
2
Bn-NH—
ESI-MS(Pos);





422(M+ + 1)


104
2
2-Me-Bn-NH—
ESI-MS(Pos);





436(M+ + 1)


105
2
2-F-Bn-NH—
ESI-MS(Pos);





440(M+ + 1)


106
2
3-F-Rn-NH—
ESI-MS(Pos);





440(M+ + 1)


107
2
4-F-Bn-NH—
ESI-MS(Pos);





440(M+ + 1)


108
2
3-MeO-Bn-NH—
ESI-MS(Pos);





452(M+ + 1)


109
2
4-MeO-Bn-NH—
ESI-MS(Pos);





452(M+ + 1)


110
2
2,4-diMeO-Bn-NH—
ESI-MS(Pos);





482(M+ + 1)


111
2
3,5-diMeO-Bn-NH—
ESI-MS(Pos);





482(M+ + 1)


112
2
3-O2N-Bn-NH—
ESI-MS(Pos);





467(M+ + 1)


113
2
4-O2N-Bn-NH—
ESI-MS(Pos);





467(M+ + 1)


114
2
Ph2CH—NH—
ESI-MS(Pos);





498(M+ + 1)
















TABLE 19







 








 










Ex
Syn
R
Data













115
2
2-fur-CH2—NH—
ESI-MS(Pos);





412(M+ + 1)


116
2
2-the-CH2—NH—
ESI-MS(Pos);





428(M+ + 1)


117
2
3-Py—CH2—NH—
ESI-MS(Pos);





423(M+ + 1)


118
2
4-Py—CH2—NH—
ESI-MS(Pos);





423(M+ + 1)


119
2
2-F—Ph—(CH2)2—NH—
ESI-MS(Pos);





454(M+ + 1)


120
2
3-F—Ph—(CH2)2—NH—
ESI-MS(Pos);





454(M+ + 1)


121
2
4-F—Ph—(CH2)2—NH—
ESI-MS(Pos);





454(M+ + 1)


122
2
4-Me—Ph—(CH2)2—NH—
ESI-MS(Pos);





450(M+ + 1)


123
2
4-MeO—Ph—(CH2)2—NH—
ESI-MS(Pos);





466(M+ + 1)


124
2
2-Cl—Ph—(CH2)2—NH—
ESI-MS(Pos);





470(M+ + 1)


125
2
4-Cl—Ph—(CH2)2—NH—
ESI-MS(Pos);





470(M+ + 1)


126
2
4-Br—Ph—(CH2)2—NH—
ESI-MS(Pos);





514, 516





(M+ + 1)


127
2
2-the-(CH2)2—NH—
ESI-MS(Pos);





442(M+ + 1)


128
2
2-Py—(CH2)2—NH—
ESI-MS(Pos);





437(M+ + 1)


129
2
3-Py—(CH2)2—NH—
ESI-MS(Pos);





437(M+ + 1)


130
2
4-Py—(CH2)2—NH—
ESI-MS(Pos);





437(M+ + 1)


131
2
2,5-diMeO—Ph—(CH2)2—NH—
ESI-MS(Pos);





496(M+ + 1)


132
2
3,4-diMeO—Ph—(CH2)2—NH—
ESI-MS(Pos);





496(M+ + 1)


133
2
indol-3-yl-(CH2)2—NH—
ESI-MS(Pos);





475(M+ + 1)


134
2
Me2NCH(Ph)CH2—NH—
ESI-MS(Pos);





479(M+ + 1)


135
2
PhS(═O)2—(CH2)2—NH—
ESI-MS(Pos);





500(M+ + 1)


136
2
(3-Me—Ph)—N(Et)—(CH2)2—NH—
ESI-MS(Pos);





493(M+ + 1)


137
2
4-Ph-1-pipa-CH2CH(Me)—NH—
ESI-MS(Pos);





534(M+ + 1)


138
2
PhO—CH2CH(4-mor-CH2)—NH—
ESI-MS(Pos);





551(M+ + 1)


139
2
4-(4-F-Bn)-2-mor-CH2—NH—
ESI-MS(Pos);





539(M+ + 1)


140
2
Et—NH—
ESI-MS(Pos);





360(M+ + 1)


141
2
nPen—NH—
ESI-MS(Pos);





402(M+ + 1)


142
2
HOCH2CH(Me)—NH—
ESI-MS(Pos);





390(M+ + 1)


143
2
HOCH(Me)CH2—NH—
ESI-MS(Pos);





390(M+ + 1)


144
2
HO(CH2)2O(CH2)2—NH—
ESI-MS(Pos);





420(M+ + 1)


145
2
(HOCH2)2CH—NH—
ESI-MS(Pos);





406(M+ + 1)


146
2
HOCH2CH(HO)CH2—NH—
ESI-MS(Pos);





406(M+ + 1)


147
2
HO(CH2)5—NH—
ESI-MS(Pos);





418(M+ + 1)


148
2
cPen—NH—
ESI-MS(Pos);





400(M+ + 1)


149
2
(1S,2S)-2-MeS-cPen—NH—
ESI-MS(Pos);





446(M+ + 1)
















TABLE 20













 










Ex
Syn
R
Data





150
2
(3S,4R)-4-MeS-3-THF-NH—
ESI-MS(Pos); 448(M+ + 1)


151
2
3-Bn-1-pyrr
ESI-MS(Pos); 476(M+ + 1)


152
2
3-PhS(═O)2-1-pyrr
ESI-MS(Pos); 526(M+ + 1)


153
2
4-(2-oxo-1-bimid)-1-pipe
ESI-MS(Pos); 532(M+ + 1)


154
2
4-(2-Cl—Ph)-1-pipa
ESI-MS(Pos); 511(M+ + 1)


155
2
4-(3-F3C—Ph)-1-pipa
ESI-MS(Pos); 545(M+ + 1)


156
2
4-(2-Py)-1-pipa
ESI-MS(Pos); 478(M+ + 1)


157
2
(1R, 2R)2-Me2N-cHex-N(ally)-
ESI-MS(Pos); 497(M+ + 1)


158
4
(1RS,2SR,3RS,4SR)-2,3,4-triHO-cHex-NH—
FAB-MS(Pos); 462(M+ + 1)


159
4
(1RS,2SR,3SR,4SR)-
FAB-MS(Pos); 492(M+ + 1)




(2,3-diHO-4-HO(CH2)2O)-cPen-NH—


160
5
HO2C(CH2)2—CH(CONMe2)—
FAB-MS(Pos); 489(M+ + 1)


161
6
HO2CCH2—NH—
FAB-MS(Pos); 390(M+ + 1)


162
6
HO2C(CH2)2—NH—
FAB-MS(Pos); 404(M+ + 1)


163
6
HO2C(CH2)3—NH—
FAB-MS(Pos); 418(M+ + 1)


164
6
4-HO2C—Ph—NH—
FAB-MS(Pos); 452(M+ + 1)


165
6
HO2C(CH2)4—NH—
FAB-MS(Pos); 432(M+ + 1)


166
6
HO2C(CH2)3—N(Me)—
FAB-MS(Pos); 432(M+ + 1)


167
6
4-HO2C-1-pipe
FAB-MS(Pos); 444(M+ + 1)


168
6
3-HO2C—Ph—NH—
FAB-MS(Pos); 452(M+ + 1)


169
6
2-HO2C—Ph—NH—
FAB-MS(Pos); 452(M+ + 1)


170
6
2-HO2C-1-pyrr
FAB-MS(Pos); 430(M+ + 1)


171
6
(S)-Ph—CH2CH(CO2H)—NH—
FAB-MS(Pos); 480(M+ + 1)


172
6
(R)-Ph—CH2CH(CO2H)—NH—
FAB-MS(Pos); 480(M+ + 1)


173
6
HOCH2—CH(CO2H)—NH—
FAB-MS(Pos); 420(M+ + 1)


174
8
H2NNH—
FAB-MS(Pos); 347(M+ + 1),





Sal: HCl


175
9
H2NOC(CH2)4—NH—
FAB-MS(Pos); 431(M+ + 1)


176
9
H2NOC(CH2)3—N(Me)—
FAB-MS(Pos); 431(M+ + 1)


177
9
4-H2NOC—Ph—NH—
FAB-MS(Pos); 451(M+ + 1)
















TABLE 21













 










Ex
Syn
R
Data





178
2
(HO)2(O)P—O(CH2)2NH—
FAB-MS(Neg);





454(M+ − 1)


179
2
(3-(MeO2CCH2)—Ph)—NH—
FAB-MS(Pos);





480(M+ + 1)


180
2
(4-(EtO2CCH2)—Ph)—NH—
FAB-MS(Pos);





494(M+ + 1)


181
6
(3-(HO2CCH2)—Ph)—NH—
FAB-MS(Pos);





466(M+ + 1)


182
6
(4-(HO2CCH2)—Ph))—NH—
FAB-MS(Pos);





466(M+ + 1)


183
1
3-EtO2C-2-thiq
FAB-MS(Pos);





520(M+ + 1)


184
6
3-HO2C-2-thiq
FAB-MS(Pos);





492(M+ + 1)


185
2
(HO)2(O)P—(CH2)3NH—
FAB-MS(Pos);





454(M+ + 1)


186
2
(S)-tBuO2C(CH2)2CH(CONH2)NH—
FAB-MS(Pos);





517(M+ + 1)


187
5
(S)-HO2C(CH2)2CH(CONH2)NH—
FAB-MS(Pos);





461(M+ + 1)


188
2
(EtO)2(O)P—CH2NH—
FAB-MS(Pos);





482(M+ + 1)


189
7
(HO)2(O)P—CH2NH—
ESI-MS(Pos);





426(M+ + 1)
















TABLE 22













 










Ex
Syn
R
Data













1
1
cPen
FAB-MS(Pos); 458(M+ + 1)


11
11
HOCH2CH(OH)CH2—
FAB-MS(Pos); 464(M+ + 1)


14
14
1-Me-3-pyrr
FAB-MS(Pos); 473(M+ + 1)


16
16
CF3CH2—
FAB-MS(Pos); 472(M+ + 1)


17
17
Boc-NH(CH2)2—
FAB-MS(Pos); 533(M+ + 1)


19
19
1-pipe-(CH2)2—
FAB-MS(Pos.); 501(M+ + 1)


20
20
1-Ac-3-pyrr
FAB-MS(Pos.); 501(M+ + 1)


21
21
H
FAB-MS(Pos); 390(M+ + 1)


25
25
1-Bn-3-pyrr
FAB-MS(Pos); 549(M+ + 1)


26
26
(1RS,2SR,3RS,4SR)-2,3,
FAB-MS(Pos); 506(M+ + 1)




4-triHO-cPen


29
29
1-MeSO2-3-pyrr
FAB-MS(Pos); 537(M+ + 1)


31
31
3-pyrr
FAB-MS(Pos); 459(M+ + 1)


190
1
Me
FAB-MS(Pos); 404(M+ + 1)


191
1
iPr
FAB-MS(Pos); 432(M+ + 1)


192
1
Bn
FAB-MS(Pos); 480(M+ + 1)


193
1
4-OMe-Bn
FAB-MS(Pos); 510(M+ + 1)


194
1
Ph
FAB-MS(Pos); 466(M+ + 1)


195
1
cHex
FAB-MS(Pos); 472(M+ + 1)


196
1
allyl
FAB-MS(Pos); 430(M+ + 1)


197
1
(1,3-dioxaln-2-yl)-CH2—
FAB-MS(Pos); 476(M+ + 1)


198
1
2-THP-O—(CH2)2—
FAB-MS(Pos); 518(M+ + 1)


199
1
(R)-3-THF
FAB-MS(Pos); 460(M+ + 1)


200
4
HO—(CH2)2—
FAB-MS(Pos); 434(M+ + 1)


201
1
(S)-3-THF
FAB-MS(Pos); 460(M+ + 1)


202
1
cPr
FAB-MS(Pos); 430(M+ + 1)


203
1
cBu
FAB-MS(Pos); 444(M+ + 1)


204
1
tBu
FAB-MS(Pos); 446(M+ + 1)


205
1
3-THF
FAB-MS(Pos); 460(M+ + 1)


206
1
MeO—(CH2)2—
FAB-MS(Pos); 448(M+ + 1)


207
1
1-Boc-3-pyrr
FAB-MS(Pos); 559(M+ + 1)


208
1
sBu
FAB-MS(Pos); 446(M+ + 1)


209
1
(Et)2CH—
FAB-MS(Pos); 460(M+ + 1)


210
8
3-pyrr
FAB-MS(Pos); 459(M+ + 1),





Sal: HCl


211
1
iPrCH(Me)—
FAB-MS(Pos); 460(M+ + 1)


212
1
iBuCH(Me)—
FAB-MS(Pos); 474(M+ + 1)


213
1
tBuCH(Me)—
FAB-MS(Pos); 474(M+ + 1)


214
1
iBu
FAB-MS(Pos); 446(M+ + 1)


215
1
oxetan-3-yl
FAB-MS(Pos); 446(M+ + 1)


216
1
4-THP
FAB-MS(Pos); 474(M+ + 1)


217
1
1-Boc-4-pipe
FAB-MS(Pos); 573(M+ + 1)
















TABLE 23













 










Ex
Syn
R
Data













218
8
4-pipe
FAB-MS(Pos); 473(M+ + 1),





Sal: HCl


219
14
1-Me-4-pipe
FAB-MS(Pos); 487(M+ + 1)


220
16




FAB-MS(Pos); 546(M+ + 1)


221
1
1-Me-azetidin-3-yl
FAB-MS(Pos); 459(M+ + 1)





Sal: HCl


 


222
16




FAB-MS(Pos); 484(M+ + 1)


 


223
16
nPrCH(Me)—
FAB-MS(Pos); 460(M+ + 1)


224
16
n(Pr)2CH—
FAB-MS(Pos); 488(M+ + 1)


225
16
nPrCH(Et)—
FAB-MS(Pos); 474(M+ + 1)


 


226
16




FAB-MS(Pos); 484(M+ + 1)


 


227
16
CF3CH(Me)—
ESI-MS(Pos); 486(M+ + 1)


228
16
cyclopent-3-en-1-yl
FAB-MS(Pos); 456(M+ + 1)


229
1
MeHNOC—CH2—
FAB-MS(Pos.); 461(M+ + 1)


230
1
(4-Me-1-pipa)-CO—CH2—
FAB-MS(Pos.); 530(M+ + 1)


231
1
(4-mor)-CO—CH2—
FAB-MS(Pos.); 517(M+ + 1)


232
19
1-pyrr-(CH2)2—
FAB-MS(Pos.); 487(M+ + 1)


233
14
Me2N(CH2)2—
FAB-MS(Pos.); 461(M+ + 1)


234
20
AcHN(CH2)2—
FAB-MS(Pos.); 475(M+ + 1)


235
29
MeSO2NH(CH2)2—
FAB-MS(Pos.); 511(M+ + 1)


236
1
2,2-diMe-1,3-dioxan-5-yl
FAB-MS(Pos.); 504(M+ + 1)


237
22
(HOCH2)2CH—
FAB-MS(Pos.); 464(M+ + 1)


238
1
(MeOCH2)2CH—
FAB-MS(Pos.); 492(M+ + 1)


239
1
(AcNHCH2)2CH—
FAB-MS(Pos.); 546(M+ + 1)


240
16
AcNH(CH2)3—
ESI-MS(Pos); 489(M+ + 1)


241
16
(FCH2)2CH—
FAB-MS(Pos); 468(M+ + 1)


242
16
FCH2CH(Me)—
FAB-MS(Pos); 450(M+ + 1)


243
16
isopropenyl
FAB-MS(Pos); 430(M+ + 1)


244
16
H2C═C(CH2F)—
FAB-MS(Pos); 448(M+ + 1)


245
16
MeOCH2CH(Me)—
FAB-MS(Pos); 462(M+ + 1)


246
16
4,4-dimethyl-cHex
FAB-MS(Pos); 500(M+ + 1)


247
16
AcNHCH2CH(Me)—
FAB-MS(Pos); 489(M+ + 1)


248
16
AcN(Me)(CH2)2—
FAB-MS(Pos); 489(M+ + 1)


249
16
AcN(Me)CH2CH(Me)—
FAB-MS(Pos); 503(M+ + 1)


250
1
3-methylcyclopent-
FAB-MS(Pos); 470(M+ + 1)




3-en-1yl


251
16
2-THP-OCH2CH(Me)—
ESI-MS(Pos); 532(M+ + 1)


252
4
HOCH2CH(Me)—
FAB-MS(Pos); 448(M+ + 1)


253
16
2,2-diethyl-1,3-dioxan-5-yl
FAB-MS(Pos); 532(M+ + 1)
















TABLE 24













 










Ex
Syn
R
Data













6
6
cPen
FAB-MS(Pos); 430(M+ + 1)


30
30
H2N(CH2)2—
FAB-MS(Pos); 405(M+ + 1)


32
32
(FCH2)2CH—
FAB-MS(Pos); 440(M+ + 1)


254
6
Me
FAB-MS(Pos); 376(M+ + 1)


255
6
iPr
FAB-MS(Pos); 404(M+ + 1)


256
6
Bn
FAB-MS(Pos); 452(M+ + 1)


257
6
4-MeO-Bn
FAB-MS(Pos); 482(M+ + 1)


258
6
Ph
FAB-MS(Pos); 438(M+ + 1)


259
6
cHex
FAB-MS(Pos); 444(M+ + 1)


260
6
Allyl
FAB-MS(Pos); 402(M+ + 1)


261
6
HOCH2CH(OH)CH2—
FAB-MS(Pos); 436(M+ + 1)


262
6
(1,3-dioxolan-2-yl)-CH2—
FAB-MS(Pos); 448(M+ + 1)


263
6
2-THP-O—(CH2)2—
FAB-MS(Pos); 490(M+ + 1)


264
6
(R)-3-THF
FAB-MS(Pos); 432(M+ + 1)


265
6
HO—(CH2)2—
FAB-MS(Pos); 406(M+ + 1)


266
6
(S)-3-THF
FAB-MS(Pos); 432(M+ + 1)


267
6
cPr
FAB-MS(Pos); 402(M+ + 1)


268
6
cBu
FAB-MS(Pos); 416(M+ + 1)


269
6
tBu
FAB-MS(Pos); 418(M+ + 1)


270
6
3-THF
FAB-MS(Pos); 432(M+ + 1)


271
6
MeO(CH2)2—
FAB-MS(Pos); 420(M+ + 1)


272
6
1-Boc-3-pyrr
FAB-MS(Pos); 531(M+ + 1)


273
6
sBu
FAB-MS(Pos); 418(M+ + 1)


274
6
(Et)2CH—
FAB-MS(Pos); 432(M+ + 1)


275
8
3-pyrr
ESI-MS(Pos); 431(M+ + 1),





Sal: HCl


276
6
iPrCH(Me)—
FAB-MS(Pos); 432(M+ + 1)


277
6
iBuCH(Me)—
FAB-MS(Pos); 446(M+ + 1)


278
6
tBuCH(Me)—
FAB-MS(Pos); 446(M+ + 1)


279
6
1-Me-3-pyrr
ESI-MS(Pos); 445(M+ + 1),





Sal: HCl


280
6
iBu
FAB-MS(Pos); 418(M+ + 1)


281
6
oxetan-3-yl
FAB-MS(Pos); 418(M+ + 1)


282
6
4-THP
FAB-MS(Pos); 446(M+ + 1)


283
6
1-Ac-3-pyrr
FAB-MS(Pos); 473(M+ + 1)


284
6
1-MeSO2-3-pyrr
FAB-MS(Pos); 509(M+ + 1)


285
6
1-Bn-3-pyrr
FAB-MS(Pos); 521(M+ + 1)


286
6
1-Me-4-pipe
FAB-MS(Pos); 459(M+ + 1)
















TABLE 25













 










Ex
Syn
R
Data













287
6




FAB-MS(Pos); 518(M+ + 1)


288
6
(1RS,2SR,3RS,4SR)-
FAB-MS(Pos); 478(M+ + 1)




2,3,4-triHO-cPen


289
6
1-Me-azetidin-3-yl
FAB-MS(Pos); 431(M+ + 1)


290
6




FAB-MS(Pos); 456(M+ + 1)


291
6
nPrCH(Me)—
FAB-MS(Pos); 432(M+ + 1)


292
6
(nPr)2CH—
FAB-MS(Pos); 460(M+ + 1)


293
6
nPrCH(Et)—
FAB-MS(Pos); 446(M+ + 1)


294
6
CF3CH2—
FAB-MS(Pos); 444(M+ + 1)


295
6




FAB-MS(Pos); 456(M+ + 1)


296
6
CF3CH(Me)—
FAB-MS(Pos); 458(M+ + 1)


297
6
cyclopent-3-en-1-yl
FAB-MS(Pos); 428(M+ + 1)


298
6
1-pipe-(CH2)2—
FAB-MS(Pos.); 473(M+ + 1)


299
6
MeHNOC—CH2—
FAB-MS(Pos.); 433(M+ + 1)


300
6
(4-Me-1-pipa)-CO—CH2—
FAB-MS(Pos.); 502(M+ + 1)


301
6
(4-mor)-(CH2)2—
FAB-MS(Pos.); 475(M+ + 1)


302
6
1-pyrr-(CH2)2—
ESI-MS(Pos.); 459(M+ + 1)


303
6
Me2N(CH2)2—
FAB-MS(Pos.); 433(M+ + 1)


304
6
AcNH(CH2)2—
FAB-MS(Pos.); 447(M+ + 1)


305
6
MeSO2NH(CH2)2—
FAB-MS(Pos.); 483(M+ + 1)


306
6
2,2-diMe-1,3-dioxan-5-yl
FAB-MS(Pos.); 476(M+ + 1)


307
22
(HOCH2)2CH—
FAB-MS(Pos.); 436(M+ + 1)


308
6
H
FAB-MS(Pos.); 362(M+ + 1)


309
6
(MeOCH2)2CH—
FAB-MS(Pos.); 464(M+ + 1)


310
6
(AcNHCH2)2CH—
FAB-MS(Pos.); 518(M+ + 1)


311
6
AcNH(CH2)3—
FAB-MS(Pos); 461(M+ + 1)


312
6
FCH2CH(Me)—
FAB-MS(Pos); 422(M+ + 1)


313
6
isopropenyl
FAB-MS(Pos); 402(M+ + 1)


314
6
H2C═C(CH2F)—
FAB-MS(Pos); 420(M+ + 1)


315
6
MeOCH2CH(Me)—
FAB-MS(Pos); 434(M+ + 1)


316
6
4,4-dimethyl-cHex
FAB-MS(Pos); 472(M+ + 1)


317
6
AcNHCH2CH(Me)—
ESI-MS(Pos); 461(M+ + 1)


318
6
AcN(Me)(CH2)2—
FAB-MS(Pos); 461(M+ + 1)


319
6
AcN(Me)CH2CH(Me)—
FAB-MS(Pos); 475(M+ + 1)


320
6
3-methylcyclopent-3-en-1yl
FAB-MS(Pos); 442(M+ + 1)


321
6
HOCH2CH(Me)—
FAB-MS(Pos); 420(M+ + 1)


322
6
2,2-diethyl-1,3-dioxan-5-yl
FAB-MS(Pos); 504(M+ + 1)
















TABLE 26













 













Ex
Syn
R1
R2
R3
R4
Data
















34
34
NHAc
F
H
CO2Et
FAB-MS(Pos);








475(M+ + 1)


323
1
H
H
H
CO2Et
FAB-MS(Pos);








400(M+ + 1)


324
1
H
Br
H
CO2Et
FAB-MS(Pos);








478, 480(M+ + 1)


325
6
H
H
H
CO2H
FAB-MS(Pos);








372(M+ + 1)


326
6
H
Br
H
CO2H
FAB-MS(Pos);








450, 452(M+ + 1)


327
1
H
Me
H
CO2Et
FAB-MS(Pos);








414(M+ + 1)


328
6
H
Me
H
CO2H
FAB-MS(Pos);








386(M+ + 1)


329
1
H
F
Cl
CO2Et
FAB-MS(Pos);








452(M+ + 1)


330
6
H
F
Cl
CO2H
FAB-MS(Pos);








424(M+ + 1)


331
1
H
Cl
H
CO2Et
FAB-MS(Pos);








434(M+ + 1)


332
6
H
Cl
H
CO2H
FAB-MS(Pos);








406(M+ + 1)


333
1
H
F
F
CO2Et
FAB-MS(Pos);








436(M+ + 1)


334
6
H
F
F
CO2H
FAB-MS(Pos);








408(M+ + 1)


335
16
F
F
H
CO2Et
FAB-MS(Pos);








436(M+ + 1)


336
6
F
F
H
CO2H
FAB-MS(Pos);








408(M+ + 1)


337
16
OMe
F
H
CO2Et
ESI-MS(Pos);








448(M+ + 1)


338
6
OMe
F
H
CO2H
FAB-MS(Pos);








420(M+ + 1)


339
16
NH2
F
H
CO2Et
ESI-MS(Pos);








433(M+ + 1)


340
6
NH2
F
H
CO2H
FAB-MS(Pos);








405(M+ + 1)


341
16
NHMe
F
H
CO2Et
FAB-MS(Pos);








447(M+ + 1)


342
6
NHMe
F
H
CO2H
FAB-MS(Pos);








419(M+ + 1)


343
16
NH(cHex)
F
H
CO2Et
FAB-MS(Pos);








515(M+ + 1)


344
6
NH(cHex)
F
H
CO2H
FAB-MS(Pos);








487(M+ + 1)


345
6
NHAc
F
H
CO2H
FAB-MS(Pos);








447(M+ + 1)


346
16
N(Me)Ac
F
H
CO2Et
FAB-MS(Pos);








531(M+ + 1)


347
6
N(Me)Ac
F
H
CO2H
FAB-MS(Pos);








503(M+ + 1)
















TABLE 27













 













Ex
Syn
R1
R2
R3
R4
Data
















33
33
NMe2
F
H
CO2Et
FAB-MS(Pos); 503(M+ + 1)


348
16
F
F
H
CO2Et
FAB-MS(Pos); 478(M+ + 1)


349
6
F
F
H
CO2H
FAB-MS(Pos); 450(M+ + 1)


350
6
NMe2
F
H
CO2H
FAB-MS(Pos); 475(M+ + 1)


351
33
1-pyrr
F
H
CO2Et
FAB-MS(Pos); 529(M+ + 1)


352
6
1-pyrr
F
H
CO2H
FAB-MS(Pos); 501(M+ + 1)


353
16
OBn
F
H
CO2Et
ESI-MS(Pos); 566(M+ + 1)


354
18
OH
F
H
CO2Et
FAB-MS(Pos); 476(M+ + 1)


355
6
OH
F
H
CO2H
FAB-MS(Pos); 448(M+ + 1)
















TABLE 28













 











Ex
Syn
R1
R2
Data














8
8
4-pipe
CO2H
FAB-MS(Pos); 391(M+ + 1),






Sal: HCl


13
13
cHexCH2—
CO2H
FAB-MS(Pos); 404(M+ + 1)


356
1
iPr
CO2Et
FAB-MS(Pos); 378(M+ + 1)


357
1
tBu
CO2Et
FAB-MS(Pos); 392(M+ + 1)


358
1
4-THP
CO2Et
FAB-MS(Pos); 420(M+ + 1)


359
1
cPen
CO2Et
FAB-MS(Pos); 404(M+ + 1)


360
1
1-Boc-4-pipe
CO2Et
FAB-MS(Pos); 519(M+ + 1)


361
1
Ph
CO2Et
FAB-MS(Pos); 412(M+ + 1)


362
1
cHep
CO2Et
FAB-MS(Pos); 432(M+ + 1)


363
1
cOct
CO2Et
FAB-MS(Pos); 446(M+ + 1)


364
1
1-Me-cHex
CO2Et
FAB-MS(Pos); 432(M+ + 1)


365
1
4-THSP
CO2Et
FAB-MS(Pos); 436(M+ + 1)


366
14
1-Me-4-pipe
CO2Et
FAB-MS(Pos); 433(M+ + 1)


367
1
4-Me-cHex
CO2Et
FAB-MS(Pos); 432(M+ + 1)


368
1
4-Me-cHex
CO2Et
FAB-MS(Pos); 432(M+ + 1)


369
1
4,4-diF-cHex
CO2Et
FAB-MS(Pos); 454(M+ + 1)


370
6
iPr
CO2H
FAB-MS(Pos); 350(M+ + 1)


371
6
tBu
CO2H
FAB-MS(Pos); 364(M+ + 1)


372
6
4-THP
CO2H
FAB-MS(Pos); 392(M+ + 1)


373
6
cPen
CO2H
FAB-MS(Pos); 376(M+ + 1)


374
6
1-Boc-4-pipe
CO2H
FAB-MS(Pos); 491(M+ + 1)
















TABLE 29













 











Ex
Syn
R1
R2
Data














375
6
Ph
CO2H
FAB-MS(Pos); 384(M+ + 1)


376
6
cHep
CO2H
FAB-MS(Pos); 404(M+ + 1)


377
6
cOct
CO2H
FAB-MS(Pos); 418(M+ + 1)


378
6
1-Me-cHex
CO2H
FAB-MS(Pos); 404(M+ + 1)


379
6
4-THSP
CO2H
FAB-MS(Pos); 408(M+ + 1)


380
6
1-Me-4-pipe
CO2H
FAB-MS(Pos); 405(M+ + 1)


381
6
4-Me-cHex
CO2H
FAB-MS(Pos); 404(M+ + 1)


382
6
4-Me-cHex
CO2H
FAB-MS(Pos); 404(M+ + 1)


383
6
4,4-diF-cHex
CO2H
FAB-MS(Pos); 426(M+ + 1)
















TABLE 30













 











Ex
Syn
R1
R2
Data














384
1
4-THSP
CO2Et
FAB-MS(Pos); 476(M+ + 1)


385
6
4-THSP
CO2H
FAB-MS(Pos); 448(M+ + 1)


386
1
4,4-diF-cHex
CO2Et
FAB-MS(Pos); 494(M+ + 1)


387
6
4,4-diF-cHex
CO2H
FAB-MS(Pos); 466(M+ + 1)


388
1
3-THP
CO2Et
FAB-MS(Pos); 460(M+ + 1)


389
6
3-THP
CO2H
FAB-MS(Pos); 432(M+ + 1)
















TABLE 31













 










Ex
Syn
R
Data













15
15
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 480(M+ + 1),





Sal:HBr


27
27
(tBuCO2CH2O)2(O)P—(CH2)2NH—
FAB-MS(Pos); 708(M+ + 1)


390
16
(HO—CH2CH2)2N—
FAB-MS(Pos); 460(M+ + 1)


391
16
3-HO-1-pipe
FAB-MS(Pos); 456(M+ + 1)


392
16
HO—(CH2)3NH—
FAB-MS(Pos); 430(M+ + 1)


393
16
3-(HO—CH2)-1-pipe
FAB-MS(Pos); 470(M+ + 1)


394
16
2-(HOCH2)-1-pipe
FAB-MS(Pos); 470(M+ + 1)


395
16
HO—CH2CHOHCH2NMe—
FAB-MS(Pos); 460(M+ + 1)


396
16
3-HO-1-pyrr
FAB-MS(Pos); 442(M+ + 1)


397
16
(S)-3-EtO2C-2-thiq
FAB-MS(Pos); 560(M+ + 1)


398
16
(R)-3-EtO2C-2-thiq
FAB-MS(Pos); 560(M+ + 1)


399
6
(S)-3-HO2C-2-thiq
FAB-MS(Pos); 532(M+ + 1)


400
6
(R)-3-HO2C-2-thiq
FAB-MS(Pos); 532(M+ + 1)


401
16
EtO2C—CH2NMe—
FAB-MS(Pos); 472(M+ + 1)


402
16
2-EtO2C-1-pyrr
FAB-MS(Pos); 498(M+ + 1)


403
6
HO2C—CH2NMe—
FAB-MS(Pos); 444(M+ + 1)


404
6
2-HO2C-1-pyrr
FAB-MS(Pos); 470(M+ + 1)


405
1
(S)-EtO2C—CHOH(CH2)2NH—
FAB-MS(Pos); 502(M+ + 1)


406
6
(S)-HO2C—CHOH(CH2)2NH—
FAB-MS(Pos); 474(M+ + 1)


407
16
4-HO-1-pipe
FAB-MS(Pos); 456(M+ + 1)


408
16
HO—(CH2)2NMe—
FAB-MS(Pos); 430(M+ + 1)


409
16
HO—(CH2)2NBn-
FAB-MS(Pos); 506(M+ + 1)


410
1
2-Py-(CH2)2NH—
FAB-MS(Pos); 477(M+ + 1)


 


411
1




FAB-MS(Pos); 528(M+ + 1)


 


412
1
(EtO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 536(M+ + 1)


413
4
(1RS,2SR,3RS,4SR)-2,3,4-triHO-cPen
FAB-MS(Pos); 488(M+ + 1)


414
1
(S)-tBuO2C—CH2CH(CO2tBu)—NH—
FAB-MS(Pos); 600(M+ + 1)


415
1
3-EtO2C-2-thiq
FAB-MS(Pos); 506(M+ + 1)


416
1
(HO)2(O)P—O(CH2)2NH—
FAB-MS(Neg); 494(M+ − 1)


417
5
(S)-HO2C—CH2CH(CO2H)—NH—
FAB-MS(Pos); 488(M+ + 1)
















TABLE 32













 










Ex
Syn
R
Data













418
1




FAB-MS(Pos); 572(M+ + 1)


 


419
6
3-HO2C-2-thiq
FAB-MS(Pos); 532(M+ + 1)


420
4
(1RS,2SR,3SR,4SR)-2,3-diHO-4-
FAB-MS(Pos); 532(M+ + 1)




(HO(CH2)2O)-cPen


421
1
(2-HO—Ph)—NH—
FAB-MS(Pos); 464(M+ + 1)


422
1
(3-HO—Ph)—NH—
FAB-MS(Pos); 464(M+ + 1)


423
1
(4-HO—Ph)—NH—
FAB-MS(Pos); 464(M+ + 1)


424
1
(S)-tBuO2C—(CH2)2CH(CO2tBu)—NH—
FAB-MS(Pos); 614(M+ + 1)


425
5
(S)-HO2C—(CH2)2CH(CO2H)—NH—
FAB-MS(Pos); 502(M+ + 1)


426
1
(EtO)2(O)P—CH(CH2cHex)CH2NH—
FAB-MS(Pos); 632(M+ + 1)


427
15
(HO)2(O)P—CH(CH2cHex)CH2NH—
FAB-MS(Pos); 576(M+ + 1),





Sal:HBr


428
1
(EtO)2(O)P—CH(Bn)-CH2NH—
FAB-MS(Pos); 626(M+ + 1)


429
7
(HO)2(O)P—CH(Bn)-CH2NH—
FAB-MS(Pos); 570(M+ + 1)


430
16
EtO2C—CH2NBn-
FAB-MS(Pos); 548(M+ + 1)


431
6
HO2C—CH2NBn-
FAB-MS(Pos); 520(M+ + 1)


432
16
EtO2C—CH(Bn)NMe—
FAB-MS(Pos); 562(M+ + 1)


433
6
HO2C—CH(Bn)NMe—
FAB-MS(Pos); 534(M+ + 1)


434
16
(BnO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 660(M+ + 1)


435
24
(BnO)(HO)(O)P—(CH2)2NH—
FAB-MS(Pos); 570(M+ + 1)


436
16
EtO2C—CH(CH2OH)NH—
FAB-MS(Pos); 488(M+ + 1)


437
6
HO2C—CH(CH2OH)NH—
FAB-MS(Pos); 460(M+ + 1)


438
16
(S)-MeO2C—CH2CH(CO2tBu)-NH—
FAB-MS(Pos); 558(M+ + 1)


439
16
(S)-MeO2C—(CH2)2CH(CO2tBu)-NH—
FAB-MS(Pos); 572(M+ + 1)


440
5
(S)-MeO2C—CH2CH(CO2H)—NH—
FAB-MS(Pos); 502(M+ + 1)


441
5
(S)-MeO2C—(CH2)2CH(CO2H)—NH—
FAB-MS(Pos); 516(M+ + 1)


442
18
(tBuCO2CH2O)(HO)(O)P—(CH2)2NH—
FAB-MS(Pos); 594(M+ + 1)


443
27
(tBuCO2CH2O)(BnO)(O)P—(CH2)2NH—
FAB-MS(Pos); 684(M+ + 1)


444
16
(S)-tBuO2C—(CH2)2CH(CO2Me)—NH—
FAB-MS(Pos); 572(M+ + 1)


445
5
(S)-HO2C—(CH2)2CH(CO2Me)—NH—
FAB-MS(Pos); 516(M+ + 1)


446
16
(S)-tBuO2C—CH2CH(CO2Me)—NH—
FAB-MS(Pos); 558(M+ + 1)


447
5
(S)-HO2C—CH2CH(CO2Me)—NH—
FAB-MS(Pos); 502(M+ + 1)


448
1
4-EtO2C-1-pipe
FAB-MS(Pos); 512(M+ + 1)


449
6
4-HO2C-1-pipe
FAB-MS(Pos); 484(M+ + 1)


450
1
2-thiq
FAB-MS(Pos); 488(M+ + 1)


451
1
HO—(CH2)2NH—
FAB-MS(Pos); 416(M+ + 1)
















TABLE 33













 










Ex
Syn
R
Data













452
1
EtO2C—(CH2)2NH—
FAB-MS(Pos);





472(M+ + 1)


453
16
3-EtO2C-1-pipe
ESI-MS(Pos);





512(M+ + 1)


454
6
3-HO2C-1-pipe
FAB-MS(Pos);





484(M+ + 1)


455
6
HO2C—(CH2)2NH—
FAB-MS(Pos);





444(M+ + 1)


456
16
2-EtO2C-1-pipe
FAB-MS(Pos);





512(M+ + 1)


457
16
BocNHNH—
FAB-MS(Pos);





487(M+ + 1)


458
16
H2N—
ESI-MS(Pos);





372(M+ + 1)


459
16
MeHN—
FAB-MS(Pos);





386(M+ + 1)


460
16
Me2N—
FAB-MS(Pos);





400(M+ + 1)


461
16
3-H2NOC-2-thiq
FAB-ESI(Pos);





531(M+ + 1)


462
8
H2N—NH—
FAB-MS(Pos);





387(M+ + 1)


463
6
2-HO2C-1-pipe
FAB-MS(Pos);





484(M+ + 1)


464
16
EtO2C—(CH2)3NH—
FAB-MS(Pos);





486(M+ + 1)


465
16
Boc-NH(CH2)2NH—
ESI-MS(Pos);





515(M+ + 1)


466
16
Me2N—(CH2)2NH—
FAB-MS(Pos);





443(M+ + 1)


467
6
HO2C—(CH2)3NH—
FAB-MS(Pos);





458(M+ + 1)


468
16
(S)-EtO2C—(CH2)2CH(CO2Et)—NH—
FAB-MS(Pos);





558(M+ + 1)


469
8
H2N—(CH2)2NH—
FAB-MS(Pos);





415(M+ + 1)





Sal: HCl


470
16
3-MeO2C-4-mor
FAB-MS(Pos);





500(M+ + 1)


471
16
3-(HO—CH2)-2-thiq
FAB-MS(Pos);





518(M+ + 1)


472
16
(S)-2-EtO2C-1-pipe
FAB-MS(Pos);





512(M+ + 1)


473
6
3-HO2C-4-mor
FAB-MS(Pos);





486(M+ + 1)


474
6
(S)-2-HO2C-1-pipe
FAB-MS(Pos);





484(M+ + 1)


475
16
(R)-2-EtO2C-1-pipe
FAB-MS(Pos);





512(M+ + 1)


476
6
(R)-2-HO2C-1-pipe
FAB-MS(Pos);





484(M+ + 1)


477
1
2-((EtO)2(O)P—CH2)-1-pipe
FAB-MS(Pos);





590(M+ + 1)


478
7
2-((HO)2(O)P—CH2)-1-pipe
FAB-MS(Pos);





534(M+ + 1)
















TABLE 34













 










Ex
Syn
R
Data













23
 16,
(R)-MeO2C—CH(CH2-(3-Py))-NH—
FAB-MS(Pos);



23

537(M+ + 1),





Sal: HCl


28
28
HO2C—C(Me)2—NH—
FAB-MS(Pos);





460(M+ + 1)


479
16
3-EtO2C-2-thiq
FAB-MS(Pos);





562(M+ + 1)


480
 6
3-HO2C-2-thiq
FAB-MS(Pos);





534(M+ + 1)


481
16
(EtO)2(O)P—(CH2)2—NH—
FAB-MS(Pos);





538(M+ + 1)


482
 7
(HO)2(O)P—(CH2)2—NH—
FAB-MS(Pos);





482(M+ + 1)


483
16
(S)-EtO2C—(CH2)2CH(CO2Et)—NH—
FAB-MS(Pos);





560(M+ + 1)


484
16
EtO2C—CH(CH2OH)—NH—
FAB-MS(Pos);





490(M+ + 1)


485
 6
(S)-HO2C—(CH2)2CH(CO2H)—NH—
FAB-MS(Pos);





504(M+ + 1)


486
 6
(R)-HO2C—CH(CH2-(3-Py))—NH—
FAB-MS(Pos);





523(M+ + 1)


487
16
(S)-MeO2C—CH2CH(CO2Me)—NH—
FAB-MS(Pos);





518(M+ + 1)


488
16
(R)-MeO2C—CH(Bn)-NH—
FAB-MS(Pos);





484(M+ + 1)


489
16
(R)-MeO2C—CH(iBu)-NH—
FAB-MS(Pos);





502(M+ + 1)


490
16
(R)-MeO2C—CH(Me)—NH—
FAB-MS(Pos);





460(M+ + 1)


491
 6
HO2C—CH(CH2OH)—NH—
FAB-MS(Pos);





462(M+ + 1)


492
 6
(S)-HO2C—CH2CH(CO2H)—NH—
FAB-MS(Pos);





490(M+ + 1)


493
 6
(R)-HO2C—CH(Bn)-NH—
FAB-MS(Pos);





522(M+ + 1)


494
 6
(R)-HO2C—CH2CH(CO2H)—NH—
FAB-MS(Pos);





490(M+ + 1)


495
 6
(S)-HO2C—CH(iBu)-NH—
FAB-MS(Pos);





488(M+ + 1)


496
16
(R)-HO2C—CH(iPr)-NH—
FAB-MS(Pos);





488(M+ + 1)


497
16
(S)-MeO2C—CH2CH(CO2tBu)-NH—
FAB-MS(Pos);





560(M+ + 1)


498
16
(R)-MeO2C—(CH2)2CH(CO2Me)—NH—
FAB-MS(Pos);





532(M+ + 1)


499
16
(S)-MeO2C—(CH2)2CH(CO2tBu)-NH—
FAB-MS(Pos);





574(M+ + 1)


500
16
(R)-EtO2C—CH(tBu)-NH—
FAB-MS(Pos);





516(M+ + 1)


501
15
(HO)2(O)P—CF2—CH2NH—
ESI-MS(Pos);





518(M+ + 1)





Sal: HBr


502
16
(R)-MeO2C—CH2CH(CO2Me)—NH—
FAB-MS(Pos);





518(M+ + 1)


503
 5
(S)-MeO2C—CH2CH(CO2H)—NH—
FAB-MS(Pos);





504(M+ + 1)


504
 5
(S)-MeO2C—(CH2)2CH(CO2H)—NH—
FAB-MS(Pos);





518(M+ + 1)


505
16
(S)-MeO2C—CH(iBu)-NH—
FAB-MS(Pos);





502(M+ + 1)


506
28
(R)-HO2C—CH(tBu)-N—
FAB-MS(Pos);





488(M+ + 1)


507
 6
(R)-HO2C—CH(iBu)-NH—
FAB-MS(Pos);





488(M+ + 1)


508
16
(1-MeO2C-cPen)-NH—
FAB-MS(Pos);





500(M+ + 1)


509
28
(1-HO2C-cPen)-NH—
FAB-MS(Pos);





486(M+ + 1)


510
 6
(R)-HO2C—CH(Me)—NH—
FAB-MS(Pos);





446(M+ + 1)


511
 6
(R)-HO2C—CH(iPr)—NH—
FAB-MS(Pos);





474(M+ + 1)


512
16
(S)-tBuO2C—(CH2)2CH(CO2Me)—NH—
FAB-MS(Pos);





574(M+ + 1)


513
 5
(S)-HO2C—(CH2)2CH(CO2Me)—NH—
FAB-MS(Pos);





518(M+ + 1)


514
16
(S)-tBuO2C—CH2CH(CO2Me)—NH—
FAB-MS(Pos);





560(M+ + 1)
















TABLE 35













 










Ex
Syn
R
Data













515
5
(S)-HO2C—CH2CH(CO2Me)—NH—
FAB-MS





(Pos);





504(M+ + 1)


516
6
(R)—HO2C—(CH2)2CH(CO2H)—NH—
FAB-MS





(Pos);





504(M+ + 1)


517
1
2-((EtO)2(O)P—CH2)-1-pipe
FAB-MS





(Pos);





592(M+ + 1)


518
7
2-((HO)2(O)P—CH2)-1-pipe
FAB-MS





(Pos.);





536(M+ + 1)


519
1
(EtO)2(O)P—CH2NH—
FAB-MS





(Pos.);





524(M+ + 1)


520
1
(EtO)2(O)P—(CH2)3NH—
FAB-MS





(Pos.);





552(M+ + 1)


521
15
(HO)2(O)P—CH2NH—
ESI-MS





(pos.);





468(M+ + 1)





Sal: HBr


522
15
(HO)2(O)P—(CH2)3NH—
ESI-MS





(Pos.):





496(M+ + 1)





Sal: HBr


523
16
(EtO)2(O)P—CF2—CH2NH—
FAB-MS





(Pos);





574(M+ + 1)


524
16
EtO2C—(CH2)2NH—
FAB-MS





(Pos);





474(M+ + 1)


525
6
HO2C—(CH2)2NH—
FAB-MS





(Pos);





446(M+ + 1)


526
6
HO2C—(CH2)3NH—
FAB-MS





(Pos);





460(M+ + 1)


527
7
(HO)2(O)P—C(Me)2—CH2NH—
FAB-MS





(Pos);





510(M+ + 1)


528
16
(EtO)2(O)P—C(Me)2—CH2NH—
FAB-MS





(Pos);





566(M+ + 1)


529
16
(S)-EtO2C—(CH2)3CH(CO2Et)—NH—
FAB-MS





(Pos);





574(M+ + 1)


530
6
(S)-HO2C—(CH2)3CH(CO2H)—NH—
FAB-MS





(Pos);





518(M+ 1)


531
16
(EtO2C—CH2)2N—
FAB-MS





(Pos);





546(M+ + 1)


532
6
(HO2C—CH2)2N—
FAB-MS





(Pos);





476(M+ + 1)


533
16
(2-oxo-3-THF)—NH—
FAB-MS





(Pos);





458(M+ + 1)


534
6
HO—(CH2)2CH(CO2H)—NH—
FAB-MS





(Pos);





476(M+ + 1)


535
16
(2,2-diMe-1,3-dioxolan-4-yl)-CH2NH—
FAB-MS





(Pos);





488(M+ + 1)


536
4
HO—CH2CH(OH)CH2—NH—
FAB-MS





(Pos);





448(M+ + 1)


537
16
3-EtO2C-cHex-NH—
FAB-MS





(Pos);





528(M+ + 1)


538
6
3-HO2C-cHex-NH—
FAB-MS





(Pos);





500(M+ + 1)


539
16
(EtO2CCH2)2CHNH—
FAB-MS





(Pos);





560(M+ + 1)


540
6
(HO2CCH2)2CHNH—
FAB-MS





(Pos);





504(M+ + 1)


541
16
HO2C—(CH2)4—NH—
FAB-MS





(Pos);





474(M+ + 1)


542
16
(S)-HO2CCHOH(CH2)2NH—
FAB-MS





(Pos);





476(M+ + 1)


543
16
EtO2C—(CH2)3NH—
FAB-MS





(Pos);





488(M+ + 1)


544
16
MeO2C—C(Me)2—NH—
FAB-MS





(Pos);





474(M+ + 1)


545
16
(EtO)2(O)P-3-pipe-
FAB-MS





(Pos);





578(M+ + 1)


546
7
(HO)2(O)P-3-pipe-
FAB-MS





(Pos);





522(M+ + 1)
















TABLE 36













 











Ex
Syn
R1
R2
Data














18
18
2,2-diMe-1,3-
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos.); 526(M+ + 1)




dioxan-5-yl


22
22
(HO—CH2)2CH—
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos.); 486(M+ + 1)


547
16
(S)-3-THF
HO—(CH2)3NH—
FAB-MS(Pos); 432(M+ + 1)


548
16
(R)-3-THF
HO—(CH2)3NH—
FAB-MS(Pos); 432(M+ + 1)


549
16
1-Me-4-pipe
HO—(CH2)3NH—
FAB-MS(Pos); 459(M+ + 1)






Sal: HCl


550
 1
1-Me-3-pyrr
HO—(CH2)3NH—
FAB-MS(Pos); 445(M+ + 1),






Sal: HCl


551
 1
iPr
(EtO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 510(M+ + 1)


552
 1
(S)-3-THF
Me2N—
FAB-MS(Pos); 402(M+ + 1)


553
15
iPr
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 454(M+ + 1),






Sal: HBr


554
 1
1-Me-3-pyrr
(EtO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 511(M+ + 1)


555
 1
(S)-3-THF
(BnO)2(O)P—(CH2)2NH—
ESI-MS(Pos); 662(M+ + 1)


556
18
(S)-3-THF
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 482(M+ + 1)


557
15
1-Me-3-pyrr
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 495(M+ + 1)






Sal: HBr


558
 1
(R)-3-THF
(BnO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 662(M+ + 1)


559
18
(R)-3-THF
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 482(M+ + 1)


560
1, 23
1-Me-4-pipe
3-EtO2C-2-thiq
FAB-MS(Pos); 589(M+ + 1),






Sal: HCl


561
1, 23
1-Me-4-pipe
2-EtO2C-1-pipe
FAB-MS(Pos); 541(M+ + 1),






Sal: HCl


562
 6
1-Me-4-pipe
3-HO2C-2-thiq
FAB-MS(Pos); 561(M+ + 1),






Sal: HCl


563
 6
1-Me-4-pipe
2-HO2C-1-pipe
FAB-MS(Pos); 513(M+ + 1),






Sal: HCl


564
1, 23
(S)-1-Me-3-pyrr
(S)-3-EtO2C-2-thiq
FAB-MS(Pos); 575(M+ + 1),






Sal: HCl


565
1, 23
(S)-1-Me-3-pyrr
(R)-3-EtO2C-2-thiq
FAB-MS(Pos); 575(M+ + 1),






Sal: HCl


566
 6
(S)-1-Me-3-pyrr
(S)-3-HO2C-2-thiq
FAB-MS(Pos); 547(M+ + 1),






Sal: HCl


567
1, 23
(R)-1-Me-3-pyrr
(S)-3-EtO2C-2-thiq
FAB-MS(Pos); 575(M+ + 1),






Sal: HCl
















TABLE 37













 











Ex
Syn
R1
R2
Data





568
1, 23
(R)-1-Me-3-pyrr
(R)-3-EtO2C-2-thiq
FAB-MS(Pos); 575(M+ + 1),






Sal: HCl


569
6
(S)-1-Me-3-pyrr
(R)-3-HO2C-2-thiq
FAB-MS(Pos); 547(M+ + 1),






Sal: HCl


570
6
(R)-1-Me-3-pyrr
(S)-3-HO2C-2-thiq
FAB-MS(Pos); 547(M+ + 1),






Sal: HCl


571
6
(R)-1-Me-3-pyrr
(R)-3-HO2C-2-thiq
FAB-MS(Pos); 547(M+ + 1),






Sal: HCl


572
1
(S)-3-THF
(S)-3-EtO2C-2-thiq
FAB-MS(Pos); 562(M+ + 1)


573
1
(S)-3-THF
(R)-3-EtO2C-2-thiq
FAB-MS(Pos); 562(M+ + 1)


574
1
(R)-3-THF
(S)-3-EtO2C-2-thiq
FAB-MS(Pos); 562(M+ + 1)


575
1
(R)-3-THF
(R)-3-EtO2C-2-thiq
FAB-MS(Pos); 562(M+ + 1)


576
6
(R)-3-THF
(S)-3-HO2C-2-thiq
FAB-MS(Pos); 534(M+ + 1)


577
6
(S)-3-THF
(S)-3-HO2C-2-thiq
FAB-MS(Pos); 534(M+ + 1)


578
6
(R)-3-THF
(R)-3-HO2C-2-thiq
FAB-MS(Pos); 534(M+ + 1)


579
1
3-THF
H2N—
FAB-MS(Pos); 374(M+ + 1)


580
6
(S)-3-THF
(R)-3-HO2C-2-thiq
FAB-MS(Pos); 534(M+ + 1)


581
1
sBu
3-EtO2C-2-thiq
FAB-MS(Pos); 548(M+ + 1)


582
1
sBu
(EtO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 524(M+ + 1)


583
7
sBu
(HO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 468(M+ + 1)


584
4
sBu
(1RS,2SR,3SR,4SR)-2,3-
FAB-MS(Pos); 520(M+ + 1)





diHO-4-HO(CH2)2O-cPen


585
6
sBu
3-HO2C-2-thiq
FAB-MS(Pos); 520(M+ + 1)


586
16 
iPr
3-EtO2C-2-thiq
FAB-MS(Pos); 534(M+ + 1)


587
6
iPr
3-HO2C-2-thiq
FAB-MS(Pos); 506(M+ + 1)


 


588
1
sBu




FAB-MS(Pos); 560(M+ + 1)


 


589
1
2,2-diMe-1,3-
(BnO)2(O)P—(CH2)2NH—
FAB-MS(Pos); 706(M+ + 1)




dioxan-5-yl


590
1
2,2-diMe-1,3-
HO—(CH2)3NH—
FAB-MS(Pos.); 476(M+ + 1)




dioxan-5-yl


591
22 
(HO—CH2)2CH—
HO—(CH2)3NH—
FAB-MS(Pos.); 436(M+ + 1)


592
1
1-Me-4-pipe
(2-HO—Ph)—NH—
FAB-MS(Pos); 493(M+ + 1)
















TABLE 38













 











Ex
Syn
R1
R2
Data














593
16
AcNH(CH2)2—
3-EtO2C-2-thiq
FAB-MS(Pos); 577(M+ + 1)


594
6
AcNH(CH2)2—
3-HO2C-2-thiq
FAB-MS(Pos); 549(M+ + 1)


595
1
1-Me-3-pyrr
(2-HO—Ph)—N—
FAB-MS(Pos); 479(M+ + 1),






Sal: HCl


 


596
16




(S)-EtO2C—(CH2)2—CH(CO2Et)—NH—
FAB-MS(Pos); 584(M+ + 1)


 


597
6




(S)-HO2C—(CH2)2—CH(CO2H)—NH—
FAB-MS(Pos); 528(M+ + 1)
















TABLE 39













 












EX
Syn
R
Data







598
1
CO2Et
ESI-MS(Neg); 431(M+ − 1)



599
6
CO2H
FAB-MS(Pos); 405(M+ + 1)

















TABLE 40













 











Ex
Syn
—R1—R2—
R3
Data














600
16
—CH═CH—CH═CH—
CO2Et
FAB-MS(Pos);






440(M+ + 1)


601
6
—CH═CH—CH═CH—
CO2H
FAB-MS(Pos);






412(M+ + 1)


602
16
—(CH2)4—
CO2Et
FAB-MS(Pos);






444(M+ + 1)


603
6
—(CH2)4—
CO2H
FAB-MS(Pos):






416(M+ + 1)


604
16
—C(═CH2)—(CH2)2—
CO2Et
FAB-MS(Pos);






442(M+ + 1)


605
6
—C(═CH2)—(CH2)2—
CO2H
FAB-MS(Pos);






414(M+ + 1)


606
16
—CH(Me)—(CH2)2—
CO2Et
FAB-MS(Pos);






444(M+ + 1)


607
6
—CH(Me)—(CH2)2—
CO2H
FAB-MS(Pos);






416(M+ + 1)


608
16
—(CH2)3—
CO2Et
FAB-MS(Pos);






430(M+ + 1)


609
6
—(CH2)3—
CO2H
FAB-MS(Pos);






402(M+ + 1)


610
16
—CH2—C(═CH2)—(CH2)2—
CO2Et
FAB-MS(Pos);






456(M+ + 1)


611
6
—CH2—C(═CH2)—(CH2)2—
CO2H
FAB-MS(Pos);






428(M+ + 1)


612
16
—CH2—CH(Me)—(CH2)2—
CO2Et
FAB-MS(Pos);






458(M+ + 1)


613
6
—CH2—CH(Me)—(CH2)2—
CO2H
FAB-MS(Pos);






430(M+ + 1)
















TABLE 41













 













Ex
Syn
R1
R2
A
R3
Data
















614
16
F
cPen
CMe
EtO2C—CH2—
FAB-MS(Pos); 472(M+ + 1)


615
6
F
cPen
CMe
HO2C—CH2—
FAB-MS(Pos); 444(M+ + 1)


616
1
F
Et
N
EtO2C—CH2—
FAB-MS(Pos.); 419(M+ + 1)


617
6
F
Et
N
HO2C—CH2—
FAB-MS(Pos.); 391(M+ + 1)


618
1
F
Et
N
(EtO)2(O)P—(CH2)2—
FAB-MS(Pos); 497(M+ + 1)


619
15
F
Et
N
(HO)2(O)P—(CH2)2—
ESI-MS(Pos.); 441(M+ + 1),








Sal: HBr


620
16
OEt
Et
N
EtO2C—CH2—
FAB-MS(Pos); 445(M+ + 1)


621
6
OEt
Et
N
HO2C—CH2—
FAB-MS(Pos.); 417(M+ + 1)


622
16
F
cPen
N
EtO2C—CH2—
FAB-MS(Pos); 459(M+ + 1)


623
6
F
cPen
N
HO2C—CH2—
FAB-MS(Pos); 431(M+ + 1)


624
16
F
(Et)2CH—
N
EtO2C—CH2—
FAB-MS(Pos); 461(M+ + 1)


625
6
F
(Et)2CH—
N
HO2C—CH2—
FAB-MS(Pos); 433(M+ + 1)


626
16
F
(Et)2CH—
N
(EtO)2(O)P—(CH2)2—
FAB-MS(Pos); 539(M+ + 1)


627
7
F
(Et)2CH—
N
(HO_2(O)P—(CH2)2—
FAB-MS(Pos); 483(M+ + 1)


628
16
F
(Et)2CH—
N
(S)-EtO2C—
FAB-MS(Pos); 561(M+ + 1)







(CH2)2CH(CO2Et)—


629
6
F
(Et)2CH—
N
(S)-HO2C—
FAB-MS(Pos); 505(M+ + 1)







(CH2)2CH(CO2H)—









NMR data of some compounds in the Examples are shown below in Tables 42 to 44.








TABLE 42





Ex
Data
















6
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.50 (m, 4H), 1.61-1.70 (m, 1H), 1.72-1.85 (m, 6H),



1.85-2.01 (m, 4H), 2.19-2.32 (m, 2H), 3.50-3.63 (m, 1H), 4.05 (d, J = 5.4 Hz, 2H), 5.12-5.22



(m, 1H), 6.33 (dd, J = 2.0, 8.3 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 7.79 (d, J = 12.2 Hz, 1H),



8.60 (s, 1H), 10.32 (t, J = 5.4 Hz, 1H),



12.64 (brs, 1H)


7
NMR (DMSO-d6) δ; 1.11-1.24 (m, 1H), 1.27-1.48 (m, 7H), 1.60-1.69 (m, 1H), 1.71-1.89 (m, 4H),



1.92-2.00 (m, 2H), 3.44-3.62 (m, 3H), 4.43 (q, J = 7.0 Hz, 2H), 6.29 (d, J = 6.4 Hz, 1H),



6.70 (d, J = 7.4 Hz, 1H), 7.75 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H), 10.16 (t, J = 5.9 Hz, 1H)


15
NMR (DMSO-d6) δ; 1.10-1.24 (m, 1H), 1.27-1.50 (m, 4H), 1.60-1.70 (m, 1H), 1.71-2.00 (m, 12H),



2.18-2.32 (m, 2H), 3.44-3.64 (m, 3H), 5.10-5.25 (m, 1H), 6.86 (d, J = 7.3 Hz, 1H), 7.76 (d, 



J = 12.2 Hz, 1H), 8.62 (s, 1H), 10.14 (brs, 1H)


18
NMR (DMSO-d6) δ; 1.10-1.24 (m, 1H), 1.25-1.50 (m, 7H), 1.51-1.56 (s, 3H), 1.60-1.69 (m, 1H),



1.71-2.02 (m, 6H), 3.40-3.57 (m, 3H), 4.02 (d, J = 13.2 Hz, 2H), 4.50 (d, J = 13.2 Hz, 2H),



4.72-4.78 (m, 1H), 6.29 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 12.2 Hz, 1H),



9.54 (s, 1H), 10.14 (t, J = 5.8 Hz, 1H)


22
NMR (DMSO-d6) δ; 1.09-1.23 (m, 1H), 1.24-1.48 (m, 4H), 1.59-1.68 (m, 1H), 1.70-1.98 (m, 6H),



3.38-3.61 (m, 3H), 3.75-3.92 (m, 4H), 4.80-4.93 (m, 1H), 5.13 (brs, 2H), 6.21 (d, J = 7.8 Hz, 1H),



6.85 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H), 8.69 (s, 1H), 10.19 (t, J = 5.8 Hz, 1H)


161
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.49 (m, 7H), 1.60-1.69 (m, 1H), 1.72-1.80 (m, 2H),



1.91-2.00 (m, 2H), 3.51-3.62 (m, 1H), 4.05 (d, J = 5.4 Hz, 2H), 4.43 (q, J = 6.9 Hz, 2H), 6.31 (dd, J =



2.4, 8.3 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H), 10.35 (t, J =



5.4 Hz, 1H), 12.63 (brs, 1H)


255
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.49 (m, 4H), 1.50 (d, J = 6.8 Hz, 6H), 1.60-1.70



(m, 1H), 1.71-1.80 (m, 2H), 1.91-2.00 (m, 2H), 3.53-3.65 (m, 1H), 4.05 (d, J = 5.4 Hz, 2H), 5.12



(quintet, J = 6.8 Hz, 1H), 6.30 (dd, J = 2.5, 8.3 Hz, 1H), 6.87 (d, J = 6.9 Hz, 1H), 7.80 (d, J =



12.2 Hz, 1H), 8.65 (s, 1H), 10.34 (t, J = 5.4 Hz, 1H), 12.62 (brs, 1H)


259
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.23-1.48 (m, 5H), 1.53-1.81 (m, 8H), 1.85-1.94 (m, 2H),



1.94-2.02 (m, 2H), 2.04-2.13 (m, 2H), 3.50-3.64 (m, 1H), 4.05 (d, J = 5.4 Hz, 2H), 4.56-4.67 (m, 1H),



6.39 (dd, J = 2.0, 8.0 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 12.7 Hz, 1H), 8.64 (s, 1H),



10.33 (t, J = 5.4 Hz, 1H), 12.63 (brs, 1H)


406
NMR (DMSO-d6) δ; 1.12-1.24 (m, 1H), 1.26-1.49 (m.4H), 1.59-2.00 (m, 13H), 2.18-2.29 (m, 2H),



3.36-3.48 (m, 2H), 3.50-3.61 (m, 1H), 3.94-4.06 (m, 1H), 5.10-5.21 (m, 1H), 5.33 (brs, 1H),



6.31 (d, 1H, J = 6.9 Hz), 6.84 (d, J = 6.9 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H), 8.62 (s, 1H), 10.14 (t, J =



5.9 Hz, 1H), 12.45 (brs, 1H)


416
NMR (DMSO-d6) δ; 1.10-1.24 (m, 1H), 1.27-1.50 (m, 4H), 1.60-1.70 (m, 1H), 1.71-2.00 (m, 10H),



2.19-2.31 (m, 2H), 3.50-3.63 (m, 3H), 3.87-3.96 (m, 2H), 5.11-5.22 (m, 1H), 6.32 (d, J = 6.8 Hz, 1H),



6.85 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 12.2 Hz, 1H), 8.62 (s, 1H), 10.22 (t, J = 5.8 Hz, 1H)

















TABLE 43





Ex
Data







417
NMR (DMSO-d6) δ; 1.10-1.24 (m, 1H), 1.27-1.50 (m, 4H), 1.60-1.70 (m, 1H),



1.71-2.00 (m, 10H), 2.18-2.33 (m, 2H), 2.72-2.88 (m, 2H), 3.50-3.66 (m, 1H), 4.75-4.82 (m, 1H),



5.11-5.21 (m, 1H), 6.30 (brs, 1H), 6.85 (d, J = 7.3 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H),



8.60 (s, 1H), 10.59 (d, J = 7.8 Hz, 1H)


419
NMR (DMSO-d6, 80° C.) δ; 1.15-1.28 (m, 1H), 1.30-1.50 (m, 4H), 1.60-1.69 (m, 1H),



1.70-2.02 (m, 10H), 2.15-2.30 (m, 2H), 2.95-3.30 (m, 2H), 3.48-3.65 (m, 1H), 4.05 (brs, 1H),



4.49 (brs, 1H), 4.60-5.10 (m, 2H), 5.82 (brd, J = 6.4 Hz, 1H), 6.82 (d, J = 6.8 Hz, 1H),



7.16 (brs, 4H), 7.74 (d, J = 12.7 Hz, 1H), 7.89 (s, 1H), 12.48 (brs, 1H)


425
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.50 (m, 4H), 1.60-1.70 (m, 1H),



1.71-2.00 (m, 11H), 2.04-2.15 (m, 1H), 2.20-2.33 (m, 4H), 3.52-3.64 (m, 1H), 4.48-4.56 (m, 1H)



5.12-5.21 (m, 1H), 6.34 (brd, J = 6.4 Hz, 1H), 6.85 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 12.2 Hz, 1H),



8.59 (s, 1H), 10.48 (d, J = 7.8 Hz, 1H), 12.50 (brs, 2H)


429
NMR (DMSO-d6) δ; 1.12-1.24 (m, 1H), 1.26-1.48 (m, 4H), 1.60-1.68 (m, 1H),



1.71-1.99 (m, 12H), 2.18-2.30 (m, 2H), 2.88 (dd, J = 7.4, 13.7 Hz, 1H), 3.12 (dd, J =



5.4, 13.7 Hz, 1H), 3.50-3.62 (m, 1H), 4.38-4.51 (m, 1H), 5.10-5.18 (m, 1H), 6.30 (d, J =



6.3 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 7.14-7.30 (m, 5H), 7.75 (d, J = 12.2 Hz, 1H), 8.57 (s, 1H),



10.18 (d, J = 7.8 Hz, 1H)


482
NMR (DMSO-d6) δ; 0.77 (t, J = 7.4 Hz, 6H), 1.12-1.52 (m, 5H), 1.61-2.00 (m, 11H),



3.44-3.55 (m, 2H), 3.58-3.70 (m, 1H), 4.80-4.90 (m, 1H), 6.26 (d, J = 6.8H, 1H),



6.93 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H), 8.51 (s, 1H), 10.16 (t, J = 5.6 Hz, 1H)


485
NMR (DMSO-d6) δ; 0.74-0.82 (m, 6H), 1.11-1.52 (m, 5H), 1.60-1.98 (m, 10H),



2.05-2.15 (m, 1H), 2.23-2.37 (m, 2H), 3.60-3.75 (m, 1H), 4.48-4.56 (m, 1H), 4.80-4.92 (m, 1H),



6.30 (d, J = 6.8H, 1H), 6.94 (d, J = 6.9 Hz, 1H), 7.80 (d, J = 12.2 Hz, 1H), 8.50 (s, 1H),



10.51 (d, J = 7.8 Hz, 1H), 12.49 (brs, 2H)


492
NMR (DMSO-d6) δ; 0.78 (t, J = 7.3 Hz, 6H), 1.11-1.51 (m, 5H), 1.62-1.98 (m, 9H),



2.75 (dd, J = 5.4, 16.6 Hz, 1H), 2.84 (dd, J = 5.6, 16.6 Hz, 1H), 3.60-3.75 (m, 1H),



4.76-4.90 (m, 2H), 6.28 (d, J = 6.8H, 1H), 6.93 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 12.2 Hz, 1H),



8.51 (s, 1H), 10.62 (d, J = 8.3 Hz, 1H), 12.68 (brs, 2H)


501
NMR (DMSO-d6) δ; 0.78 (t, J = 7.3 Hz, 6H), 1.10-1.50 (m, 5H), 1.60-2.00 (m, 9H),



3.60-3.70 (m, 1H), 3.80-4.05 (m, 2H), 4.80-4.93 (m, 1H), 6.95 (d, J = 6.8 Hz, 1H),



7.79 (d, J = 12.3 Hz, 1H), 8.54 (s, 1H), 10.48 (t, J = 5.8 Hz, 1H)


522
NMR (DMSO-d6) δ; 0.78 (t, J = 7.4 Hz, 6H), 1.11-1.50 (m, 5H), 1.51-2.00 (m, 13H),



3.34-3.39 (m, 2H), 3.60-3.70 (m, 1H), 4.80-4.90 (m, 1H), 6.94 (d, J = 6.9 Hz, 1H),



7.79 (d, J = 12.2 Hz, 1H), 8.53 (s, 1H), 10.16 (t, J = 5.6 Hz, 1H)


527
NMR (DMSO-d6, 80° C.) δ; 0.79 (t, J = 7.3 Hz, 6H), 1.01 (d, J = 13.7 Hz, 6H),



1.13-1.48 (m, 5H), 1.58-1.97 (m, 9H), 3.25-3.45 (m, 2H), 3.54 (brs, 1H), 4.65 (brs, 1H), 5.70-5.84



(m, 1H), 6.82 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 12.6 Hz, 1H), 8.52 (s, 1H), 10.05 (brs, 1H)


553
NMR (DMSO-d6) δ; 1.10-1.25 (m, 1H), 1.27-1.50 (m, 4H), 1.51 (d, J = 6.3 Hz, 6H),



1.60-1.70 (m, 1H), 1.71-1.80 (m, 2H), 1.81-1.99 (m, 4H), 3.45-3.56 (m, 2H), 3.56-3.66 (m, 1H),



5.07-5.20 (m, 1H), 6.88 (d, J = 7.3 Hz, 1H), 7.78 (d, J = 12.2 Hz, 1H), 8.69 (s, 1H),



10.15 (brs, 1H)


556
NMR (DMSO-d6) δ; 1.10-1.50 (m, 5H), 1.60-1.70 (m, 1H), 1.70-1.90 (m, 4H),



1.90-2.02 (m, 2H), 2.05-2.17 (m, 1H), 2.55-2.67 (m, 1H), 3.42-3.59 (m, 3H), 3.76-3.84 (m, 1H),



3.88-3.96 (m, 1H), 4.02-4.11 (m, 1H), 4.22-4.30 (m, 1H), 5.45 (brs, 1H),



6.34 (brd, J = 5.9 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H),



10.13 (t, J = 5.8 Hz, 1H)

















TABLE 44





Ex
Data







559
NMR (DMSO-d6) δ; 1.10-1.50 (m, 5H), 1.60-1.70 (m, 1H), 1.70-1.90 (m, 4H),



1.90-2.02 (m, 2H), 2.05-2.17 (m, 1H), 2.55-2.67 (m, 1H), 3.42-3.59 (m, 3H), 3.76-3.84 (m, 1H),



3.88-3.96 (m, 1H), 4.02-4.11 (m, 1H), 4.22-4.30 (m, 1H), 5.45 (brs, 1H),



6.34 (brd, J = 6.4 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 12.2 Hz, 1H), 8.65 (s, 1H),



10.13 (t, J = 5.8 Hz, 1H)


576
NMR (DMSO-d6, 80° C.) δ; 1.15-1.30 (m, 1H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 1H),



1.70-1.82 (m, 2H), 1.94-2.03 (m, 2H), 2.08-2.22 (m, 1H), 2.50-2.64 (m, 1H), 2.90-3.35 (m, 2H),



3.46-3.58 (m, 1H), 3.74-3.86 (m, 1H), 3.89-4.00 (m, 1H), 4.00-4.25 (m, 3H),



4.35-5.10 (m, 2H), 5.35 (brs, 1H), 5.86 (brd, J = 6.8 Hz, 1H), 6.88 (brd, J = 6.4 Hz, 1H),



7.16 (brs, 4H), 7.73 (d, J = 12.2 Hz, 1H), 7.92 (s, 1H)


578
NMR (DMSO-d6, 80° C.) δ; 1.15-1.30 (m, 1H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 1H),



1.70-1.82 (m, 2H), 1.94-2.03 (m, 2H), 2.08-2.22 (m, 1H), 2.50-2.64 (m, 1H), 2.94-3.35 (m, 2H),



3.46-3.58 (m, 1H), 3.74-3.85 (m, 1H), 3.90-4.00 (m, 1H), 4.00-4.25 (m, 3H),



4.35-5.15 (m, 2H), 5.35 (brs, 1H), 5.87 (brd, J = 6.3 Hz, 1H), 6.88 (brd, J = 7.3 Hz, 1H),



7.16 (brs, 4H), 7.73 (d, J = 12.2 Hz, 1H), 7.92 (s, 1H), 12.46 (brs, 1H)


583
NMR (DMSO-d6) δ; 0.84 (t, J = 7.4 Hz, 3H), 1.12-1.46 (m, 5H), 1.49 (d, J = 6.3 Hz, 3H),



1.61-1.69 (m, 1H), 1.70-1.90 (m, 6H), 1.91-2.00 (m, 2H), 3.43-3.65 (m, 3H), 4.93 (q, J =



6.5 Hz, 1H), 6.29 (d, J = 6.4 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 7.70 (d, J = 12.2 Hz, 1H),



8.58 (s, 1H), 10.15 (t, J = 5.6 Hz, 1H)


619
NMR (DMSO-d6) δ; 1.10-1.23 (m, 1H), 1.29-1.50 (m, 7H), 1.62-1.69 (m, 1H),



1.72-1.80 (m, 2H), 1.80-1.90 (m, 2H), 1.92-1.99 (m, 2H), 3.45-3.56 (m, 2H), 3.60-3.70 (m, 1H),



4.58 (q, J = 7.3 Hz, 2H), 6.73 (d, J = 7.3 Hz, 1H), 7.70 (d, J = 11.7 Hz, 1H),



10.00 (t, J = 5.4 Hz, 1H)


627
NMR (DMSO-d6) δ; 0.83 (t, J = 7.4 Hz, 6H), 1.10-1.24 (m, 1H), 1.26-1.52 (m, 4H),



1.55-2.02 (m, 11H), 3.44-3.55 (m, 2H), 3.62-3.75 (m, 1H), 4.94-5.04 (m, 1H),



6.65 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 11.7 Hz, 1H),



10.00 (t, J = 5.6 Hz, 1H)


629
NMR (DMSO-d6) δ; 0.70-0.77 (m, 6H), 1.11-1.24 (m, 1H), 1.28-1.52 (m, 4H),



1.63-1.70 (m, 1H), 1.72-1.86 (m, 4H), 1.90-2.03 (m, 5H), 2.05-2.17 (m, 1H), 2.25-2.39 (m, 2H),



3.65-3.76 (m, 1H), 4.51-4.57 (m, 1H), 4.98-5.07 (m, 1H), 6.70 (d, J = 8.3 Hz, 1H),



6.93 (d, J = 6.8 Hz, 1H), 7.75 (d, J = 11.7 Hz, 1H), 10.49 (d, J = 7.3 Hz, 1H)









The structures of alternative compounds of the invention are shown below in Tables 45 to 67. These can be produced readily by the production processes described above, the processes described in the Examples or processes obvious to persons skilled in the art or modified processes thereof.







TABLE 45













 








Ex
R





A1
(HO)2(O)P—CF2CH2NH—


A2
(S)-HO2C—(CH2)3CH(CO2H)NH—


A3
(HO2C—CH2)2CH—NH—


A4
(HO2C—(CH2)2)(HO2C—CH2)N—


A5
(HO2C—(CH2)3)(HO2C—CH2)N—


A6
(HO2C—(CH2)3)(HO2C—(CH2)2)N—


A7
(HO2C)2CHNH—


A8
((HO2C—(CH2)2)2N—


A9
HO2C—CH2CH(CH2OH)CH2NH—


A10
HO2C—(CH2)2—CH(CH2OH)NH—


A11
(HO2C—CH2)2CHCH2NH—


A12
HO2C—CH(OH)CH2NH—


A13
HO2C—CH2CH(OH)CH2NH—


A14
HO—(CH2)3—CH(CO2H)NH—


A15
HO—CH2CH(CO2H)CH2NH—


A16
HO2C—CF2CH2NH—


A17
HO2C—CH2CF2CH2NH—


A18
HO2C—CF2—(CH2)2—NH—


A19
HO2C—CF2CH2CH(CO2H)NH—


A20
HO2C—CH2CF2CH(CO2H)NH—


A21
HO2C—CF2CH(CO2H)NH—


A22
2-((HO)2(O)P)-cHex-NH—


A23
3-((HO)2(O)P)-cHex-NH—


A24
4-((HO)2(O)P)-1-pipe


A25
(HO)2(O)P—CHF—CH2NH—


A26
HO2C—CHF—CH2NH—


A27
HO2C—CH2—CHF—CH2NH—


A28
HO2C—CHF—(CH2)2—NH—


A29
HO2C—CHF—CH2CH(CO2H)NH—


A30
HO2C—CH2—CHF—CH(CO2H)NH—


A31
HO2C—CHF—CH(CO2H)NH—
















TABLE 46













 








Ex
R





B1
(HO)2(O)P—O—(CH2)2—NH—


B2
(HO2C—(CH2)2)(HO2C—CH2)N—


B3
(HO2C—(CH2)3)(HO2C—CH2)N—


B4
(HO2C—(CH2)3)(HO2C—(CH2)2)N—


B5
(HO2C)2CHNH—


B6
((HO2C—(CH2)2)2N—


B7
HO2C—CH2CH(CH2OH)CH2NH—


B8
HO2C—(CH2)2—CH(CH2OH)NH—


B9
(HO2C—CH2)2CHCH2NH—


B10
HO2C—CH(OH)CH2NH—


B11
HO2C—CH2CH(OH)CH2NH—


B12
HO—(CH2)3—CH(CO2H)NH—


B13
HO—CH2CH(CO2H)CH2NH—


B14
HO2C—CF2CH2NH—


B15
HO2C—CH2CF2CH2NH—


B16
HO2C—CF2—(CH2)2—NH—


B17
HO2C—CF2CH2CH(CO2H)NH—


B18
HO2C—CH2CF2CH(CO2H)NH—


B19
HO2C—CF2CH(CO2H)NH—


B20
2-((HO)2(O)P)-cHex-NH—


B21
3-((HO)2(O)P)-cHex-NH—


B22
4-((HO)2(O)P)-1-pipe


B23
(HO)2(O)P—CHF—CH2NH—


B24
HO2C—CHF—CH2NH—


B25
HO2C—CH2—CHF—CH2NH—


B26
HO2C—CHF—(CH2)2—NH—


B27
HO2C—CHF—CH2CH(CO2H)NH—


B28
HO2C—CH2—CHF—CH(CO2H)NH—


B29
HO2C—CHF—CH(CO2H)NH—
















TABLE 47













 








Ex
R





C1
HO2C—CH2NH—


C2
(S)-HO2C—(CH2)2CH(CO2H)NH—


C3
(HO)2(O)P—(CH2)2NH—


C4
(HO)2(O)P—CF2CH2NH—


C5
(S)-HO2C—CH2CH(CO2H)NH—


C6
(S)-HO2C—(CH2)3CH(CO2H)NH—


C7
(HO2C—CH2)2CH—NH—


C8
(HO)2(O)P—O—(CH2)2—NH—


C9
(HO2C—(CH2)2)(HO2C—CH2)N—


C10
(HO2—(CH2)3)(HO2C—CH2)N—


C11
(HO2C—(CH2)3)(HO2C—(CH2)2)N—


C12
(HO2C)2CHNH—


C13
((HO2C—(CH2)2)2N—


C14
HO2C—CH2CH(CH2OH)CH2NH—


C15
HO2C—(CH2)2—CH(CH2OH)NH—


C16
(HO2C—CH2)2CHCH2NH—


C17
HO2C—CH(OH)CH2NH—


C18
HO2C—CH2CH(OH)CH2NH—


C19
HO—(CH2)3—CH(CO2H)NH—


C20
HO—CH2CH(CO2H)CH2NH—


C21
HO2C—CF2CH2NH—


C22
HO2C—CH2CF2CH2NH—


C23
HO2C—CF2—(CH2)2—NH—


C24
HO2C—CF2CH2CH(CO2H)NH—


C25
HO2C—CH2CF2CH(CO2H)NH—


C26
HO2C—CF2CH(CO2H)NH—


C27
2-((HO)2(O)P)-cHex-NH—


C28
3-((HO)2(O)P)-cHex-NH—


C29
4-((HO)2(O)P)-1-pipe


C30
(HO)2(O)P—CHF—CH2NH—


C31
HO2C—CHF—CH2NH—


C32
HO2C—CH2—CHF—CH2NH—


C33
HO2C—CHF—(CH2)2—NH—


C34
HO2C—CHF—CH2CH(CO2H)NH—


C35
HO2C—CH2—CHF—CH(CO2H)NH—


C36
HO2C—CHF—CH(CO2H)NH—
















TABLE 48













 








Ex
R





D1
(S)-HO2C—(CH2)2CH(CO2H)NH—


D2
(HO)2(O)P—(CH2)2NH—


D3
(HO)2(O)P—CF2CH2NH—


D4
(S)-HO2C—CH2CH(CO2H)NH—


D5
(S)-HO2C—(CH2)3CH(CO2H)NH—


D6
(HO2C—CH2)2CH—NH—


D7
(HO)2(O)P—O—(CH2)2—NH—


D8
(HO2C—(CH2)2)(HO2C—CH2)N—


D9
(HO2C—(CH2)3)(HO2C—CH2)N—


D10
(HO2C—(CH2)3)(HO2C—(CH2)2)N—


D11
(HO2C)2CHNH—


D12
((HOC—(CH2)2)2N—


D13
HO2C—CH2CH(CH2OH)CH2NH—


D14
HO2C—(CH2)2—CH(CH2OH)NH—


D15
(HO2C—CH2)2CHCH2NH—


D16
HO2C—CH(OH)CH2NH—


D17
HO2C—CH2CH(OH)CH2NH—


D18
HO—(CH2)3—CH(CO2H)NH—


D19
HO—CH2CH(CO2H)CH2NH—


D20
HO2C—CF2CH2NH—


D21
HO2C—CH2CF2CH2NH—


D22
HO2C—CF2—(CH2)2—NH—


D23
HO2C—CF2CH2CH(CO2H)NH—


D24
HO2C—CH2CF2CH(CO2H)NH—


D25
HO2C—CF2CH(CO2H)NH—


D26
2-((HO)2(O)P)-cHex-NH—


D27
3-((HO)2(O)P)-cHex-NH—


D28
4-((HO)2(O)P)-1-pipe


D29
(HO)2(O)P—CHF—CH2NH—


D30
HO2C—CHF—CH2NH—


D31
HO2C—CH2—CHF—CH2NH—


D32
HO2C—CHF—(CH2)2—NH—


D33
HO2C—CHF—CH2CH(CO2H)NH—


D34
HO2C—CH2—CHF—CH(CO2H)NH—


D35
HO2C—CHF—CH(CO2H)NH—
















TABLE 49













 









Ex
R1
R2





E1
3,4-diMe-cPen
H


E2
3-Me-cPen
H


E3
3,4-diMe-cyclopent-3-en-1-yl
H


E4
3,3-diMe-cPen
H


E5
3,4-diF-cPen
H


E6
3-F-cPen
H


E7
3,3-diF-cPen
H


E8
3,4-diF-cyclopent-3-en-1-yl
H


E9
3-F-cyclopent-3-en-1-yl
H


E10
3-THF
H


E11
2-Py
H


E12
3-Py
H


E13
4-Py
H









E14
—CH(Et)—(CH2)3—



E15
—CH(Et)—(CH2)2—


E16
—CH2—C(Me)2—(CH2)2—


E17
—CH2—CHF—(CH2)2


E18
—CH2—CF2—(CH2)2—









E19
(Et)2CH—
Cl


E20
cPen
C1


E21
(Et)2CH—
CF3


E22
cPen
CF3
















TABLE 50













 









Ex
R1
R2





F1
FH2C—CH(Me)—
H


F2
F2HC—CH(Me)—
H


F3
iPr
H


F4
(HO—CH2)2CH—
H


F5
1-Me-3-pyrr
H


F6
3-THF
H


F7
2,3-diMe-1,3-dioxan-5-yl
H


F8
2,2-diEt-1,3-dioxan-5-yl
H


F9
3,4-diMe-cPen
H


F10
3-Me-cPen
H


F11
3,4-diMe-cyclopent-3-en-1-yl
H


F12
3-Me-cyclopent-3-en-1-yl
H


F13
3,3-diMe-cPen
H


F14
3,4-diF-cPen
H


F15
3-F-cPen
H


F16
3,3-fiF-cPen
H


F17
3,4-diF-cyclopent-3-en-1-yl
H


F18
3-F-cyclopent-3-en-1-yl
H


F19
3-THP
H


F20
2-Py
H


F21
3-Py
H


F22
4-Py
H









F23
—CH(Et)—(CH2)3—



F24
—CH(Et)—(CH2)2—


F25
—CH2—C(═CH2)—(CH2)2—


F26
—CH2—CH(Me)—(CH2)2—


F27
—CH2—C(Me)2—(CH2)2—


F28
—CH2—CHF—(CH2)2—


F29
—CH2—CF2—(CH2)2—









F30
(Et)2CH—
Cl


F31
cPen
Cl


F32
(Et)2CH—
CF3


F33
cPen
CF3
















TABLE 51













 









Ex
R1
R2





G1
FH2C—CH(Me)—
H


G2
F2HC—CH(Me)—
H


G3
iPr
H


G4
Et
H


G5
(HO—CH2)2CH—
H


G6
1-Me-3-pyrr
H


G7
3-THF
H


G8
2,2-diMe-1,3-dioxan-5-yl
H


G9
2,2-diEt-1,3-dioxan-5-yl
H


G10
3,4-diMe-cPen
H


G11
3-Me-cPen
H


G12
3,4-diMe-cyclopent-3-en-1-yl
H


G13
3-Me-cyclopent-3-en-1-yl
H


G14
3,3-diMe-cPen
H


G15
3,4-diF-cPen
H


G16
3-F-cPen
H


G17
3,3-diF-cPen
H


G18
3,4-diF-cyclopent-3-en-1-yl
H


G19
3-F-cyclopent-3-en-1-yl
H


G20
3-THF
H


G21
2-Py
H


G22
3-Py
H


G23
4-Py
H









G24
—CH(Et)—(CH2)3—



G25
—CH(Et)—(CH2)2—


G26
—CH2—C(═CH2)—(CH2)2—


G27
—CH2—CH(Me)—(CH2)2—


G28
—CH2—C(Me)2—(CH2)2—


G29
—CH2—CHF—(CH2)2—


G30
—CH2—CF2—(CH2)2—









G31
(Et)2CH—
Cl


G32
cPen
Cl


G33
(Et)2CH—
CF3


G34
cPen
CF3
















TABLE 52













 









Ex
R1
R2





H1
FH2C—CH(Me)—
H


H2
F2HC—CH(Me)—
H


H3
iPr
H


H4
Et
H


H5
(HO—CH2)2CH—
H


H6
1-Me-3-pyrr
H


H7
3-THF
H


H8
2,2-diMe-1,3-dioxan-5-yl
H


H9
2,2-diEt-1,3-dioxan-5-yl
H


H10
3,4-diMe-cPen
H


H11
3-Me-cPen
H


H12
3,4-diMe-cyclopent-3-en-1-yl
H


H13
3-Me-cyclopent-3-en-1-yl
H


H14
3,3-diMe-cPen
H


H15
3,4-diF-cPen
H


H16
3-F-cPen
H


H17
3,3-diF-cPen
H


H18
3,4-diF-cyclopent-3-en-1-yl
H


H19
3-F-cyclopent-3-en-1-yl
H


H20
3-THP
H


H21
2-Py
H


H22
3-Py
H


H23
4-Py
H









H24
—CH(Et)—(CH2)3—



H25
—CH(Et)—(CH2)2—


H26
—CH2—C(═CH2)—(CH2)2—


H27
—CH2—CH(Me)—(CH2)2—


H28
—CH2—C(Me)2—(CH2)2—


H29
—CH2—CHF—(CH2)2—


H30
—CH2—CF2—(CH2)2—









H31
(Et)2CH—
Cl


H32
cPen
Cl


H33
(Et)2CH—
CF3


H34
cPen
CF3
















TABLE 53













 











Ex
R1
R2







I1
FH2C—CH(Me)-
H



I2
F2HC—CH(Me)-
H



I3
3,4-diMe-cPen
H



I4
3-Me-cPen
H



I5
3,4-diMe-cyclopent-3-en-1-yl
H



I6
3-Me-cyclopent-3-en-1-yl
H



I7
3,3-diMe-cPen
H



I8
2,2-diEt-1,3-dioxan-5-yl
H



I9
3,4-diF-cPen
H



I10
3-F-cPen
H



I11
3,3-diF-cPen
H



I12
3,4-diF-cyclopent-3-en-1-yl
H



I13
3-F-cyclopent-3-en-1-yl
H



I14
3-THP
H



I15
2-Py
H



I16
3-Py
H



I17
4-Py
H










I18
—CH(Et)-(CH2)3—



I19
—CH(Et)-(CH2)2—



I20
—CH2—C(═CH2)—(CH2)2—



I21
—CH2—CH(Me)-(CH2)2—



I22
—CH2—C(Me)2-(CH2)2—



I23
—CH2—CHF—(CH2)2—



I24
—CH2—CF2—(CH2)2—











I25
(Et)2CH—
Cl



I26
cPen
Cl



I27
(Et)2CH—
CF3



I28
cPen
CF3

















TABLE 54













 











Ex
R1
R2







J1
FH2C—CH(Me)-
H



J2
F2HC—CH(Me)-
H



J3
iPr
H



J4
Et
H



J5
(HO—CH2)2CH—
H



J6
1-Me-3-pyrr
H



J7
3-THF
H



J8
2,2-diMe-1,3-dioxan-5-yl
H



J9
2,2-diEt-1,3-dioxan-5-yl
H



J10
3,4-diMe-cPen
H



J11
3-Me-cPen
H



J12
3,4-diMe-cyclopent-3-en-1-yl
H



J13
3-Me-cyclopent-3-en-1-yl
H



J14
3,3-diMe-cPen
H



J15
3,4-diF-cPen
H



J16
3-F-cPen
H



J17
3,3-diF-cPen
H



J18
3,4-diF-cyclopent-3-en-1-yl
H



J19
3-F-cyclopent-3-en-1-yl
H



J20
3-THP
H



J21
2-Py
H



J22
3-Py
H



J23
4-Py
H










J24
—CH(Et)-(CH2)3—



J24
—CH(Et)-(CH2)2—



J25
—CH2—C(═CH2)—(CH2)2—



J26
—CH2—CH(Me)-(CH2)2—



J27
—CH2—C(Me)2-(CH2)2—



J28
—CH2—CHF—(CH2)2—



J29
—CH2—CF2—(CH2)2—











J30
(Et)2CH—
Cl



J31
cPen
Cl



J32
(Et)2CH—
CF3



J33
cPen
CF3

















TABLE 55













 











Ex
R1
R2







K1
FH2C—CH(Me)-
H



K2
F2HC—CH(Me)-
H



K3
iPr
H



K4
Et
H



K5
(HO—CH2)2CH—
H



K6
1-Me-3-pyrr
H



K7
3-THF
H



K8
2,2-diMe-1,3-dioxan-5-yl
H



K9
2,2-diEt-1,3-dioxan-5-yl
H



K10
3,4-diMe-cPen
H



K11
3-Me-cPen
H



K12
3,4-diMe-cyclopent-3-en-1-yl
H



K13
3-Me-cyclopent-3-en-1-yl
H



K14
3,3-diMe-cPen
H



K15
3,4-diF-cPen
H



K16
3-F-cPen
H



K17
3,3-diF-cPen
H



K18
3,4-diF-cyclopent-3-en-1-yl
H



K19
3-F-cyclopent-3-en-1-yl
H



K20
3-THP
H



K21
2-Py
H



K22
3-Py
H



K23
4-Py
H










K24
—CH(Et)-(CH2)3—



K25
—CH(Et)-(CH2)2—



K26
—CH2—C(═CH2)—(CH2)2—



K27
—CH2—CH(Me)-(CH2)2—



K28
—CH2—C(Me)2-(CH2)2—



K29
—CH2—CHF—(CH2)2—



K30
—CH2—CF2—(CH2)2—











K31
(Et)2CH—
Cl



K32
cPen
Cl



K33
(Et)2CH—
CF3



K34
cPen
CF3

















TABLE 56













 











Ex
R1
R2







L1
FH2C—CH(Me)-
H



L2
F2HC—CH(Me)-
H



L3
iPr
H



L4
Et
H



L5
(HO—CH2)2CH—
H



L6
1-Me-3-pyrr
H



L7
3-THF
H



L8
2,2-diMe-1,3-dioxan-5-yl
H



L9
2,2-diEt-1,3-dioxan-5-yl
H



L10
3,4-diMe-cPen
H



L11
3-Me-cPen
H



L12
3,4-diMe-cyclopent-3-en-1-yl
H



L13
3-Me-cyclopent-3-en-1-yl
H



L14
3,3-diMe-cPen
H



L15
3,4-diF-cPen
H



L16
3-F-cPen
H



L17
3,3-diF-cPen
H



L18
3,4-diF-cyclopent-3-en-1-yl
H



L19
3-F-cyclopent-3-en-1-yl
H



L20
3-THP
H



L21
2-Py
H



L22
3-Py
H



L23
4-Py
H










L24
—CH(Et)-(CH2)3—



L25
—CH(Et)-(CH2)2—



L26
—CH2—C(═CH2)—(CH2)2—



L27
—CH2—CH(Me)-(CH2)2—



L28
—CH2—C(Me)2-(CH2)2—



L29
—CH2—CHF—(CH2)2—



L30
—CH2—CF2—(CH2)2—











L31
(Et)2CH—
Cl



L32
cPen
Cl



L33
(Et)2CH—
CF3



L34
cPen
CF3

















TABLE 57













 










Ex
R







M1
Cl



M2
Br



M3
Me



M4
NC—



M5
CF3



M6
HO—



M7
H2N—



M8
4-mor



M9
1-pipe



M10
Me2N—



M11
Et2N—



M12
AcN(Me)-



M13
AcNH—

















TABLE 58













 










Ex
R







O1
Cl



O2
Br



O3
Me



O4
NC—



O5
CF3



O6
H2N—



O7
4-mor



O8
1-pipe



O9
Et2N—



O10
AcN(Me)-



O11
AcNH—

















TABLE 59





















Ex
R







P1
Cl



P2
Br



P3
Me



P4
NC—



P5
CF3



P6
HO—



P7
H2N—



P8
4-mor



P9
1-pipe



P10
Me2N—



P11
Et2N—



P12
AcN(Me)-



P13
AcNH—

















TABLE 60













 










Ex
R







Q1
Cl



Q2
Br



Q3
Me



Q4
NC—



Q5
CF3



Q6
HO—



Q7
H2N—



Q8
4-mor



Q9
1-pipe



Q10
Me2N—



Q11
Et2N—



Q12
AcN(Me)-



Q13
AcNH—

















TABLE 61













 










Ex
R







R1
Cl



R2
Br



R3
Me



R4
NC—



R5
CF3



R6
HO—



R7
H2N—



R8
4-mor



R9
1-pipe



R10
Me2N—



R11
Et2N—



R12
AcN(Me)-



R13
AcNH—

















TABLE 62













 










Ex
R







S1
Cl



S2
Br



S3
Me



S4
NC—



S5
CF3



S6
HO—



S7
H2N—



S8
4-mor



S9
1-pipe



S10
Me2N—



S11
Et2N—



S12
AcN(Me)-



S13
AcNH—

















TABLE 63













 










Ex
R







T1
Cl



T2
Br



T3
Me



T4
NC—



T5
CF3



T6
HO—



T7
H2N—



T8
4-mor



T9
1-pipe



T10
Me2N—



T11
Et2N—



T12
AcN(Me)-



T13
AcNH—

















TABLE 64













 










Ex
R







U1
Cl



U2
Br



U3
Me



U4
NC—



U5
CF3



U6
HO—



U7
H2N—



U8
4-mor



U9
1-pipe



U10
Me2N—



U11
Et2N—



U12
AcN(Me)-



U13
AcNH—

















TABLE 65













 










Ex
R1
R2
R3





V1
4-F-cHex
cPen
HO2C—CH2NH—


V2
4-F-cHex
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


V3
4-F-cHex
cPen
(HO)2(O)P—(CH2)2NH—


V4
4-F-cHex
cPen
(HO)2(O)P—CF2CH2NH—


V5
4-F-cHex
(Et)2CH—
HO2C—CH2NH—


V6
4-F-cHex
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


V7
4-F-cHex
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


V8
4-F-cHex
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


V9
4,4-diF-cHex
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


V10
4,4-diF-cHex
cPen
(HO)2(O)P—(CH2)2NH—


V11
4,4-diF-cHex
cPen
(HO)2(O)P—CF2CH2NH—


V12
4,4-diF-cHex
(Et)2CH—
HO2C—CH2NH—


V13
4,4-diF-cHex
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


V14
4,4-diF-cHex
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


V15
4,4-diF-cHex
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


V16
3-THP
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


V17
3-THP
cPen
(HO)2(O)P—(CH2)2NH—


V18
3-THP
cPen
(HO)2(O)P—CF2CH2NH—


V19
3-THP
(Et)2CH—
HO2C—CH2NH—


V20
3-THP
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


V21
3-THP
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


V22
3-THP
(Et)2CH—
(HO)2(O)P—CF2CH2NH—
















TABLE 66













 










Ex
R1
R2
R3





W1
4-F-cHex
cPen
HO2C—CH2NH—


W2
4-F-cHex
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


W3
4-F-cHex
cPen
(HO)2(O)P—(CH2)2NH—


W4
4-F-cHex
cPen
(HO)2(O)P—CF2CH2NH—


W5
4-F-cHex
(Et)2CH—
HO2C—CH2NH—


W6
4-F-cHex
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


W7
4-F-cHex
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


W8
4-F-cHex
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


W9
4,4-diF-cHex
cPen
HO2C—CH2NH—


W10
4,4-diF-cHex
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


W11
4,4-diF-cHex
cPen
(HO)2(O)P—(CH2)2NH—


W12
4,4-diF-cHex
cPen
(HO)2(O)P—CF2CH2NH—


W13
4,4-diF-cHex
(Et)2CH—
HO2C—CH2NH—


W14
4,4-diF-cHex
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


W15
4,4-diF-cHex
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


W16
4,4-diF-cHex
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


W17
3-THP
cPen
(S)—HO2C—(CH2)2CH(CO2H)NH—


W18
3-THP
cPen
(HO)2(O)P—(CH2)2NH—


W19
3-THP
cPen
(HO)2(O)P—CF2CH2NH—


W20
3-THP
(Et)2CH—
HO2C—CH2NH—


W21
3-THP
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


W22
3-THP
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


W23
3-THP
(Et)2CH—
(HO)2(O)P—CF2CH2NH—
















TABLE 67













 










Ex
R1
R2
R3





X1
H
Et
(S)—HO2C—(CH2)2CH(CO2H)NH—


X2
H
Et
(HO)2(O)P—CF2CH2NH—


X3
H
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


X4
H
c-Pen
(S)—HO2C—(CH2)2CH(CO2H)NH—


X5
H
c-Pen
(HO)2(O)P—(CH2)2NH—


X6
H
c-Pen
(HO)2(O)P—CF2CH2NH—


X7
F
Et
HO2C—CH2NH—


X8
F
Et
(S)—HO2C—(CH2)2CH(CO2H)NH—


X9
F
Et
(HO)2(O)P—(CH2)2NH—


X10
F
Et
(HO)2(O)P—CF2CH2NH—


X11
F
(Et)2CH—
HO2C—CH2NH—


X12
F
(Et)2CH—
(S)—HO2C—(CH2)2CH(CO2H)NH—


X13
F
(Et)2CH—
(HO)2(O)P—(CH2)2NH—


X14
F
(Et)2CH—
(HO)2(O)P—CF2CH2NH—


X15
F
c-Pen
HO2C—CH2NH—


X16
F
c-Pen
(S)—HO2C—(CH2)2CH(CO2H)NH—


X17
F
c-Pen
(HO)2(O)P—(CH2)2NH—


X18
F
c-Pen
(HO)2(O)P—CF2CH2NH—

## Claims

1. A platelet aggregation inhibitor comprising a quinolone derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:



wherein, the symbols in the formula have the following meanings:
X: C—R7 or N;
Y: C—R6 or N;
R11: —H;
R12: a lower alkyl which is substituted;
R2: a lower alkyl which is substituted or a hetero ring which is substituted;
R3: a halogen;
R4: a cycloalkyl;
R5: —H;
R6: —H; and
R7: —H.

2. A P2Y12 inhibitor comprising the compound according to claim 1 as an active ingredient.

3. A method for inhibiting platelet aggregation in an individual, comprising administering a therapeutically effective amount of the compound of claim 1 to the individual.

4. A method for inhibiting P2Y12 in an individual needing therapy for circulatory diseases involving thrombosis via platelet aggregation, comprising administering a therapeutically effective amount of the compound of claim 1 to the individual.

5. A quinolone derivative represented by the formula (I-a) or a pharmaceutically acceptable salt thereof:



wherein, the symbols in the formula have the following meanings:
X: C—R7 or N;
Y: C—R6 or N;
R11: —H;
R12: a lower alkyl which is substituted;
R2: a lower alkyl which is substituted, or a hetero ring which is substituted;
R3: a halogen;
R4: a cycloalkyl;
R5: —H;
R6: —H; and
R7: —H.

6. The compound according to claim 5, wherein X is CH.

7. The compound according to claim 6, wherein R12 is a lower alkyl substituted with one or more groups selected from the Group Q (provided that at least one is substituted with a group of the Group P):
Group P: —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2; and
Group Q: —F, —OH, —CO2H, —SO3H, —P(O)(OH)2, and —OP(O)(OH)2.

8. The compound according to claim 5, which is
{2-[({[7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3S)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid,
{2-[({7-(cyclohexylamino)-6-fluoro-4-oxo-1-[(3R)-tetrahydrofuran-3-yl]-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid,
{2-[({7-(cyclohexylamino)-6-fluoro-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinolin-3-yl}carbonyl)amino]ethyl}phosphonic acid, or
[2-({[7-(cyclohexylamino)-1-(2,2-dimethyl-1,3-dioxan-5-yl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}amino)ethyl]phosphonic acid, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition comprising a compound according to any one of claims 5, 6, 7 or 8 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, which is a platelet aggregation inhibitor.

11. The pharmaceutical composition according to claim 9, which is a P2Y12 inhibitor.

12. A method for inhibiting platelet aggregation in an individual, comprising administering a therapeutically effective amount of the compound of any one of claims 5, 6, 7 or 8 to the individual.

13. A method for inhibiting P2Y12 in an individual needing therapy for circulatory diseases involving thrombosis via platelet aggregation, comprising administering a therapeutically effective amount of the compound of any one of claims 5, 6, 7 or 8 to the individual.