# Patent

## Title
2-acylaminothiazole derivative or salt thereof

## Abstract

2-Acylaminothiazole derivatives or salts thereof which have a platelet increasing activity based on an excellent human c-mpl-Ba/F3 cell growth function and a function of accelerating formation of megakaryocytic colonies and which are useful for treating thrombocytopenia are provided.

## Background
TECHNICAL FIELD
The present invention relates to novel 2-acylaminothiazole derivatives or salts thereof which are useful as medicaments, especially a thrombocytopenia treating agent, and medicaments comprising one or more said compounds as active ingredients.
BACKGROUND ART
Platelets are non-nucleated blood cells which play a main role in physiological hemostasis and pathologic thrombus generation. Platelets are constantly produced in vivo from megakaryocytes, precursor cells. Platelets are, like other blood cells, produced from multipotential stem cells. Multipotential stem cells become megakaryocytic precursor cells, from which megakaryoblasts, promegakaryoblasts and megakaryocytes are formed in this order. During maturation of the megakaryocytes, immature megakaryocytes conduct DNA synthesis only without cell division to form polyploids. Thereafter, maturation of cytoplasms begins to form platelet separation membranes, and the cytoplasms are split to release platelets.
Meanwhile, a decrease in platelets due to various hematopoietic disorders in chemotherapy, radiotherapy or the like of anemia, myelodysplastic syndrome or malignant tumor induces serious conditions such as invitation of bleeding tendency. Therefore, various attempts of technical development for increasing platelets have been made for the purpose of treating the same. At present, a potent method for treating thrombocytopenia is platelet transfusion. However, a sufficient amount of platelets is not yet supplied, and life of platelets transfused is short. For these reasons, it is hard to satisfactorily improve thrombocytopenia. Moreover, platelet transfusion involves problems such as viral infection, production of alloantibody and graft versus host disease (GVHD). Accordingly, the development of medications for relaxing an inhibitory state of a hematopoietic function induced by various diseases or therapies and accelerating recovery of the number of platelets has been expected.
Under these circumstances, it has been reported that thrombopoietin (hereinafter referred to as TPO) which is a main factor participating in division to megakaryocytic cells and is a c-Mpl ligand is cloned to stimulate division and growth of megakaryocytic cells and accelerate production of platelets (Kaushansky K. et al., Nature, 369, 568-571, 1994; Non-patent Document 1). TPO has already been subjected to a clinical test as a platelet increasing agent, and usefulness and tolerance in humans are being confirmed. However, in a clinical test of PEG-rHuMGDF (TPO whose 163rd amino acid seen from the N-terminal has been modified with polyethylene glycol) which is a type of TPO, a neutralizing antibody has been confirmed (Li J. et. al., Blood, 98, 3241-3248, 2001: Non-patent Document 2, and Basser R. L. et al., Blood, 99, 2599-2602, 2002: Non-patent Document 3). Accordingly, there is a fear of TPO immunogenicity. Further, since TPO is a protein, it is decomposed in digestive organs, and is thus not practical as an oral administration drug. For the same reason, a low-molecular peptide is not considered either to be practical as an oral administration drug. Under these circumstances, the development of an orally administrable non-peptide c-Mpl ligand with less immunogenicity has been under way for treatment of thrombocytopenia.
As the foregoing compounds, benzodiazepine derivatives (Patent Document 1), acylhydrazone derivatives (Patent Document 2), diazonaphthalene derivatives (Patent Document 3), pyrrocarbazole derivatives (Patent Document 4), pyrrophenanthridine derivatives (Patent Document 5) and pyrrophthalimide derivatives (Patent Document 6) have been known.
WO 01/07423 (Patent Document 7) describes that compounds represented by the following general formula (VII) have a platelet increasing function.




(As to symbols in the formula, refer to the document.)

The document describes the compounds containing thiazole which may be substituted as X1 and —NHCO— as Y1. In the present invention, however, R3 in the compounds of the invention is not substituted with a substituent having an A1 group such as a thiazolyl group in the document. Moreover, regarding compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom, there is not any concrete disclosure by Examples or the like in the document.
WO 01/53267 (Patent Document 8) describes that compounds represented by the following general formula (VIII) have a platelet increasing function.

X1—Y1-Z1-W1  (VIII)

(As to symbols in the formula, refer to the document.)

The document describes the compounds containing thiazole which may be substituted as X1 and —NHCO— as Y1. In the present invention, however, R3 in the compounds of the present invention is not substituted with a substituent having a W1 group in the document. Regarding compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom, there is not any concrete disclosure by Examples or the like in the document.
WO 02/62775 (Patent Document 9) describes that compounds represented by the following general formula (IX) have a platelet increasing function.




(As to symbols in the formula, refer to the document.)

The document describes the compounds in which the 5-position of 2-acylaminothiazole is directly substituted with a nitrogen atom. However, it does not describe compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom in the present invention.
WO 03/062233 (Patent Document 10) describes that compounds represented by the following general formula (X) have a platelet increasing function.




(As to symbols in the formula, refer to the document.)

The document describes the compounds in which the 5-position of 2-acylaminothiazole is directly substituted with a nitrogen atom. However, it does not describe compounds in which the 5-position of thiazole is substituted with a lower alkyl substituted with a nitrogen atom in the present invention.
In addition to the foregoing Patent Documents 7 to 10, 2-acylaminothiazole compounds are described as cholecystokinin and gastrin receptor antagonists in U.S. Pat. No. 3,199,451 (Patent Document 11) or as compounds having antiinflammatory characteristics in Chemical and Pharmaceutical Bulletin, 25, 9, 2292-2299, 1977 (Non-patent Document 4). However, none of them indicate at all the platelet increasing function in the present invention.
Under such circumstances, the development of an orally administrable non-peptide c-Mpl ligand with less antigenicity has been in demand for treatment of thrombocytopenia.













[Patent Document 1]
JP-A-11-152276


[Patent Document 2]
WO 99/11262 pamphlet


[Patent Document 3]
WO 00/35446 pamphlet


[Patent Document 4]
WO 98/09967 pamphlet


[Patent Document 5]
JP-A-10-212289


[Patent Document 6]
JP-A-2000-44562


[Patent Document 7]
WO 01/07423 pamphlet


[Patent Document 8]
WO 01/53267


[Patent Document 9]
WO 02/62775 pamphlet


[Patent Document 10]
WO 03/062233 pamphlet


[Patent Document 11]
Patent No. 3199451


[Non-Patent Document 1]
Nature, 1994, No. 369, p. 568-571


[Non-Patent Document 2]
Blood, 2001, vol. 98, p. 3241-3248


[Non-Patent Document 3]
Blood, 2002, vol. 99, p. 2599-2602


[Non-Patent Document 4]
Chemical and Pharmaceutical Bulletin,



1977, vol. 25, No. 9, p. 2292-2299









[Non-patent Document 1] Nature, 1994, No. 369, p. 568-571
[Non-patent Document 2] Blood, 2001, vol. 98, p. 3241-3248
[Non-patent Document 3] Blood, 2002, vol. 99, p. 2599-2602
[Non-patent Document 4] Chemical and Pharmaceutical Bulletin, 1977, vol. 25, No. 9, p. 2292-2299
DISCLOSURE OF THE INVENTION
The present inventors have assiduously conducted investigations on compounds having a platelet increasing function, and have found that novel 2-acylaminothiazole derivatives have an excellent platelet increasing function. They have thus completed the present invention.
That is, according to the present invention, the following (1) to (15) are provided.
(1) A platelet increasing agent comprising a 2-acylaminothiazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.




[Symbols in the formula have the following meanings.

A: a lower alkylene
R1: a group represented by the formula (II), or cyclic amino which may be substituted.




[Symbols in the formula have the following meanings.

R11: H, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted. When A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2. When A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A.
R12: a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted.]
R2: thienyl or phenyl, each of which may be substituted.
R3: an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.]
(2) The pharmaceutical composition of (1), wherein A is methylene.
(3) The pharmaceutical composition of (2), wherein R2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting of a lower alkyl which may be substituted with one or more halogens, and a halogen.
(4) The pharmaceutical composition of any of (1) to (3), which is a thrombocytopenia treating agent.
(5) The pharmaceutical composition of any of (1) to (3), which is a c-Mpl ligand.
(6) A 2-acylaminothiazole derivative represented by the formula (III) or a pharmaceutically acceptable salt thereof.




[Symbols in the formula have the following meanings.

B: a group represented by A according to (1).
R4: a group represented by R1 according to (1).
R5: a group represented by R2 according to (1).
R6: a group represented by R3 according to (1), provided that unsubstituted phenyl and indole which may be substituted are excluded.]
(7) The compound of (6), wherein B is methylene.
(8) The compound of (7), wherein R5 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting of a lower alkyl which may be substituted with one or more halogens, and a halogen.
(9) The compound of (8), wherein R6 is pyridyl which may be substituted, or phenyl which is substituted.
(10) The compounds of (8), wherein R6 is pyridin-3-yl whose 5-position is substituted with a group selected from the group consisting of chloro and fluoro, and whose 6-position is substituted, or phenyl whose 3-position is substituted with a group selected from the group consisting of chloro and fluoro, whose 5-position is substituted with a group selected from the group consisting of —H, chloro and fluoro, and whose 4-position is substituted.
(11) Compounds selected from the group consisting of compound group X and compound group Y, preferably compound group X, among the compounds of (6).
Here, “compound group X” is a compound group consisting of
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-(5-{[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidin-4-carboxylic acid,
1-{5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-3-fluoro-2-pyridyl}piperidin-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(dimethylaminomethyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
4-[{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}(methyl)amino]butyric acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[[(2S)-2-methoxypropyl](methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[(3-hydroxypropyl)amino]nicotinamide,
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-(3-oxopiperazin-1-yl)nicotinamide and
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[4-(hydroxymethyl)piperidino]nicotinamide, and
pharmaceutically acceptable salts thereof, and
“compound group Y” is a compound group consisting of
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
4-[{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}(methyl)amino]butyric acid,
4-[{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}(methyl)amino]butyric acid,
1-{5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-3-fluoro-2-pyridyl}piperidine-4-carboxylic acid,
(1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}azetidin-3-yl)acetic acid,
(1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}azetidin-3-yl)acetic acid,
1-(3-chloro-5-{[5-{[isopropyl(methyl)amino]methyl}-4-(4-methylthiophen-2-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3R)-3-methylpyrrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[[(2R)-2-methoxypropyl](methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-(5-{[5-(azepan-1-ylmethyl)-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-(5-{[5-azocan-1-ylmethyl)-4-(4-chlorothiophen-2-yl)thiazole-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclohexyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid and
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid, and
pharmaceutically acceptable salts thereof.
(12) A pharmaceutical composition comprising the compound according to any of (6) to (10) as an active ingredient.
(13) The pharmaceutical composition according to (11), which is a platelet increasing agent.
(14) The pharmaceutical composition according to (11), which is a thrombocytopenia treating agent.
(15) The pharmaceutical composition according to (11), which is a c-Mpl ligand.
A in the compounds represented by formula (I) and B in the compounds represented by formula (III) are preferably methylene.
R1 in the compounds represented by formula (I) and R4 in the compounds represented by formula (III) are preferably a group represented by formula (II) in which R11 is lower alkyl and R12 is lower alkyl or cycloalkyl which may be substituted respectively, or cyclic amino which may be substituted with lower alkyl; more preferably a group represented by formula (II) in which R11 is methyl and R12 is lower alkyl or cycloalkyl which may be substituted respectively, or cyclic amino which may be substituted with methyl.
R2 in the compounds represented by formula (I) and R5 in the compounds represented by formula (III) are preferably thienyl which may be substituted; more preferably thienyl substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more halogens, and halogen; further preferably thienyl substituted with one or more groups selected from the group consisting of chloro and methyl; especially preferably 4-chlorothiophen-2-yl or 4-methylthiophen-2-yl. In another embodiment, R2 in the compounds represented by formula (I) and R5 in the compounds represented by formula (III) can be preferably phenyl which may be substituted; more preferably phenyl substituted with one or more groups selected from the group consisting of lower alkyl which may be substituted with one or more halogens, and halogen; further preferably phenyl substituted with one or more groups selected from the group consisting of trifluoromethyl, chloro and fluoro; especially preferably 3-trifluoromethylphenyl, 4-fluorophenyl or 3-chlorophenyl.
R3 in the compounds represented by formula (I) and R6 in the compounds represented by formula (III) are preferably pyridyl which may be substituted; more preferably pyridyl substituted with at least one halogen; more preferably pyridin-3-yl whose 5-position is substituted with a group selected from the member consisting of chloro and fluoro and whose 6-position is substituted. Of these, preferable is pyridin-3-yl whose 6-position is substituted with a group selected from the group consisting of piperidin-1-yl or piperazin-1-yl, each of which may be substituted with one or more groups selected from the group consisting of lower alkyl substituted with substituent group W, substituent group W and oxo, —O-lower alkyl, —NH-lower alkyl or —N(lower alkyl)-lower alkyl which may be substituted with one or more groups selected from substituent group W respectively, and whose 5-position is substituted with a group selected from the member consisting of chloro and fluoro.
Here, “substituent group W” indicates a group consisting of —OH, —O—RZ, —OCO—RZ, carboxyl, —CO2—RZ, —CO—RZ and carbamoyl which may be substituted with one or two RZs (when carbamoyl is substituted with two RZs, they may be the same or different), cyano, amino which may be substituted with one or two RZs (when amino is substituted with two RZs, they may be the same or different), —NHCO—RZ, —NHSO2—RZ, sulfamoyl which may be substituted with one or two RZs (when sulfamoyl is substituted with two RZs, they may be the same or different), —SO3H, —P(O)(OH)2, —P(O)(OH)(ORZ), —P(O)(ORZ)2, aromatic heterocycle, non-aromatic heterocycle and RZ. “RZ” represents lower alkyl, cycloalkyl or non-aromatic heterocycle, each of which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl (this lower alkyl may be substituted with one or more groups selected from the member consisting of —OH, —O-lower alkyl and amino), —OCO-lower alkyl, carboxyl, —CO2-lower alkyl, —CO-lower alkyl, carbamoyl which may be substituted with one or two lower alkyls (when carbamoyl is substituted with two lower alkyls, they may be the same or different), cyano, amino which may be substituted with one or two lower alkyls (when amino is substituted with two lower alkyls, they may be the same or different), —NHCO-lower alkyl, —NHSO2-lower alkyl, sulfamoyl which may be substituted with one or two lower alkyls (when sulfamoyl is substituted with two lower alkyls, they may be the same or different), —SO3H, —P(O)(OH)2, —P(O)(OH)(O-lower alkyl), —P(O)(O-lower alkyl)2, aromatic heterocycle, non-aromatic heterocycle and halogen (this applies to the following).
In another embodiment, R3 in the compounds represented by formula (I) and R6 in the compounds represented by formula (III) can be preferably phenyl which may be substituted; more preferably phenyl substituted with at least one halogen; further preferably phenyl whose 3-position is substituted with a group selected from the member consisting of chloro and fluoro, whose 5-position is substituted with a group selected from the member consisting of —H, chloro and fluoro and whose 4-position is substituted. Of these, preferable is phenyl whose 4-position is substituted with a group selected from the group consisting of piperidin-1-yl or piperazin-1-yl, each of which may be substituted with one or more groups selected from the member consisting of lower alkyl substituted with substituent group W, substituent group W and oxo, —O-lower alkyl, —NH-lower alkyl or —N(lower alkyl)-lower alkyl which may be substituted with one or more groups selected from substituent group W respectively, and whose 3-position is substituted with a group selected from the member consisting of chloro and fluoro, and whose 5-position is substituted with a group selected from the member consisting of —H, chloro and fluoro.
In R11, “when A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2” specifically means, for example, a partial structure of compounds shown in Table 30.
In R11, “when A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A” specifically means, for example, a partial structure of compounds shown in Table 33.
The compounds of the present invention are 2-acylaminothiazole derivatives whose 2-position is substituted with an acylamino group and whose 5-position is substituted with lower alkyl substituted with a nitrogen atom, in which point the characteristic feature of a chemical structure lies. The compounds of the present invention exhibit a human c-mpl-Ba/F3 cell growth activity, an activity of accelerating division of human CD34+ cells to megakaryocytes and a good oral activity in a mouse oral administration test. Consequently, the compounds have a pharmacological property in that they exhibit a platelet increasing function.
The compounds of the present invention are further described below.
In the present specification, the word “lower” means a linear or branched carbon chain having from 1 to 6 carbon atoms unless otherwise instructed.
Accordingly, “lower alkyl” indicates C1-6 alkyl. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like. Methyl, ethyl, propyl and isopropyl, which are C1-3 alkyl, are preferable.
“Lower alkylene” is a divalent group of C1-6 alkyl. Methylene, ethylene, trimethylene, methylethylene, tetramethylene, dimethylmethylene and dimethylethylene, which are C1-4 alkylene, are preferable. Methylene and ethylene are more preferable, and methylene is especially preferable.
“Cycloalkyl” means a C3-8 carbon ring, and it may partially have one or more unsaturated bonds. Accordingly, specific examples thereof can include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl and the like.
“Aryl” means a C6-14 monocyclic to tricyclic aromatic ring. Phenyl and naphthyl are preferable, and phenyl is more preferable.
“Cyclic amino” means a monovalent group of a 3- to 8-membered non-aromatic cyclic amine which has at least one nitrogen atom and may have further one or more hetero atoms selected from the member consisting of nitrogen, oxygen and sulfur, provided when plural hetero atoms are provided, they may be the same or different and at least one nitrogen atom has a bonding site. Specific examples thereof can include monovalent groups of azetidine, pyrrolidine, piperidine, azepane, azocane, azonane, azecane, piperazine, homopiperazine, morpholine and thiomorpholine, and the like.
“Non-aromatic heterocycle” means a monovalent group of a non-aromatic heterocycle having one or more hetero atoms selected from the member consisting of nitrogen, oxygen and sulfur, provided when plural hetero atoms are provided, they may be the same or different. Specific examples thereof can include monovalent groups of tetrahydrofuran, tetrahydropyran, tetrahydrothiofuran, tetrahydrothiopyran, oxetane, azetidine, pyrrolidine, piperidine, azepane, piperazine, homopiperazine, morpholine and thiomorpholine, and the like.
“Aromatic heterocycle” means a monovalent group of a 5- or 6-membered aromatic heterocycle having one or more hetero atoms selected from the member consisting of nitrogen, oxygen and sulfur, provided plural hetero atoms are provided, they may be the same or different, or the heterocycle which is partially hydrogenated. Specific examples thereof can include monovalent groups of pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, oxazole, thiazole, thiophene and furan. These heterocycles may be condensed with a benzene ring.
Examples of “halogen” include fluoro, chloro, bromo and iodo, and fluoro and chloro are preferable.
In the present specification, with respect to permissible substituents of the terms “which may be substituted” and “substituted”, any substituents are available so long as they are ordinarily used as substituents of the respective groups. One or more of these substituents may be present in the respective groups.
Regarding permissible substituents in “cyclic amino which may be substituted” in R1 and R4, “cycloalkyl which may be substituted” in R11, “cycloalkyl or non-aromatic heterocycle which may be substituted respectively” in R12 and “thienyl or phenyl which may be substituted respectively” in R2 and R5, the following groups (a) to (h) are listed.
(a) halogen;
(b) —OH, —O—RZ, —O-aryl, —OCO—RZ, oxo (═O);
(c) —SH, —S—RZ, —S-aryl, —SO—RZ, —SO-aryl, —SO2—RZ, —SO2-aryl, sulfamoyl which may be substituted with one or two RZs;
(d) amino which may be substituted with one or two RZs, —NHCO—RZ, —NHCO-aryl, —HNCO2—RZ, —NHCONH2, NHSO2—RZ, —NHSO2-aryl, —NHSO2NH2, nitro;
(e) —CHO, —CO—RZ, —CO2H, —CO2—RZ, carbamoyl which may be substituted with one or two RZs, cyano;
(f) aryl or cycloalkyl, each of which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, amino which may be substituted with one or two lower alkyls, halogen and RZ;
(g) aromatic heterocycle or non-aromatic heterocycle, each of which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, amino which may be substituted with one or two lower alkyls, halogen and RZ; and
(h) lower alkyl which may be substituted with one or more groups selected from substituents shown in (a) to (g).
Permissible substituents in “lower alkyl which may be substituted” and “lower alkylene which may be substituted” in R11 and “lower alkyl which may be substituted” in R12 include the groups listed in (a) to (g).
Examples of permissible substituents in “aromatic heterocycle, aryl or cyclic amino which may be substituted respectively” in R3 and R6 can include halogen, lower alkyl which may be substituted with one or more halogens, —OH, —O—RZ, oxo, amino which may be substituted with one or two RZs and a group represented by formula (III). When the substituent is amino substituted with two RZs, the two RZs may be the same or different.

—X—Y-Z  (III)

[Symbols in the formula have the following meanings.

X: cyclic aminediyl which may be substituted with one or more groups selected from the group consisting of —OH, —O-lower alkyl, halogen, oxo and RZ.
Y: single bond, —O-lower alkylene or —N(lower alkyl)-lower alkylene.
Z: substituent group W, -cyclic aminediyl-substituent group W or —CO-cyclic aminediyl-substituent group W.]
“Cyclic aminediyl” means a divalent group of 3- to 8-membered non-aromatic cyclic amine which has at least one nitrogen atom and may have further one or more hetero atoms selected from the member consisting of nitrogen, oxygen and sulfur, provided when plural hetero atoms are provided, they may be the same or different and at least one nitrogen atom has a bonding site. Specific examples thereof can include divalent groups of azetidine, pyrrolidine, piperidine, azepane, azocane, azonane, azecane, piperazine, homopiperazine, morpholine and thiomorpholine.
The compounds represented by formula (I) which are an active ingredient of medications of the present invention or the compounds represented by formula (III) which are compounds of the present invention sometimes contain an asymmetric carbon atom according to the type of the substituent, and optical isomers may be present based on this. The present invention includes all of a mixture of these optical isomers and optical isomers which are isolated. Further, with respect to the compounds according to the present invention, tautomers sometimes exist. The present invention includes tautomers which are separated or a mixture thereof. Still further, the present invention includes labeled compounds, namely the compounds of the present invention with one or more atoms substituted with a radioactive isotope or a nonradioactive isotope.
The compounds according to the present invention are sometimes formed into salts which are included in the present invention so long as they are pharmaceutically acceptable salts. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid or 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, salts with inorganic bases containing metals such as sodium, potassium, calcium and magnesium or organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine, ammonium salts and the like. The present invention also includes hydrates, solvates and polycrystalline substances of the compounds of the present invention and the pharmaceutically acceptable salts thereof. The present invention also includes all of compounds which are converted to the compounds represented by formula (I) or (III) or the salts thereof by being metabolized in vivo, so-called prodrugs. Groups that form the prodrugs of the present invention include groups described in Prog. Med. 5:2157-2161 (1985) and groups described in Hirokawa Shoten, 1990, “Iyakuhin no Kaihatsu”, vol. 7, Bunshi Shekkei pp. 163-198.
(Process)
The compounds and the pharmaceutically acceptable salts thereof according to the present invention can be produced by utilizing characteristics based on the basic structure or the types of the substituents and applying various known synthesis processes. Typical processes are described below. Some types of functional groups are substituted with appropriate protective groups, namely groups easily convertible to the very functional groups in the stage of starting materials or intermediates, which is sometimes effective in the production technique. Thereafter, protective groups are removed, as required, to be able to obtain the desired compounds. Examples of such functional groups can include a hydroxyl group, a carboxyl group, an amino group and the like. Examples of the protective groups can include protective groups described in, for example, Green and Wuts, “Protective Groups in Organic Synthesis (third edition)”. These may properly be used according to reaction conditions.




(wherein R7 represents a group represented by the foregoing formula (II) in which R11 is H, lower alkyl which may be substituted or cycloalkyl which may be substituted or represents a cyclic amino group which may be substituted; and R8 represents the foregoing group represented by R2 or R5; R9 represents the forgoing group represented by R3 or R6 or a group which is convertible to R3 or R6 by a method which can ordinarily be employed by a skilled person. This applies to the following.)

This process is a process for producing a compound, among the compounds of the present invention represented by formula (I) or (III), in which A is methylene, R1 and R2 (or R4 and R5) are not crosslinked, and R1 or R4 and A are not ring-closed.
(Step A)
This step is a step in which compound (1c) is produced by amidation of compound (1a) or its salt with compound (1b) or its reactive derivative in a usual manner and removing a protective group as required.
As the amidation in this step, amidation which can ordinarily be used by a skilled person is employable. Especially, a method in which phosphorus oxychloride is used in a pyridine solvent, and a method in which a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC.HCl), dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphorylazide or diethylphosphorylcyanide is used in the presence of 1-hydroxybenzotriazole (HOBt) are advantageously used.
The reaction varies with reactive derivatives or a condensing agent used. Usually, the reaction is conducted in an organic solvent inactive to the reaction under cooling, under cooling to room temperature or under room temperature to heating, examples of the organic solvent including halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ether and tetrahydrofuran (THF), esters such as ethyl acetate (EtOAc), acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like.
(Step B)
This step is a step in which compound (I) or (III) of the present invention is produced by introducing an aminomethyl group in the 5-position of thiazole of compound (1c) using a Mannich reaction with compound (1e). A method described in Altertson, N. F.; J Am Chem Soc 1948, 70, 669 or Bhargava, P. N.; Sharma, S. C.; Bull Chem Soc Jpn 1965, 38, 909. or a method corresponding thereto can be employed.
(Step C, Step D)
These steps are steps in which compound (I) or (III) of the present invention is produced by introducing an acetoxymethyl group in the 5-position of thiazole of compound (1c) and then conducting a nucleophilic substitution reaction with compound (1e) under a basic condition.
The acetoxymethylation in step C can be conducted under room temperature to heating or under room temperature to reflux by reacting compound (1c) with a formaldehyde aqueous solution or a p-formaldehyde in an acetic acid solvent. The reaction may be conducted by adding acetic acid in a solvent inactive to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons or ethers instead of an acetic acid solvent. In this case, a reactivity tends to be decreased. Further, the reaction may be conducted by addition of acetic anhydride.
The nucleophilic substitution reaction in step D can be conducted by reacting compound (1d) with compound (1e) in an organic solvent inactive to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF or DMSO in the presence of an organic base such as triethylamine or diisopropylethylamine and/or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate or sodium hydrogencarbonate. For acceleration of the reaction, a catalyst such as dimethylaminopyridine may be added. Instead of the organic base and/or the inorganic base, a larger amount of compound (1e) may be used. The reaction varies with the base used. It can be conducted under cooling to room temperature, under room temperature to heating or under room temperature to reflux.




(wherein X represents a leaving group such as halogen; Y represents lower alkyl; and n represents an integer of from 1 to 6. This applies to the following.)

This process is a process for producing a compound, among the compounds of the present invention represented by formula (I) or (III), in which A or B is lower alkylene except methylene, R1 and R2 or R4 and R are not crosslinked, and R1 and A or R4 and B are not ring-closed.
(Step A)
This step is a step in which compound (2c) is produced by condensing compound (2a) and compound (2b). A method described in HAND, E. S.; JOHNSON, S. C.; BAKER, D. C.; J Org Chem 1997, 62(5), 1348-1355 or a method corresponding thereto can be employed.
(Step B)
This step is a step in which the a-position of ketone in compound (2c) is halogenated and the compound is then reacted with thiourea to form a thiazole ring. A method described in Org. Syn. Coll. Vol. II, 1943, 32-32., and Maruzen, 1992, “Dai 4 han Jikken Kagaku Koza 19”, pp. 431-435, or a method corresponding thereto can be employed.
(Step C)
This step is a step in which compound (2d) or the carboxylic acid compound subjected to hydrolysis as required is amidated according to step A in the first process and the amide bond is then converted to an aminomethylene bond by a reduction reaction. A method described in Maruzen, 1992, “Dai 4 han Jikken Kagaku Koza 26”, pp. 227-228, or a method corresponding thereto can be employed.
(Step D)
This step is a step in which compound (I) or (III) of the present invention is produced by amidation of compound (2e) with compound (1b). The step can be conducted according to step A in the first process.




(wherein R12 represents the foregoing group. This applies to the following.)

This process is a process for producing a compound, among the compounds of the present invention represented by formula (I) or (III), in which R1 and R2 (or R4 and R5) are crosslinked by R11. R11 is present as methylene crosslinked on R2 or R5 when A or B is methylene and R1 or R4 is a group represented by formula (II) according to the foregoing definition.
(Step A)
This step is a step in which an aminomethyl group is introduced into the 5-position of thiazole of compound (1c) using a Mannich reaction with compound (1c) and phenyl or thienyl represented by R2 nucleophilically attacks iminium formed by the subsequent second-stage Mannich reaction to give a tricyclic compound, the compound of the present invention. The step can be conducted according to step B in the first process.




(wherein m represents an integer of from 1 to 6. This applies to the following.)

This process is a process for producing a compound, among the compounds of the present invention represented by formula (I) or (III), in which R1 and A (or R4 and B) are ring-closed by R11. R11 is present as lower alkylene which may be substituted and which is ring-closed on A or B when A or B is methylene and R1 or R4 is a group represented by formula (II) according to the foregoing definition.
(Step A)
This step can be conducted according to a method of. Van Tamelin, E. E.; Knapp, G. C.; J. Am. Chem. Soc., 77, 1860, 1955.
In the first to fourth processes, the next step can proceed by converting a group represented by R9 to R3 or R6 in an appropriate time of the foregoing step. As to the conversion method, for example, a method can be described in which in step A, 5,6-dichloropyridin-3-yl or 3,4,5-difluorophenyl is introduced as R9, and ipso substitution is conducted by a nucleophilic reaction in an appropriate time, for example, before step B, before step C or before step D in the first process to convert the group to R3 or R6, a partial structure of the compounds according to the present invention.
Further, some compounds represented by formula (I) or (III) may be produced from the compounds of the present invention which have been obtained in the foregoing manner by arbitrarily combining steps that can ordinarily be employed by a skilled person, such as known alkylation, acylation, substitution reaction, oxidation, reduction and hydrolysis.
The thus-produced compounds according to the present invention are isolated and purified either in free form or as salts thereof by undergoing salt-forming treatment in a usual manner. Isolation and purification are performed by ordinary chemical procedures such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various chromatographies.
Various isomers can be isolated in a usual manner by utilizing a difference in physicochemical properties between isomers. For example, a racemic mixture can be introduced into optically pure isomers by a general racemic compound resolution method, for example, a method in which the mixture is formed into a diastereomer salt with a general optically active acid such as tartaric acid to conduct optical resolution. A diastereo-mixture can be separated by, for example, fractional crystallization or various chromatographies. An optically active compound can be produced using an appropriate optically active starting material.
INDUSTRIAL APPLICABILITY
The compounds according to the present invention have an excellent platelet increasing function. Therefore, the compounds according to the present invention are useful for treating and/or preventing various thrombocytopenias such as thrombocytopenia in anemia and myelodysplastic syndrome, thrombocytopenia caused by chemotherapy and radiotherapy of malignant tumor, thrombocytopenia in idiopathic thrombocytopenic purpura, thrombocytopenia in hepatic diseases and thrombocytopenia caused by HIV. When there is a possibility of causing thrombocytopenia by chemotherapy or radiotherapy, previous administration is also possible before conducting these therapies.
Pharmacological functions of the compounds according to the present invention were confirmed by the following tests.
(i) Human c-mpl-Ba/F3 Cell Growth Test
In a 96-well microplate, 2×105 cells/ml of human c-mpl-Ba/F3 cells were cultured at 37° C. in 10% fetal bovine serum-containing RPMI1640 medium (100 μl/well) containing each test compound at each concentration. After 24 hours from the start-up of culture, 10 μl/well of WST-1/1-methoxy PMS (cell counting kit, Dojin) was added. Immediately after addition and 2 hours after addition, absorbance of A450/A650 was measured with a microplate reader (Model 3350: Bio-Rad), and an increase in absorbance for 2 hours was defined as a growth activity of each test compound. The results are shown in Table 1.
Symbols in the table have the following meanings.
pot: Concentration of each test compound at which to accelerate cell growth by 30% of a maximum cell growth activity of compound A (compound A and rhTPO in rhTPO)
Efficacy: Maximum cell growth activity of each test compound when a maximum cell growth activity of compound A (compound A and rhTPO in rhTPO) is defined as 100%.
Compound A refers to a compound in Example 9 of the foregoing Patent Document 10.







TABLE 1







Human c-mpl-Ba/F3 cell growth activity











Test Compound
Pot [nM]
Efficacy [%]















Example 65
4.3
114



Example 71
2.0
110



Example 84
4.2
103



Example 85
3.3
107



Example 90
2.0
94



Example 100
2.9
117



Example 101
3.1
108



Example 104
3.5
105



Example 106
2.1
112



Example 107
1.5
112



Example 109
3.9
95



Example 111
6.0
87



Example 150
3.6
102



Example 151
8.4
99



Example 153
6.1
99



Example 222
4.4
102



Example 226
4.6
88



Example 227
3.2
88



Example 315
3.2
98



Comparative Compound 1
4.4
101



Comparative Compound 2
2.1
96



Comparative Compound 3
6.9
96



Comparative Compound 4
251
95



Compound A
10
87



rhTPO
0.012
100










In the table, Comparative Compound 1 is a compound of Compound No. A-1 in the foregoing Patent Document 7; Comparative Compound 2 is a compound of Compound No. A-14 in the foregoing Patent Document 8; Comparative Compound 3 is a compound of Compound No. J-14 in the foregoing Patent Document 8; and Comparative Compound 4 is a compound in Example 2 of the foregoing Patent Document 9. Structures of Comparative Compounds 1 to 4 and Compound A are shown below.




From the foregoing results, the compounds of the present invention have been confirmed to have the Ba/F3 cell growth function mediated by human c-Mpl.
(ii) Test for Measuring a Function of Accelerating Formation of Megakaryocytic Colonies
Human CD34+ cells were cultured in a 2-well chamber slide in the presence of a test product at 37° C. for from 10 to 14 days using MegaCultTM-C (StemCell Technologies). After dehydration and fixation were conducted according to the attached manual, dying was conducted with an anti-glycoprotein IIb/IIIa antibody. The number of colonies for 1 well was counted by a microscope on condition that a population of 3 or more dyed megakaryocytes was one colony. An EC30 value of each test compound was calculated from a dose curve.
Consequently, with respect to the EC30 value of the compounds of the present invention, the compound in Example 71 is 20 nM, the compound in Example 100 34 nM, the compound in Example 104 36 nM, the compound in Example 106 23 nM, and the compound in Example 315 45 nM. It has been confirmed that the compounds of the present invention have the excellent function of accelerating formation of megakaryocytic colonies.
(iii) Mouse Oral Administration Test
3 mg/kg or 10 mg/kg (100 mg/kg in Comparative Compounds 1 to 3) of a test compound dissolved or suspended in a 0.5% methylcellulose aqueous solution was orally administered to a male ICR mouse. After 2 hours from administration, a blood was sampled from the subabdominal large vein using 1/10-volume 3.8% sodium citrate as an anticoagulant. Centrifugation was performed at 12,000 rpm for 3 minutes. The resulting plasma was heated at 56° C. for 30 minutes, and added to a system of the human c-mpl-Ba/F3 cell growth test described in (i) such that the final concentration of the plasma reached 0.3%, 1% or 3% (10% in Comparative Compounds 1 to 3) to measure a cell growth activity. The cell growth activity (%) of each plasma was measured when the maximum cell growth activity of each test compound was defined as 100%.







TABLE 2







Human c-mpl-Ba/F3 cell growth activity


of a plasma after oral administration












Test
Dose
Dilution
Cell growth



Compound
[mg/kg p.o.]
rate [%]
activity[%]
















Example 65
3
3
≧80



Example 71
3
3
≧80



Example 84
3
1
≧80



Example 85
3
1
≧80



Example 90
3
0.3
≧80



Example 100
3
3
≧80



Example 101
3
1
76



Example 104
3
1
63



Example 106
3
1
63



Example 109
3
1
59



Example 150
3
0.3
28



Example 151
10
3
24



Example 153
10
3
29



Example 314
3
3
52



Comparative
100
10
<10



Compound 1



Comparative
100
10
<10



Compound 2



Comparative
100
10
<10



Compound 3










Comparative Compounds 1 to 3 in the table are the same as Comparative Compounds 1 to 3 in the foregoing Table 1 respectively.
From the foregoing results, it has been confirmed that the compounds of the present invention have an oral activity in mice. Especially, it has been found that in the comparative compounds, the oral activity is little shown even “under a condition of 100 mg/kg—10% dilution”, whereas in the compounds of the present invention, the good oral activity is exhibited even “under a condition of a lower dose of 3 mg/kg or 10 mg/kg—higher dilution of 3% or less”. This is quite unexpected, and is considered to have been achieved by introduction of lower alkylene having an amino group as a substituent in the 5-position of thiazole. In Comparative Compound 2 and Comparative Compound 3, the cell growth activity has been less than 10% also in the lower dose (10 mg/kg p.o.).
It has been confirmed that a platelet increasing activity is observed by administering the compound of the present invention to a mouse in which human platelet production has been identified after transplantation of human hematopoietic stem cells.
The medication of the present invention can be prepared by an ordinary method using at least one of the compounds represented by formula (I) or (III) according to the present invention as well as a carrier, an excipient and other additives for use in drugs which are commonly used in formulation. The administration may be any of oral administration with tablets, pills, capsules, granules, powders, liquid preparations or the like and parenteral administration with injections such as intravenous injection and intramuscular injection, administration with suppositories, transnasal administration, permucosal administration or percutaneous administration.
As a solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, one or more active substances are mixed with at least one inactive diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or magnesium aluminate metasilicate. The composition may contain, according to a usual method, additives other than an inactive diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calmellose calcium, a stabilizer and a solubilizer. Tablets or pills may be coated, as required, with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate, or a gastric or enteric film.
A liquid composition for oral administration contains an emulsifying agent, a liquor, a suspending agent, a syrup, an elixir and the like which are pharmaceutically acceptable, and an inactive diluent which is generally used, such as purified water or ethanol (EtOH). This composition may contain, in addition to the inactive diluent, aids such as a wetting agent and a suspending agent, a sweetener, a flavor, an aromatic and a preservative.
An injection for parenteral administration contains a liquor and a suspending agent which are sterile and aqueous or non-aqueous and an emulsifying agent. Examples of the aqueous liquor and suspending agent include distilled water for injection and a physiological saline solution. Examples of the non-aqueous liquor and suspending agent include vegetable oils such as propylene glycol, polyethylene glycol and olive oil, alcohols such as EtOH, polysorbate 80 and the like. Such a composition may further contain aids such as a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizer and a solubilizing agent. These are sterilized by filtration through a bacteria holding filter, incorporation of a disinfectant or irradiation. Further, these may be formed into a sterile solid composition which is used by being dissolved in sterile water or a sterile solvent for injection before use.
In case of oral administration, a dose for one day is generally from approximately 0.0001 to 50 mg/kg, preferably from approximately 0.001 to 10 mg/kg, more preferably from 0.01 to 1 mg/kg per body weight. This is administered either once or in divided portions, from 2 to 4 times. In case of intravenous administration, a dose for one day is from approximately 0.0001 to 1 mg/kg, preferably from approximately 0.0001 to 0.1 mg/kg. This is administered either once or plural times per day. The dose is properly determined according to each case in consideration of the condition, the age, the sex and the like of patients.


BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is specifically described below by referring to Examples. However, the invention is not limited at all by these Examples. Starting compounds used in Examples include novel substances, and processes for producing such starting compounds from known products are described as Reference Examples.
REFERENCE EXAMPLE 1
Potassium carbonate and allyl bromide were added to a DMF solution of 3,4,5-trifluorobenzoic acid, and the mixture was stirred overnight to obtain a crude allyl ester. Potassium carbonate was added to a DMF solution of the crude allyl ester and ethyl isonipecotate, and the mixture was stirred overnight at room temperature to obtain a piperidine substitution product. Morpholine and tetrakis(triphenylphosphine)palladium (catalytic amount) were added to a THF solution of the piperidine substitution product, and the mixture was stirred at 60° C. for 2 hours and at room temperature for 4 days. After the solvent was distilled off, ether and EtOAc were added, and the mixture was washed 10 times with an saturated sodium hydrogencarbonate aqueous solution. Conc. hydrochloric acid was added to the collected aqueous layer, and the resulting precipitate was collected by filtration to obtain 4-[4-(ethoxycarbonyl)piperidin-1-yl]-3,5-difluorobenzoic acid.
REFERENCE EXAMPLE 2
Potassium carbonate and 3-(tert-butyldimethylsilyloxy)propyl bromide were added to a DMF solution of ethyl 3-chloro-5-fluoro-4-hydroxybenzoate, and the mixture was stirred at 50° C. to obtain ethyl 4-[3-(tert-butyldimethylsilyloxy)propoxy]-3-chloro-5-fluorobenzoate.
Compounds in Reference Examples 3 and 4 shown in Table 3 were produced in the same manner as in Reference Example 2 using the corresponding starting materials respectively.
REFERENCE EXAMPLE 5
Anhydrous piperazine was added to a THF solution of methyl 3,4-difluorobenzoate, and the mixture was stirred at 60° C. for 18 hours to obtain methyl 3-fluoro-4-piperazin-1-ylbenzoate.
REFERENCE EXAMPLE 6
Di-tert-butyl dicarbonate and 4-dimethylaminopyridine were added to a 1,2-dichloroethane solution of the compound in Reference Example 5, and the mixture was stirred at room temperature for 10 minutes to obtain tert-butyl 4-[2-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate.
REFERENCE EXAMPLE 7
N-chlorosuccinimide was added to a DMF solution of the compound in Reference Example 6, and the mixture was stirred at room temperature for 3 hours to obtain tert-butyl 4-[2-chloro-6-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate.
REFERENCE EXAMPLE 8
A 1M NaOH aqueous solution (aq) was added to an MeOH-THF mixed solution of the compound in Reference Example 2, and the mixture was stirred at room temperature for 16 hours to obtain 4-[3-(tert-butyldimethylsilyloxy)propoxy]-3-chloro-5-fluorobenzoic acid.
Compounds in Reference Examples 9 to 11 shown in Table 3 were produced in the same manner as in Reference Example 8 using the corresponding starting materials respectively.
REFERENCE EXAMPLE 12
Thionyl chloride was added to an MeOH solution of the compound in Reference Example 11, and the mixture was stirred at room temperature for 22 hours to obtain 4-[3-(methoxycarbonyl)propoxy]-3-fluorobenzoic acid.
Symbols in the table have the following meanings (this applies to the following).
Rf: Reference Example No.
Data: Physical data (MS:FAB-MS(M+H)+; MN:FAB-MS(M−H)−; MM:FAB-MS(M)+),
R, R1, R2, R3, R4, X, Y: Substituents in the general formulas (Me: methyl, Et: ethyl, iPr: isopropyl, cPr: cyclopropyl, nBu: normal butyl, iBu: isobutyl, tBu: tertiary butyl, Ph: phenyl, Py: pyridyl, Boc: tert-butyloxycarbonyl, The:thienyl, azet: azetidin-1-yl, pyrr: pyrrolidin-1-yl, pipe: piperidin-1-yl, pipa: piperazin-1-yl, mor: morpholin-4-yl, TBS: tertiary butyldimethylsilyl, di:di. The number before the substituent indicates a substitution position. Accordingly, for example, 3,5-diF-4-(4-EtO2C-pipe)Ph refers to 3,5-difluoro-4-(4-ethoxycarbonylpiperidin-1-yl)phenyl, and 4-Me-2-The refers to 4-methylthiophen-2-yl).







TABLE 3













 









Rf
R1, R2, R3, R
Data















1
R1 = F,
R2 = 4-EtO2C-pipe,
R3 = F,
R = H
MS; 314.


2
R1 = Cl,
R2 = TBSO(CH3)3O—,
R3 = F,
R = Et
MS; 391.


3
R1 =
R2 = TBSO(CH2)2O—,
R3 = H,
R = Et
MS; 355.



OMe,


4
R1 = F,
R2 = EtO2C(CH2)3O—,
R3 = H,
R = Me
MS; 285.


5
R1 = F,
R2 = pipa,
R3 = H,
R = Me
MS; 239.


6
R1 = F,
R2 = 4-Boc-pipa,
R3 = H,
R = Me
MS; 339.


7
R1 = Cl,
R2 = 4-Boc-pipa,
R3 = F,
R = Me
MS; 373.


8
R1 = Cl,
R2 = TBSO(CH2)3O—,
R3 = F,
R = H
MS; 363.


9
R1 = Cl,
R2 = 4-Boc-pipa,
R3 = F,
R = H
MS; 359.


10
R1 =
R2 = TBSO(CH2)2O—,
R3 = H,
R = H
MS; 327.



OMe,


11
R1 = F,
R2 = HO2C(CH2)3O—,
R3 = H,
R = H
MN; 241.


12
R1 = F,
R2 = MeO2C(CH2)3O—,
R3 = H,
R = H
MS; 257.









REFERENCE EXAMPLE 13
Bromine was added to an ether solution of 4-chloro-2-acetylthiophene under ice cooling, and the mixture was stirred at room temperature for 2 hours to obtain a brominated compound. Thiourea was added to an EtOH solution of the brominated compound at room temperature, and the mixture was stirred overnight at 80° C. to obtain 2-amino-4-(4-chlorothiophen-2-yl)thiazole.
A compound in Reference Example 14 shown in Table 4 was obtained in the same manner as in Reference Example 13 using the corresponding starting material.







TABLE 4













 









Rf
R
Data





13
Cl
MS; 217.


14
Me
MS; 197.









REFERENCE EXAMPLE 15
Phosphorus oxychloride was added to a pyridine suspension of the compound in Reference Example 13 and 5,6-dichloronicotinic acid. The temperature was gradually raised, and the mixture was stirred overnight at room temperature to obtain 5,6-dichloro-N-[4-(4-chlorothiophen-2-yl)thiazol-2-yl]nicotinamide.
Compounds in Reference Examples 16 to 22 shown in Table 5 were produced in the same manner as in Reference Example 15 using the corresponding starting materials.







TABLE 5













 









Rf
R
Data





15
5,6-diCl-3-Py
MS; 390.


16
2-MeO-4-Py
MS; 352.


17
3,5-diF-4-(4-EtO2C-pipe)Ph
MS; 512.


18
3-Cl-5-F-4-TBSO(CH2)3O—Ph
MS; 561.


19
3-Cl-5-F-4-(4-Boc-pipa)Ph
MS; 557.


20
3-Cl-4-MeOCH2O—Ph
MS; 415.


21
3-MeO-4-TBSO(CH2)2O—Ph
MS; 624.


22
3-F-4-MeO2C(CH2)3O—Ph
MS; 455.









REFERENCE EXAMPLE 23
Pyridine, triethylamine and ethyl isonipecotate were added to the compound in Reference Example 15, and the mixture was stirred at 70° C. for 16 hours to obtain ethyl 1-(3-chloro-5-{[4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylate.
Compounds in Reference Examples 24 to 31 shown in Table 6 were produced in the same manner as in Reference Example 23 using the corresponding starting materials respectively.







TABLE 6













 









Rf
R
Data





23
4-EtO2C-pipe
MS; 511.


24
3-EtO2C-pipe
MS; 511.


25
3-MeO2C-pyrr
MS; 483.


26
(R)-3-MeO2CCH2O-pyrr
MS; 513.


27
4-EtO2CCH2-pipe
MS; 525.


28
2-EtO2C-mor
MS; 513.


29
(S)-3-MeO2C-pyrr
MS; 483.


30
3-EtO2C-azet
MS; 483.


31
4-tBuO2CCH2O-pipe
MS; 569.









REFERENCE EXAMPLE 32
Acetic acid and a formaldehyde aqueous solution (36%) were added to the compound in Reference Example 23, and the mixture was stirred overnight at 100° C. to obtain ethyl 1-(5-acetoxymethyl-4-(4-chlorothiophen-2-yl)thiazol-2-yl)carbamoyl)-3-chloro-2-pyridyl)piperidine-4-carboxylate.
A compound in Reference Example 33 shown in Table 7 was produced in the same manner as in Reference Example 32 using the corresponding starting material.







TABLE 7













 









Rf
X, Y
Data





32
X = N, Y = C—Cl
MS; 583.


33
X = C—F, Y = C—F
MS; 584.









Compounds in Reference Examples 34 and 35 shown in Table 8 were produced in the same manner as in Example 1 to be described later using the corresponding starting materials respectively.







TABLE 8













 









Rf
R
Data





34
pipe
MS; 487.


35
nBuN(Me)
MS; 489.









REFERENCE EXAMPLE 36
A 4M HCl-EtOAc solution was added to a chloroform-EtOH mixed solution of the compound in Reference Example 19 under ice cooling, and the mixture was stirred at room temperature for 17 hours to obtain 3-chloro-N-[4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-fluoro-4-piperazin-1-ylbenzamide hydrochloride.
REFERENCE EXAMPLE 37
Potassium carbonate and ethyl bromoacetate were added to a DMF solution of the compound in Reference Example 36, and the mixture was stirred at room temperature for 23 hours to obtain ethyl [4-(2-chloro-4-{[4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-6-fluorophenyl)piperazin-1-yl]acetate.







TABLE 9













 









Rf
R
Data





36
H
MS; 457.


37
EtO2CCH2
MS; 543.









REFERENCE EXAMPLE 38
Phosphorus oxychloride was added to a pyridine suspension of 2-amino-4-[3-(trifluoromethyl)phenyl]thiazole and 5,6-dichloronicotinic acid at −30° C. The temperature was gradually raised, and the mixture was stirred overnight at room temperature. After the solvent was distilled off under reduced pressure, pyridine and EtOH were added, and the mixture was stirred at 50° C. for 30 minutes. Triethylamine and ethyl isonipecotate were added at room temperature, and the solution was stirred at 80° C. for 15 hours to obtain ethyl 1-[3-chloro-5-({4-[3-trifluoromethyl)phenyl]thiaozl-2-yl}carbamoyl)-2-pyridyl]piperidine-4-carboxylate.
Compounds in Reference Examples 39 and 40 shown in Table 10 were produced in the same manner as in Reference Example 38 using the corresponding starting materials respectively.







TABLE 10













 









Rf
R
Data





38
3-F3C—Ph
MS; 539.


39
4-F—Ph
MS; 489.


40
4-Me-2-The
MS; 491.









The compound in Reference Example 41 shown in Table 11 was produced in the same manner as in Reference Example 8, and the compound in Reference Example 42 in the same manner as in Example 8 to be described later, using the corresponding starting materials respectively.







TABLE 11













 









Rf
R
Data





41
HO
MS; 483.


42
MeO2CCH2NH
MS; 554.









REFERENCE EXAMPLE 43
Phenyl chloroformate and pyridine were added to a THF solution of the compound in Reference Example 13, and the mixture was stirred at room temperature for 1.5 hours to obtain phenyl N-[4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamate.
REFERENCE EXAMPLE 44
A mixture of ethyl N-(piperidin-4-yl)isonipecotate hydrochloride and isopropyl N-(piperidin-4-yl)isonipecotate and triethylamine were added to a DMF solution of the compound in Reference Example 43, and the mixture was stirred at 80° C. for 12 hours to obtain an ester mixture. The ester mixture was dissolved in MeOH, and triethylamine and sodium ethoxide were added. The solution was stirred at from room temperature to 50° C. for 18 hours to obtain methyl 1′-{[4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-1,4′-bipiperidine-4-carboxylate.







TABLE 12













 









Rf
R
Data





43
PhO
MS; 337.


44
4-(4-MeO2C-pipe)pipe
MS; 469.









REFERENCE EXAMPLE 45
The compound in Reference Example 45 shown in Table 13 was produced in the same manner as in Reference Example 13 using 4-(4-chlorothiophen-2-yl)-4-oxobutanoic acid ester (methyl ester:ethyl ester 3:2 mixture) as a starting material.
REFERENCE EXAMPLE 46
A compound in Reference Example 46 shown in Table 13 was produced in the same manner as in Reference Example 8 using the corresponding starting material.
REFERENCE EXAMPLE 47
Butylmethylamine, WSC.HCl, HOBt and triethylamine were added to a DMF solution of the compound in Reference Example 46, and the mixture was stirred at room temperature for 18 hours to obtain N-butyl-N-methyl-[2-amino-4-(4-chlorothiophen-2-yl)thiazol-5-yl]acetamide.
REFERENCE EXAMPLE 48
A THF solution of the compound in Reference Example 47 was added to a THF suspension of lithium aluminum hydride, and the mixture was stirred under reflux for 3 hours to obtain 2-amino-5-{2-[butyl(methyl)amino]ethyl}-4-(4-chlorothiophen-2-yl)thiazole.
REFERENCE EXAMPLE 49
A compound in Reference Example 49 shown in Table 13 was produced in the same manner as in Reference Example 15 using the corresponding starting material.







TABLE 13













 









Rf
R1, R2
Data





45
R1 = RO2CCH2(R; Me:Et = 3:2), R2 = H
GC-MS; 288,




302.


46
R1 = HO2CCH2, R2 = H
MS; 275.


47
R1 = nBuN(Me)COCH2, R2 = H
MS; 344.


48
R1 = nBuN(Me)(CH2)2, R2 = H
MS; 330.


49
R1 = nBuN(Me)(CH2)2, R2 = 5,6-diCl-3-Py-CO—
MN; 501, 503.









REFERENCE EXAMPLE 50
Ethyl isonipecotate was added to a DMF solution of 2,6-dichloro-5-fluoronicotinic acid, and the mixture was stirred at 80° C. to obtain 2-chloro-6-[4-(ethoxycarbonyl)piperidin-1-yl]-5-fluoronicotinic acid.
REFERENCE EXAMPLE 51
Triethylamine and 10% palladium supported on carbon were added to a THF-EtOH solution of the compound in Reference Example 50, and the mixture was stirred at room temperature in a 4-atm hydrogen atmosphere to obtain 6-[4-(ethoxycarbonyl)piperidin-1-yl]-5-fluoronicotinic acid.







TABLE 14













 











Rf
R
Data







50
Cl
MS; 331.



51
H
MS; 297.










Compounds in Reference Examples 52 and 53 shown in Table 15 were produced in the same manner as in Example 3 to be described later, compounds in Reference Examples 54 to 56 shown in Table 15 in the same manner as in Reference Example 15 and compounds in Reference Examples 57 to 64 shown in Table 15 in the same manner as in Example 1 to be described later, using the corresponding starting materials respectively.







TABLE 15













 











Rf
R1
R2
R3
Data





52
H
4-Cl-2-The
5-Cl-6-(MeO2C(CH2)2N(Me))-3-Py
MN; 471.


53
H
4-Cl-2-The
5-Cl-6-(MeO2C(CH2)3N(Me))-3-Py
MN; 483.


54
H
4-Cl-2-The
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 495.


55
H
4-Cl-2-The
3-F3C-4-Me-Ph
MS; 403.


56
H
4-Me-2-The
5,6-diCl-3-Py
MS; 370.


57
iPrN(Me)—
4-Cl-2-The
5,6-diCl-3-Py
MS; 475, 477.


58
iBuN(Me)—
4-Cl-2-The
5,6-diCl-3-Py
MS; 491.


59
2-Me-pyrr—
4-Cl-2-The
5,6-diCl-3-Py
MS; 487.


60
(S)-2-Me-pyrr—
4-Cl-2-The
5,6-diCl-3-Py
MS; 487.


61
(R)-2-Me-pyrr—
4-Cl-2-The
5,6-diCl-3-Py
MS; 487.


62
iBuN(Me)—
4-Me-2-The
5,6-diCl-3-Py
MS; 469.


63
cBuCH2N(Me)—
4-Me-2-The
5,6-diCl-3-Py
MS; 481.


64
2-Me-pyrr—
4-Me-2-The
5,6-diCl-3-Py
MS; 467.









EXAMPLE 1
3 ml of acetic acid, 24 μl of a formaldehyde aqueous solution (36%) and 47 μl of N-butyl-N-methylamine were added to 150 mg of ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 90° C. for 18 hours. After the solvent was distilled off under reduced pressure, a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using hexane:EtOAc (7:1 to 5:1) as an elution solvent to obtain 147 mg of ethyl 1-(5-{[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate.
EXAMPLE 2
39 μl of N-(2-methoxyethyl)methylamine, 51 μl of triethylamine and 23 mg of 4-(dimethylamino)pyridine were added to a 6 ml EtOH suspension of 107 mg of ethyl 1-(5-{[5-[(acetoxy)methyl]-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 50° C. for 2 hours. After the solvent was distilled off, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with EtOAc, and washed with water and with brine(saturated sodium chloride aqueous solution). The resulting product was dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a hexane:EtOAc (10:1 to 3.5:1) as an elution solvent to obtain 90 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
EXAMPLE 3
110 μl of a formaldehyde aqueous solution (35%) and 76 μl of acetic acid were added to 2 ml of 1.2-dichloroethane solution of 79 mg of ethyl 1-[3-chloro-5-({4-(4-chlorothiophen-2-yl)-5-[(cyclobutylamino)methyl]thiazol-2-yl}carbamoyl)-2-pyridyl]piperidine-4-carboxylate, and the mixture was stirred at room temperature for 1 hour. Subsequently, 45 mg of NaBH(OAc)3 was added, and the solution was stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane:EtOAc=4:1 to 2:1) to obtain 58 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
EXAMPLE 4
1.3 ml of ethyl isonipecotate was added to a 5 ml THF solution of 413 mg of 5,6-dichloro-N-[4-(4-chlorothiophen-2-yl)-5-(piperidin-1-ylmethyl)-1,3-thiazol-2-yl]nicotinamide, and the mixture was stirred for 5 days. After the solvent was distilled off under reduced pressure, a saturated sodium hydrogencarbonate aqueous solution was added, and the resulting precipitate was collected by filtration. The precipitate was dissolved in chloroform, and a saturated sodium hydrogencarbonate aqueous solution was added. The mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using hexane:EtOAc (4:1 to 3:1) as an elution solvent to obtain 468 mg of ethyl 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(piperidinomethyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylate.
EXAMPLE 5
0.4 ml of a 1M sodium hydroxide aqueous solution was added to a 1.5 ml EtOH suspension of 76 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate, and the mixture was stirred at 60° C. for 2 hours. 0.6 ml of 1M hydrochloric acid and 0.5 ml of water were added at room temperature, and the resulting precipitate was collected by filtration, washed with 50% ethanol water, and dried under reduced pressure to obtain 73 mg of 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid hydrochloride.
EXAMPLE 6
19 mg of sodium boron hydride was added to a 5 ml THF solution of 128 mg of ethyl [4-(5-{5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)-2-oxopiperazin-1-yl]acetate, and the mixture was refluxed with stirring. A solution of 128 mg of MeOH in 2 ml of THF was slowly added thereto dropwise, and the mixture was stirred under reflux for 1 hour. The reaction solution was ice-cooled, and water was then added. The solution was extracted with chloroform, washed with brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography using chloroform:MeOH (99:1 to 98:2) as an elution solvent. The resulting crude product was suspended in methanol, and insoluble matters were removed by filtration. Then, the solvent was distilled off under reduced pressure. The thus-obtained residue was dissolved in EtOAc, and a 4M HCl-EtOAc solution was added, followed by stirring. The resulting precipitate was then collected by filtration, and dried under reduced pressure to obtain 15 mg of N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[4-(2-hydroxyethyl)-3-oxopiperazin-1-yl]nicotinamide hydrochloride.
EXAMPLE 7
40 mg of the compound in Example 132 was dissolved in 6 ml of MeOH, and 1.6 ml of conc. hydrochloric acid was added, followed by stirring for 2 hours. Then, concentration was conducted, and the precipitate was filtered, and washed with EtOAc to obtain 32 mg of N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-4-(2-hydroxymethoxy)-3-methoxybenzamide hydrochloride.
EXAMPLE 8
30 μl of triethylamine, 30 μl of morpholine, 45 mg of WSC.HCl and 30 mg of HOBt were added to 2 ml of a THF solution of 52 mg of 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid hydrochloride, and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction solution. The organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform:MeOH=100:1 to 50:1, hexane:EtOAc=2:1, then chloroform:MeOH=20:1), and suspended in 2 ml of diethyl ether. 2 ml of 4M HCl-EtOAc was added, and the precipitate was collected by filtration to obtain 25 mg of 5-chloro-N-(4-(4-chlorothiophen-2-yl)-5-{[(3-methoxypropyl)(methyl)amino]methyl}thiazol-2-yl)-6-[4-(morpholinocarbonyl)piperidino]nicotinamide hydrochloride.
EXAMPLE 9
3 ml of a 4M HCl-dioxane solution was added to 188 mg of the compound in Example 190, and the mixture was stirred at 50° C. for 18 hours. The reaction solution was cooled at room temperature, and the solid precipitated was then filtered to obtain 160 mg of [(1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}-4-piperidyl)oxy]acetic acid hydrochloride.
EXAMPLE 10
200 mg of the compound in Reference Example 23 was dissolved in 5 ml of formic acid, and 37 μl of methoxyethylamine and 92 μl of a formaldehyde aqueous solution (35%) were added, followed by stirring at 70° C. for 15 hours. After the reaction solution was concentrated, chloroform was added, and the organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with brine, followed by drying over sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane:EtOAc=5:1 to 3:1) to obtain 110 mg of ethyl 1-{3-chloro-5-{[7-chloro-5-(2-methoxyethyl)-5,6-dihydro-4H-thiazolo[5,4-c]thieno[2,3-e]azepin-2-yl]carbamoyl}-2-pyridine}-4-carboxylate.
EXAMPLE 11
100 mg of 6-[(2-aminoethyl)amino]-N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloronicotinamide trihydrochloride was suspended in 5 ml of THF, and 85 μl of triethylamine was added, followed by cooling to 0° C. 13 μl of methanesulfonyl chloride was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water, and extracted with chloroform. The organic layer was washed with water and with brine, and then dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (chloroform:MeOH =10:1) to obtain 75 mg of N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-({2-[(methylsulfonyl)amino]ethyl}amino)nicotinamide.
The structures and the physical data of the compounds in Examples are shown in Tables 16 to 26 below. Symbols in the tables have the following meanings (this applies to the following).
Ex: Example No. (When only a numeral is shown in column Ex., it is indicated that the compound in this Example No. is a free compound, and when a slash “/” and “HCl” are described next to a numeral, it is indicated that the compound in this Example No. was hydrochloride.)
Syn: Process (A numeral indicates that a compound was synthesized in the same manner as the compound in Example to which the numeral is allotted as Example No., using the corresponding starting material.)
R: Substituent in the general formula (nPr: normal propyl, cBu: cyclobutyl, cHex: cyclohexyl, MOM: methoxymethyl, Ac: acetyl, Ms: methanesulfonyl, THF: tetrahydrofuryl, THP: tetrahydropyranyl)







TABLE 16













 












Ex
Syn
R
Data
















1
1
nBuN(Me)—
MS; 610.



2
2
MeO(CH2)2N(Me)—
MS; 612.



3
3
cBuN(Me)—
MS; 608.



4
4
pipe-
MS; 608.



12
1
Me2N—
MS; 568.



13
1
pyrr-
MS; 594.



14
1
mor-
MS; 610.



15
1
4-Me-pipa-
MS; 623.



16
1
4-cHex-pipa-
MS; 691.



17
1
Et2N—
MS; 650.



18
1
EtO(CH2)2N(Me)—
MS; 626.



19
1
(2-THF)CH2N(Me)—
MS; 638.



20
1
nPrO(CH2)2N(Me)—
MS; 640.



21
1
EtO(CH2)2N(Et)—
MS; 640.



22
1
iPrO(CH2)2N(Me)—
MS; 640.



23
1
4-(3-F-pyrr)pipe-
MS; 694.



24
1
MeO(CH2)3N(Me)—
MS; 625.



25
1
MeO(CH2)2N(Et)—
MS; 626



26
1
(2S,6R)-2,6-diMe-mor-
MS; 638



27
1
4-EtO2C-pipe-
MN; 678.



28
1
iPrN(Me)—
MS; 596.



29
1
2-Me-pyrr-
MS; 608.



30
1
(S)-2-Me-pyrr-
MS; 608.



31
1
(R)-2-Me-pyrr-
MS; 608.



32
1
(R)-3-Me-pyrr-
MS; 608.



33
1
(S)-3-Me-pyrr-
MS; 608.



34
1
3-EtO-pyrr-
MS; 638.



35
1
4-MeO-pipe-
MS; 638.



36
1
3-MeO-pipe-
MS; 638.



37
1
(S)-2-MeOCH2-pyrr-
MS; 638.



38
1
(R)-2-MeOCH2-pyrr-
MS; 638.



39
2
(R)-MeOCH2CH(Me)N(Me)
MS; 626.



40
2
(S)-MeOCH2CH(Me)N(Me)
MS; 626.



41
2
azet-
MS; 580.



42
2
Azepan-1-yl
MS; 622.



43
2
Azocan-1-yl
MS; 636.



44
2
Azonan-1-yl
MS; 650.



45
2
Azecan-1-yl
MS; 664.



46
2
(2R,6S)-2,6-diMe-pipe
MS; 636.



47
2
Me2N(CH2)2N(Me)—
MS; 625.



48
2
cHexN(Me)—
MS; 636.



49
2
MeO(CH2)2NH—
MS; 597.



50
2
cPrNH—
MS; 580.



51
2
cBuNH—
MS; 594.



52
2
cHexNH—
MS; 622.



53
2
iPrNH—
MS; 582.



54
2
tBuNH—
MS; 596.



55
2
(4-THP)NH—
MS; 624.



56
2
(3-THF)NH—
MS; 610.



57
2
MeOCH2CH(Me)NH—
MS; 612.



58
3
(4-THP)N(Me)—
MS; 638.



59
3
(3-THF)N(Me)—
MS; 624.



60
3
MeOCH2CH(Me)N(Me)—
MS; 626.



61
3
cPrN(Me)—
MS; 594.



62
3
iBuN(Me)—
MS; 610.



63
10
(R)-(MeO)(Me)CHCH2N(Me)—
MS; 626.



64
10
(S)-(MeO)(Me)CHCH2N(Me)—
MS; 626.

















TABLE 17













 










Ex
Syn
R
Data





5/HCl
5
MeO(CH2)2N(Me)—
MS; 584.


65/HCl
5
Me2N—
MS; 540.


66/HCl
5
pyrr-
MS; 566.


67/HCl
5
mor-
MN; 580.


68/HCl
5
4-Me-pipa-
MS; 595.


69/HCl
5
4-cHex-pipa-
MS; 663.


70/HCl
5
Et2N—
MS; 568.


71/HCl
5
nBuN(Me)—
MS; 582.


72/HCl
5
EtO(CH2)2N(Me)—
MS; 598.


73/HCl
5
(2-THF)CH2N(Me)—
MS; 610.


74/HCl
5
nPrO(CH2)2N(Me)—
MS; 612.


75/HCl
5
EtO(CH2)2N(Et)—
MS; 612.


76/HCl
5
iPrO(CH2)2N(Me)—
MS; 612.


77/HCl
5
4-(3-F-pyrr)pipe-
MS; 667.


78/HCl
5
MeO(CH2)3N(Me)—
MN; 596.


79/HCl
5
MeO(CH2)2N(Et)—
MS; 598.


80
5
(2S,6R)-2,6-diMe-mor-
MN; 608.


81/HCl
5
(R)-MeOCH2CH(Me)N(Me)—
MS; 598.


82/HCl
5
(S)-MeOCH2CH(Me)N(Me)—
MS; 598.


83/HCl
5
azet-
MS; 552.


84/HCl
5
Azepan-1-yl
MS; 594.


85/HCl
5
Azocan-1-yl
MS; 608.


86/HCl
5
Azonan-1-yl
MS; 622.


87/HCl
5
Azecan-1-yl
MS; 636.


88/HCl
5
(2R,6S)-2,6-diMe-pipe-
MS; 608.


89/HCl
5
Me2N(CH2)2N(Me)—
MS; 597.


90/HCl
5
cHexN(Me)—
MS; 608.


91/HCl
5
MeO(CH2)2NH—
MS; 569.


92/HCl
5
cPrNH—
MN; 550.


93/HCl
5
cBuNH—
MN; 564.


94/HCl
5
cHex-NH—
MN; 592.


95/HCl
5
iPrNH—
MN; 552.


96/HCl
5
tBuNH—
MN; 566.


97/HCl
5
(4-THP)N(Me)—
MS; 610.


98/HCl
5
(3-THF)N(Me)—
MS; 596.


99/HCl
5
MeOCH2CH(Me)N(Me)—
MS; 598.


100/HCl
5
cBuN(Me)—
MS; 580.


101/HCl
5
cPrN(Me)—
MS; 566.


102/HCl
5
pipe-
MN; 578.


103/HCl
5
iBuN(Me)—
MS; 582.


104/HCl
5
iPrN(Me)—
MS; 568.


105/HCl
5
2-Me-pyrr-
MS; 580.


106/HCl
5
(S)-2-Me-pyrr-
MS; 580.


107/HCl
5
(R)-2-Me-pyrr-
MS; 580.


108/HCl
5
(R)-3-Me-pyrr-
MS; 580.


109/HCl
5
(S)-3-Me-pyrr-
MS; 580.


110/HCl
5
(R)-MeOCH(Me)CH2N(Me)—
MS; 598.


111/HCl
5
(S)-MeOCH(Me)CH2N(Me)—
MS; 598.


112/HCl
5
3-EtO-pyrr-
MS; 610.


113/HCl
5
4-MeO-pipe-
MS; 610.


114/HCl
5
3-MeO-pipe-
MS; 610.


115/HCl
5
(S)-2-MeOCH2-pyrr-
MS; 610.


116/HCl
5
(R)-2-MeOCH2-pyrr-
MS; 610.
















TABLE 18













 












Ex
Syn
R1
R2
R3
Data





117
1
MeO(CH2)2N(Me)—
4-(EtO2CCH2)pipa—
Cl
MS; 644.


118
1
nBuN(Me)—
4-(EtO2CCH2)pipa—
Cl
MS; 642.


119/HCl
1
nBuN(Me)—
HO(CH2)3O—
Cl
MS; 546.


120/HCl
1
nBuN(Me)—
AcO(CH2)3O—
Cl
MS; 588.


121
1
iBuN(Me)—
MeO2C(CH2)3O—
H
MM: 554.


122
2
Azocan-1-yl
4-EtO2C-pipe
F
MS; 637.


123
2
nBuN(Me)—
4-EtO2C-pipe
F
MS; 611.


124/HCl
5
MeO(CH2)2N(Me)—
4-(HO2CCH2)pipa—
Cl
MN; 614.


125/HCl
5
nBuN(Me)—
4-(HO2CCH2)pipa—
Cl
MS; 614.


126/HCl
5
Azocan-1-yl
4-HO2C-pipe
F
MS; 609.


127/HCl
5
nBuN(Me)—
4-HO2C-pipe
F
MS; 583.


128/HCl
5
iBuN(Me)—
HO2C(CH2)3O—
H
MN; 538.
















TABLE 19













 












Ex
Syn
R1
R2
R3
Data





7/HCl
7
nBuN(Me)—
HO(CH2)2O—
OMe
MS; 510


129
1
nBuN(Me)—
OMOM
Cl
MS; 514.


130/HCl
1
nBuN(Me)—
OH
Cl
MS; 470.


131
1
nBuN(Me)—
MeO2C(CH2)3O—
F
MS; 554.


132
1
nBuN(Me)—
TBSO(CH2)2O—
OMe
MS; 624.


133
1
nBuN(Me)—
Me
CF3
MS; 502.


134/HCl
5
nBuN(Me)—
HO2C(CH2)3O—
F
MS; 540.
















TABLE 20













 











Ex
Syn
R1
R2
Data














6/HCl
6
nBu
3-oxo-4-HO(CH2)2-pipa—
MS; 597.


11/HCl
11
nBu
MsHN(CH2)2NH—
MS; 591.


135
1
nBu
3-MeO2C-pyrr
MS; 582.


136
1
nBu
(R)-3-(MeO2CCH2O)pyrr-
MS; 612.


137
1
nBu
(S)-3-MeO2C-pyrr-
MS; 582.


138
1
nBu
3-EtO2C-azet-
MS; 582.


139
1
nBu
4-(tBuO2CCH2O)pipe-
MS; 668.


140
1
nBu
2-EtO2C-mor-
MS; 612.


141
1
nBu
4-(MeO2CCH2NHCO)pipe-
MS; 653.


142
3
nBu
4-OH-4-EtO2C-pipe-
MS; 626.


143
3
nBu
tBuO2C(CH2)2NH—
MS; 598.


144
3
iBu
3-(EtO2CCH2)azet-
MS; 596.


145
3
iBu
EtO2C(CH2)3NH—
MS; 584.


146
3
iBu
tBuO2C(CH2)2NH—
MS; 598.


147
3
iBu
MeO2C(CH2)3N(Me)—
MS; 584.


148
3
iBu
EtO2C(CH2)2N(Me)—
MS; 584.


149
3
iBu
EtO2CCH2N(Me)—
MS; 570.


150/HCl
4
nBu
4-HOCH2-pipe-
MS; 568.


151/HCl
4
nBu
HO(CH2)3NH—
MS; 528.


152/HCl
4
nBu
MeO(CH2)2O(CH2)2NH—
MS; 572.


153/HCl
4
nBu
3-oxo-pipa-
MS; 553.


154/HCl
4
nBu
H2N(CH2)2NH—
MS; 513.


155
4
nBu
4-(4-MeO2C-pipe)-pipe-
MS; 679.


156
4
nBu
3-oxo-4-EtO2CCH2-pipa-
MS; 639.


157
4
nBu
EtO2C(CH2)3NH—
MS; 584.


158/HCl
5
nBu
HO2C(CH2)3NH—
MS; 556.


159/HCl
5
nBu
4-(4-HO2C-pipe)-pipe-
MN; 663.


160/HCl
5
nBu
3-oxo-4-HO2CCH2-pipa-
MS; 611.


161/HCl
5
nBu
3-HO2C-pyrr-
MS; 568.


162/HCl
5
nBu
(R)-3-(HO2CCH2O)-pyrr-
MN; 596.


163/HCl
5
nBu
(S)-3-HO2C-pyrr-
MS; 568.


164/HCl
5
nBu
3-HO2C-azet-
MS; 554.


165/HCl
5
nBu
2-HO2C-mor-
MS; 584.


166/HCl
5
nBu
4-(3-HO2C-azet-CO)pipe-
MN; 663.


167/HCl
5
nBu
4-(HO2C(CH2)2NHCO)pipe-
MS; 653.


168/HCl
5
nBu
4-(HO2CCH2NHCO)pipe-
MS; 639.


169/HCl
5
nBu
4-HO-4-HO2C-pipe-
MS; 598.


170/HCl
5
iBu
3-(HO2CCH2)azet-
MS; 568.


171/HCl
5
iBu
HO2C(CH2)3NH—
MS; 556.


172/HCl
5
iBu
HO2C(CH2)3N(Me)—
MS; 570.


173/HCl
5
iBu
HO2C(CH2)2N(Me)—
MS; 556.


174/HCl
5
iBu
HO2CCH2N(Me)—
MS; 542.


175
8
nBu
4-(3-EtO2C-azet-CO)pipe
MS; 693.


176/HCl
8
nBu
4-(MeO(CH2)2NHCO)pipe
MS; 639.


177/HCl
8
nBu
4-(H2NCOCH2NHCO)pipe
MS; 638.


178/HCl
8
nBu
4-(MeO(CH2)2O(CH2)2NHCO)pipe-
MS; 683.


179
8
nBu
4-(EtO2C(CH2)2NHCO)pipe-
MS; 681.


180
8
nBu
4-(HO(CH2)2NHCO)pipe-
MS; 625.


181/HCl
9
nBu
4-HO2CCH2O-pipe-
MS; 612.


182/HCl
9
nBu
HO2C(CH2)2NH—
MS; 542.


183/HCl
9
iBu
HO2C(CH2)2NH—
MS; 542.
















TABLE 21













 










Ex
Syn
R
Data





9/HCl
9
4-(HO2CCH2O)pipe-
MN; 612.


184
1
3-EtO2C-pipe-
MS; 612.


185
1
3-MeO2C-pyrr-
MS; 584.


186
1
(R)-3-(MeO2CCH2O)pyrr-
MS; 614.


187
1
4-EtO2CCH2-pipe-
MS; 626.


188
1
2-EtO2C-mor-
MN; 612.


189
1
3-EtO2C-azet-
MS; 584.


190
1
4-(tBuO2CCH2O)-pipe-
MS; 670.


191/HCl
5
3-HO2C-pipe-
MS; 584.


192/HCl
5
3-HO2C-pyrr
MS; 570.


193/HCl
5
(R)-3-(HO2CCH2O)pyrr-
MS; 600.


194/HCl
5
4-HO2CCH2-pipe-
MS; 598.


195/HCl
5
2-HO2C-mor-
MS; 586.


196/HCl
5
3-HO2C-azet-
MS; 556.
















TABLE 22













 











Ex
Syn
R1
R2
Data





8/HCl
8
MeO(CH2)3N(Me)—
4-(mor-CO)pipe-
MS; 667.


197
8
MeO(CH2)3N(Me)—
4-(MeO(CH2)2NHCO)pipe-
MS; 655.


198
1
Me2N—
3-MeO2C-pyrr-
MN; 538.


199
1
(S)-2-Me-pyrr-
MeO2C(CH2)3N(Me)—
MS; 582.


200
1
(R)-2-Me-pyrr-
MeO2C(CH2)3N(Me)—
MS; 582.


201
1
Et2CHN(Me)—
MeO2C(CH2)3N(Me)—
MS; 598.


202
1
(S)-3-Me-pyrr-
MeO2C(CH2)3N(Me)—
MS; 582.


203
1
2-Me-pyrr-
MeO2C(CH2)2N(Me)—
MS; 568.


204
1
iPrN(Me)—
MeO2C(CH2)2N(Me)—
MS; 556.


205
1
(nPr)(Me)CHN(Me)—
MeO2C(CH2)2N(Me)—
MS; 584.


206
1
(S)-3-Me-pyrr-
MeO2C(CH2)2N(Me)—
MS; 568.


207
1
iPrN(Me)—
(S)-MeO2C-pyrr-
MS; 568.


208
3
2-Me-pyrr-
3-(EtO2CCH2)azet-
MS; 594.


209
3
(S)-2-Me-pyrr-
3-(EtO2CCH2)azet-
MS; 594.


210
3
(R)-2-Me-pyrr-
3-(EtO2CCH2)azet-
MS; 594.


211
3
iPrN(Me)—
3-(EtO2CCH2)azet-
MS; 582.


212
3
2-Me-pyrr-
MeO2C(CH2)3N(Me)—
MS; 582.


213
3
iPrN(Me)—
MeO2C(CH2)3N(Me)—
MS; 570.


214
3
2-Me-pyrr-
EtO2C(CH2)3NH—
MS; 582.


215
3
(S)-2-Me-pyrr-
EtO2C(CH2)3NH—
MS; 582.


216
3
(R)-2-Me-pyrr-
EtO2C(CH2)3NH—
MS; 582.


217
3
2-Me-pyrr-
tBuO2C(CH2)2NH—
MS; 596.


218/HCl
4
pipe-
4-H2NOC-pipe-
MN; 579.


219/HCl
5
Me2N—
3-HO2C-pyrr-
MS; 526.


220/HCl
5
2-Me-pyrr-
3-(HO2CCH2)azet-
MN; 564.


221/HCl
5
(S)-2-Me-pyrr-
3-(HO2CCH2)azet-
MN; 564.


222/HCl
5
(R)-2-Me-pyrr-
3-(HO2CCH2)azet-
MN; 564.


223/HCl
5
iPrN(Me)—
3-(HO2CCH2)azet-
MN; 552.


224/HCl
5
2-Me-pyrr-
HO2C(CH2)3N(Me)—
MS; 568.


225/HCl
5
(S)-2-Me-pyrr-
HO2C(CH2)3N(Me)—
MS; 568.


226/HCl
5
(R)-2-Me-pyrr-
HO2C(CH2)3N(Me)—
MS; 568.


227/HCl
5
iPrN(Me)—
HO2C(CH2)3N(Me)—
MS; 556.


228/HCl
5
Et2CHN(Me)—
HO2C(CH2)3N(Me)—
MS; 584.


229/HCl
5
(S)-3-Me-pyrr-
HO2C(CH2)3N(Me)—
MN; 566.


230/HCl
5
2-Me-pyrr-
HO2C(CH2)2N(Me)—
MS; 554.


231/HCl
5
iPrN(Me)—
HO2C(CH2)2N(Me)—
MN; 540.


232/HCl
5
(nPr)(Me)CHN(Me)—
HO2C(CH2)2N(Me)—
MS; 570.


233/HCl
5
(S)-3-Me-pyrr-
HO2C(CH2)2N(Me)—
MS; 554.


234/HCl
5
2-Me-pyrr-
HO2C(CH2)3NH—
MS; 554.


235/HCl
5
(S)-2-Me-pyrr-
HO2C(CH2)3NH—
MN; 552.


236/HCl
5
(R)-2-Me-pyrr-
HO2C(CH2)3NH—
MN; 552.


237/HCl
5
iPrN(Me)—
(S)-3-HO2C-pyrr-
MN; 552.


238/HCl
9
2-Me-pyrr-
HO2C(CH2)2NH—
MN; 538.
















TABLE 23













 











Ex
Syn
R1
R2
Data





239
1
nBuN(Me)—
4-EtO2C-pipe-
MN; 588.


240
1
Me2N—
4-EtO2C-pipe-
MS; 588.


241
1
iBuN(Me)—
4-EtO2C-pipe-
MN; 588.


242
1
cHexN(Me)—
4-EtO2C-pipe-
MS; 588.


243
1
iPrN(Me)—
4-EtO2C-pipe-
MN; 588.


244
1
cBuN(Me)—
4-EtO2C-pipe-
MN; 687.


245
1
Et2CHN(Me)—
4-EtO2C-pipe-
MN; 687.


246
1
(nPr)(Me)CHN(Me)—
4-EtO2C-pipe-
MS; 604.


247
1
(iPr)(Me)CHN(Me)—
4-EtO2C-pipe-
MS; 604.


248
1
tBuN(Me)—
4-EtO2C-pipe-
MS; 590.


249
1
cBuCH2N(Me)—
4-EtO2C-pipe-
MS; 602.


250
1
Azepan-1-yl
4-EtO2C-pipe-
MS; 602.


251
1
4-Me-pipe-
4-EtO2C-pipe-
MS; 602.


252
1
3-Me-pipe-
4-EtO2C-pipe-
MS; 602.


253
1
2-Me-pipe-
4-EtO2C-pipe-
MS; 602.


254
1
2-Me-pyrr-
4-EtO2C-pipe-
MS; 588.


255
1
(S)-2-Me-pyrr-
4-EtO2C-pipe-
MS; 588.


256
1
(R)-2-Me-pyrr-
4-EtO2C-pipe-
MS; 588.


257
1
(R)-3-Me-pyrr-
4-EtO2C-pipe-
MS; 588.


258
1
(S)-3-Me-pyrr-
4-EtO2C-pipe-
MS; 588.


259
1
3,3-diMe-pyrr-
4-EtO2C-pipe-
MN; 600.


260
3
iBuN(Me)—
4-HO-4-EtO2C-pipe-
MS; 606.


261
3
iBuN(Me)—
EtO2C(CH2)3NH—
MS; 564.


262
3
iBuN(Me)—
MeO2C(CH2)3N(Me)—
MS; 564.


263
3
cBuCH2N(Me)—
4-HO-4-EtO2C-pipe-
ESI-MS(Pos); 618.


264
3
2-Me-pyrr-
4-HO-4-EtO2C-pipe-
MS; 604.


265
3
2-Me-pyrr-
EtO2C(CH2)3NH—
MS; 562.


266
3
2-Me-pyrr-
MeO2C(CH2)3N(Me)—
ESI-MS(Pos); 562.


267/HCl
5
nBuN(Me)—
4-HO2C-pipe-
MS; 562.


268/HCl
5
Me2N—
4-HO2C-pipe-
MS; 520.


269/HCl
5
iBuN(Me)—
4-HO2C-pipe-
MS; 562.


270/HCl
5
cHexN(Me)—
4-HO2C-pipe-
MS; 588.


271/HCl
5
iPrN(Me)—
4-HO2C-pipe-
MS; 548.


272/HCl
5
cBuN(Me)—
4-HO2C-pipe-
MS; 560.


273/HCl
5
Et2CHN(Me)—
4-HO2C-pipe-
MS; 576.


274/HCl
5
(nPr)(Me)CHN(Me)—
4-HO2C-pipe-
MS; 576.


275/HCl
5
(iPr)(Me)CHN(Me)—
4-HO2C-pipe-
MS; 576.


276/HCl
5
cBuCH2N(Me)—
4-HO2C-pipe-
MS; 574.


277/HCl
5
Azepan-1-yl
4-HO2C-pipe-
MS; 574.


278/HCl
5
4-Me-pipe-
4-HO2C-pipe-
MS; 574.


279/HCl
5
3-Me-pipe-
4-HO2C-pipe-
MS; 574.


280/HCl
5
2-Me-pipe-
4-HO2C-pipe-
MS; 574.


281/HCl
5
2-Me-pyrr-
4-HO2C-pipe-
MN; 558.


282/HCl
5
(S)-2-Me-pyrr-
4-HO2C-pipe-
MS; 560.


283/HCl
5
(R)-2-Me-pyrr-
4-HO2C-pipe-
MS; 560.


284/HCl
5
(R)-3-Me-pyrr-
4-HO2C-pipe-
MN; 558.


285/HCl
5
(S)-3-Me-pyrr-
4-HO2C-pipe-
MN; 558.


286/HCl
5
3,3-diMe-pyrr-
4-HO2C-pipe-
MS; 574.


287/HCl
5
iBuN(Me)—
4-HO-4-HO2C-pipe-
MS; 578.


288/HCl
5
iBuN(Me)—
HO2C(CH2)3NH—
MS; 536.


289/HCl
5
iBuN(Me)—
HO2C(CH2)3N(Me)—
MS; 550.


290/HCl
5
cBuCH2N(Me)—
4-HO-4-HO2C-pipe-
MS; 590.


291/HCl
5
2-Me-pyrr-
4-HO-4-HO2C-pipe-
MS; 576.


292/HCl
5
2-Me-pyrr-
HO2C(CH2)3NH—
MS; 534.


293/HCl
5
2-Me-pyrr-
HO2C(CH2)3N(Me)—
MS; 548.
















TABLE 24













 












Ex
Syn
R1
R2
R3
Data





294
1
pipe
4-F—Ph—
4-EtO2C-pipe-
MS; 586.


295
1
pipe
3-F3C—Ph—
4-EtO2C-pipe-
MS; 636.


296
1
nBuN(Me)—
4-F—Ph—
4-EtO2C-pipe-
MS; 588.


297
1
nBuN(Me)—
4-Me-5-(nBuN(Me)CH2)-2-The-
4-EtO2C-pipe-
MN; 687.


298/HCl
5
pipe
4-F—Ph—
4-HO2C-pipe-
MS; 558.


299/HCl
5
pipe
3-F3C—Ph—
4-HO2C-pipe-
MS; 608.


300/HCl
5
nBuN(Me)—
4-F—Ph—
4-HO2C-pipe-
MS; 560.
















TABLE 25













 











Ex
Syn
R1
R2
Data





301/HCl
1
pipe
2-MeO-4-Py
MS; 449.


302
1
nBuN(Me)—
4-(4-MeO2C-pipe)pipe
MS; 568.


303
1
nBuN(Me)CH2—
5-Cl-6-(4-EtO2C-pipe)-3-Py
MS; 624.


304
1
nPrN(Me)—
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 580.


305
1
iBuN(Me)—
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 594.


306
1
2-Me-pyrr-
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 592.


307
1
(S)-2-Me-pyrr-
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 592.


308
1
(R)-2-Me-pyrr-
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 592.


309
1
iPrN(Me)—
5-F-6-(4-EtO2C-pipe)-3-Py
MS; 580.


310/HCl
5
nBuN(Me)CH2—
5-Cl-6-(4-HO2C-pipe)-3-Py
MS; 596.


311/HCl
5
nPrN(Me)—
5-F-6-(4-HO2C-pipe)-3-Py
MS; 552.


312/HCl
5
iBuN(Me)—
5-F-6-(4-HO2C-pipe)-3-Py
MS; 566.


313/HCl
5
2-Me-pyrr-
5-F-6-(4-HO2C-pipe)-3-Py
MS; 564.


314/HCl
5
(S)-2-Me-pyrr-
5-F-6-(4-HO2C-pipe)-3-Py
MN: 562.


315/HCl
5
(R)-2-Me-pyrr-
5-F-6-(4-HO2C-pipe)-3-Py
MS; 564.


316/HCl
5
iPrN(Me)—
5-F-6-(4-HO2C-pipe)-3-Py
MN: 550.
















TABLE 26













 












Ex
Syn
R1
R2
R3
Data















 10
10
MeO(CH2)2—
EtO2C—
Cl
MS; 610.


317/HCl
5
cBu
HO2C—
Cl
MS; 578.


318/HCl
5
MeO(CH2)2—
HO2C—
Cl
MS; 582.


319/HCl
5
(R)-(MeO)(Me)CHCH2—
HO2C—
Cl
MS; 596.


320/HCl
5
(S)-(MeO)(Me)CHCH2—
HO2C—
Cl
MS; 596.


321
5
Me
HO2C—
Cl
ESI-MS(Pos); 538.


322/HCl
5
Me
HO2C—
Me
MS; 518.


323
10
cBu
EtO2C—
Cl
MS; 606.


324
10
(R)-(MeO)(Me)CHCH2—
EtO2C—
Cl
MS; 624.


325
10
(S)-(MeO)(Me)CHCH2—
EtO2C—
Cl
MS; 624.


326
10
Et
EtO2C—
Cl
MN; 578.


327
10
Me
EtO2C—
Cl
ESI-MS(Pos); 566.


328
10
Me
EtO2C—
Me
MS; 546.









NMR data of selected Example compounds are shown in Table 27 below. Each data shows peak δ (ppm) in 1H-NMR using tetramethylsilane as an internal standard and DMSO-δ6 as a measuring solvent unless otherwise instructed.








TABLE 27





Ex
Data
















5
1.62-1.74(2H, m), 1.90-1.98(2H, m), 2.52-2.58(1H,



m), 2.81(3H, s), 3.05(2H, t, J=11.2Hz), 3.34(5H, s),



3.72(2H, brs), 4.00(2H, d, J=13.2Hz), 4.60-4.90(2H,



m), 7.65(1H, s), 7.73(1H, s), 8.43(1H, d, J=1.9Hz),



8.87(1H, d, J=2.4Hz), 10.33(1H, brs), 12.28(1H, brs),



13.00(1H, s).


65
1.61-1.73(2H, m), 1.90-1.99(2H, m), 2.51-2.54(1H,



m), 2.81(6H, m), 3.05(2H, t, J=11.3Hz), 4.01(2H, d,



J=13.2Hz), 4.74(2H, brs), 7.69(1H, s), 7.72(1H, s),



8.43(1H, d, J=1.5Hz), 8.87(1H, d, J=1.9 Hz),



9.95(1H, brs), 12.27(1H, brs), 12.99(1H, s).


71
0.87(3H, t, J=7.4Hz), 1.18-1.32(2H, m), 1.58-1.74(4H,



m), 1.90-1.99(2H, m), 2.51-2.57(1H, m), 2.74(3H, d,



J=3.9Hz), 2.98-3.17(4H, m), 4.01(2H, d, J=13.2Hz),



4.63-4.84(2H, m), 7.69(1H, s), 7.74(1H, s), 8.43(1H, d,



J=2.4Hz), 8.87(1H, d, J=1.9Hz), 10.33(1H, brs),



12.28(1H, brs), 13.00(1H, s).


84
1.52-1.98(12H, m), 2.52-2.58(1H, m), 3.05(2H, t,



J=11.2Hz), 3.13-3.24(2H, m), 3.30-3.43(2H, m),



4.00(2H, d, J=12.7Hz), 4.74(2H, d, J=5.4Hz), 7.65(1H,



s), 7.73(1H, s), 8.42(1H, d, J=2.0Hz), 8.87(1H, d,



J=1.9Hz), 10.18(1H, brs), 12.27(1H, brs), 12.99(1H, s).


85
1.48-1.77(10H, m), 1.82-1.99(4H, m), 2.52-2.59(1H,



m), 3.05(2H, t, J=11.3Hz), 3.16-3.43(4H, m), 4.00(2H,



d, J=12.7Hz), 4.74(2H, d, J=4.9Hz), 7.65(1H, d,



J=0.9Hz), 7.74(1H, d, J=1.0Hz), 8.43(1H, d, J=1.5Hz),



8.87(1H, d, J=1.9Hz), 9.98(1H, brs), 12.29(1H, brs),



12.99(1H, s).


90
1.03-2.07(14H, m), 2.52-2.57(1H, m), 2.69(3H, d,



J=4.4Hz), 3.05(2H, t, J=11.5Hz), 3.11-3.22(1H,



m), 4.01(2H, d, J=13.2Hz), 4.58-4.89(2H, m), 7.66(1H,



s), 7.75(1H, s), 8.42(1H, d, J=2.0Hz), 8.87(1H, d,



J=2.0Hz), 10.11(1H, brs), 12.27(1H, brs), 13.01(1H, s).


100
1.60-1.77(4H, m), 1.89-2.00(2H, m), 2.01-2.20(2H,



m), 2.18-2.36(2H, m), 2.50-2.58(1H, m), 2.59-



2.63(3H, d, J=4.4Hz), 3.05(2H, t, J=11.7Hz), 3.72-



3.84(1H, m), 3.95-4.05(2H, m), 4.51-4.62(1H, m),



4.65-4.75(1H, m), 7.69(1H, s), 7.74(1H, s), 8.42(1H, d,



J=2.2Hz), 8.87(1H, d, J=2.2Hz), 10.51(1H, brs),



12.28(1H, brs), 13.02(1H, brs)


101
0.50-1.10(4H, m), 1.62-1.75(2H, m), 1.89-2.05(2H, m),



2.50-2.58(1H, m), 2.87(3H, brs), 3.05 (2H, t, J=11.2Hz),



3.11-3.15(1H, m), 3.92-4.06(2H, m), 4.64-5.08(2H, m),



7.62-7.83(2H, m), 8.42(1H, d, J=2.0Hz), 8.86(1H, d,



J=2.0Hz), 10.25(1H, brs), 12.25(1H, brs), 13.00(1H, brs).


104
1.22(3H, d, J=6.9Hz), 1.30(3H, d, J=6.8Hz), 1.60-



1.74(2H, m), 1.90-2.00(2H, m), 2.50-2.58(1H, m),



2.67(3H, d, J=4.9Hz), 3.05(2H, t, J=11.3Hz), 3.30-



3.45(1H, m), 4.00(2H, d, J=3.2Hz), 4.55-4.65(1H, m),



4.72-4.82(1H, m), 7.65(1H, s), 7.74(1H, d, J=1.5Hz),



8.42(1H, d, J=1.9Hz), 8.87(1H, d, J=2.0Hz), 10.05-



10.25(1H, brs), 12.97(1H, s,).


106
1.42(3H, d, J=, 6.3Hz), 1.61-1.73(3H, m), 1.87-



1.96(4H, m), 2.20-2.23(1H, m), 2.49-2.57(1H, m),



3.03-3.08(2H, m), 3.13-3.22(1H, m), 3.48-3.64(2H,



m), 4.01(2H, d, J=13.2Hz), 4.62-4.68 (2H, m), 4.95(1H,



d, J=11.8Hz)7.66(1H, d, J=1.0Hz), 7.74(1H, d,



J=1.0Hz), 8.43(1H, d, J=2.0Hz), 8.87(1H, d, J=2.4Hz),



10.21(1H, brs), 13.01(1H, s).


107
1.42(3H, d, J=, 6.3Hz), 1.61-1.72(3H, m), 1.88-



1.96(4H, m), 2.20-2.28(1H, m), 2.49-2.51(1H, m),



3.04-3.09(2H, m), 3.15-3.20(1H, m), 3.42-3.54(2H,



m), 4.01(2H, d, J=12.7Hz), 4.66(1H, dd, J=7.8, 15.1Hz),



4.97(1H, d, J=11.2Hz), 7.65(1H, d, J=1.0Hz), 7.74(1H,



d, J=1.0Hz), 8.42(1H, d, J=2.0Hz), 8.87(1H, d,



J=2.2Hz), 9.98(1H, brs), 13.01(1H, s).


108
1.05(3H, dd, J=1.5, 6.4Hz), 1.55-1.72(3H, m), 1.90-



2.00(2H, m), 2.05-2.20(1H, m), 2.28-2.40 (1H, m), 2.50-



2.60(1H, m), 2.70-2.80(1H, m), 3.05(2H, t, J=10.8Hz),



3.00-3.60(3H, m), 3.95-4.05(2H, d, J=13.2Hz), 4.75-



4.80(2H, m), 7.67-7.69(1H, m), 7.72(1H, d, J=1.0Hz),



8.43(1H, d, J=1.9Hz), 8.83(1H, d, J=1.9Hz), 10.75-



10.95(1H, brd), 12.97(1H, s)..


109
1.05(3H, d, J=, 6.3Hz), 1.64-1.72(3H, m), 1.91-



1.96(2H, m), 2.08-2.33(2H, m), 2.50-2.51(1H, m),



2.73-2.80(1H, m), 3.03-3.08(2H, m), 3.25-3.63(3H,



m), 4.01(2H, d, J=13.2Hz), 4.76-4.86 (2H, m), 7.68(1H,



d, J=1.5Hz), 7.73(1H, d, J=1.5Hz), 8.43(1H, d,



J=1.9Hz), 8.87(1H, d, J=1.9Hz), 10.73(1H, brs),



12.99(1H, s).


110
1.05-1.13(3H, m), 1.62-1.72(2H, m), 1.91-



1.98(2H, m), 2.50-2.56(1H, m), 2.76-2.84(3H, m),



3.00-3.10(2H, m), 3.30-3.60(5H, m), 3.76-3.93(1H,



m), 3.96-4.40(2H, m), 4.62-4.85(2H, m), 7.64(1H, d,



J=3.9), 7.74(1H, s), 8.43(1H, d, J=1.9Hz), 8.87(1H, d,



J=2.0Hz), 9.76-10.04(1H, m), 13.00(1H, s).


111
1.05-1.13(3H, m), 1.62-1.72(2H, m), 1.91-1.96(2H,



m), 2.50-2.55(1H, m), 2.76-2.84(3H, m), 3.00-



3.10(2H, m), 3.25-3.60(5H, m), 3.76-3.93(1H, m),



3.96-4.40(2H, m), 4.62-4.85(2H, m), 7.61-7.65(1H,



m).74(1H, s), 8.43(1H, d, J=1.9Hz), 8.87(1H, d,



J=2.4Hz), 9.66-9.93(1H, m), 12.27(1H, brs), 13.01(1H, s).


150
0.87(3H, t, J=7.3Hz), 1.17-1.34(4H, m), 1.58-1.72(3H,



m), 1.78(2H, d, J=13.2Hz), 2.73(3H, d, J=4.4Hz),



2.92(2H, t, J=11.5Hz), 2.96-3.18(2H, m), 3.31(2H, d,



J=6.3Hz), 4.11(2H, d, J=12.7Hz), 4.62-4.83(2H, m),



7.70(1H, s), 7.74(1H, s), 8.41(1H, d, J=2.0Hz), 8.86(1H,



d, J=2.0Hz), 10.62(1H, brs), 12.97(1H, s).


151
0.87(3H, t, J=7.3Hz), 1.16-1.34(2H, m), 1.57-1.80(4H,



m), 2.72(3H, d, J=4.4Hz), 2.94-3.17(2H, m),



3.45-3.60(4H, m), 4.60-4.80(2H, m), 7.50(1H, brs),



7.70(1H, s), 7.73(1H, s), 8.32(1H, d, J=2.0Hz), 8.77



(1H, d, J=2.0Hz), 10.86(1H, brs), 12.79(1H, s).


153
0.87(3H, t, J=7.3Hz), 1.18-1.32(2H, m), 1.57-1.72(2H,



m), 2.74(3H, d, J=4.4Hz), 2.96-3.19(2H, m), 3.32(2H,



brs), 3.73-4.09(4H, m), 4.62-4.84(2H, m), 7.70(1H, d,



J=1.0Hz), 7.74(1H, d, J=1.0Hz), 8.07(1H, s), 8.48(1H,



d, J=2.0Hz), 8.89(1H, d, J=2.0Hz), 10.39(1H, brs),



13.05(1H, s).


221
1.44(3H, d, J=6.3Hz), 1.62-1.72(1H, m), 1.87-1.97(2H,



m), 2.18-2.26(1H, m), 2.66(2H, d, J=7.4Hz), 2.92-



2.99(1H, m), 3.12-3.20(1H, m), 3.49-3.57(3H, m), 4.01-



4.05(2H, m), 4.46(1H, t, 8.8Hz), 4.62(1H, dd, J=7.3,



15.1Hz), 4.91(1H, dJ=14.7Hz).68(1H, d, J=1.0Hz),



7.73(1H, d, J=1.4Hz), 8.27(1H, d, J=2.0Hz),



8.77(1H, d, J=2.0Hz), 10.56(1H, brs), 12.84(1H, s).


222
1.43(3H, d, J=6.4Hz), 1.62-1.71(1H, m),



1.87-1.98(2H, m), 2.18-2.23(1H, m), 2.66(2H, d,



J=7.8Hz), 2.89-2.99(1H, m), 3.12-3.21(1H, m),



3.48-3.57(3H, m), 4.01-4.05(2H, m), 4.43-4.48(1H,



m), 4.60-4.66(1H, m), 4.92(1H, d, J=12.2Hz), 7.67(1H,



s), 7.74(1H, d, J=1.0Hz), 8.27(1H, d, J=2.0Hz),



8.77(1H, d, J=2.0Hz), 10.42(1H, brs), 12.84(1H, s).


225
1.42(3H, d, J=, 6.4Hz), 1.60-1.70(1H, m),



1.86-1.97(4H, m), 2.23-2.26(3H, m), 3.13(3H, s),



3.15-3.20(1H, m), 3.40-3.60(4H, m), 4.62-4.67(1H,



m), 4.95(1H, d, J=15.1Hz), 7.65(1H, d, J=0.9Hz),



7.74(1H, d, J=1.5Hz), 8.38(1H, d, J=1.9Hz), 8.82(1H,



d, J=2.4Hz), 10.08(1H, brs), 12.93(1H, s).


226
1.45(3H, d, J=, 6.3Hz), 1.63-1.73(1H, m), 1.84-



1.97(4H, m), 2.18-2.27(3H, m), 3.13(3H, s), 3.16-



3.20(1H, m), 3.39-3.59(4H, m), 4.63(1H, dd,



J=7.3, 15.1Hz), 4.90(1H, d, J=12.2Hz), 7.68(1H, d,



J=1.0Hz), 7.74(1H, d, J=1.0Hz), 8.39(1H, d,



J=2.0Hz), 8.82(1H, d, J=1.9Hz), 10.75(1H, brs), 12.92



(1H, s).


227
1.22(3H, d, J=6.9Hz), 1.32(3H, d, J=6.3Hz), 1.84-



1.91(2H, m), 2.23-2.27(2H, m), 2.65(3H, d,



J=4.9Hz), 3.13(3H, s), 3.56-3.61(3H, m), 4.58(1H, dd,



J=5.9, 15.2Hz), 4.76(1H, dd, J=3.9, 4.7Hz).67(1H, s),



7.74(1H, s), 8.39(1H, d, J=2.0Hz), 8.82(1H, d,



J=1.9Hz), 10.57(1H, brs), 12.91(1H, s).


271
1.19(3H, d, J=6.9Hz), 1.30(3H, d, J=6.3Hz), 1.60-



1.72(2H, m), 1.90-1.98(2H, m), 2.28(3H, s), 2.52-



2.58(1H, m), 2.65(3H, d, J=5.3Hz), 3.05(2H, t,



J=11.2Hz), 3.52-3.64(1H, m), 4.00(2H, d, J=13.2Hz),



4.55-4.80(2H, m), 7.30(1H, s), 7.40(1H, s), 8.42(1H, d,



J=2.5Hz), 8.75(1H, d, J=2.0Hz), 9.80-9.90(1H, brs),



12.97(1H, s).


314
1.45(3H, d, J=6.3Hz), 1.55-1.72(3H, m), 1.90-



2.00(4H, m), 2.15-2.25(1H, m), 2.55-2.65(1H. m),



3.20-3.32(3H, m), 3.45-3.55(2H, m), 4.45(2H, d,



J=13.2Hz), 4.59-4.67(1H, m), 4.85-4.95(1H, m),



7.69(1H, d, J=1.5Hz), 7.72(1H, d, J=1.4Hz), 8.14(1H,



dd, J=1.9, 15.1Hz), 8.75(1H, t, J=0.9Hz), 10.75(1H,



brs), 12.90(1Hs).


315
1.42(3H, d, J=6.4Hz), 1.55-1.70(3H, m), 1.85-



2.00(4H, m), 2.15-2.25(1H, m), 2.54-2.65(1H, m),



3.10-3.22(3H, m), 3.45-3.60(2H, m), 4.23(2H, d,



J=13.2Hz), 4.55-4.65(1H, m), 4.85-4.95(1H, m),



7.65(1H, d, J=1.0Hz), 7.75(1H, s), 8.13(1H, dd, J=2.0,



15.1Hz), 8.75(1H, s), 10.67(1H, brs), 12.90(1H, s).









Structures of the other compounds of the present invention are shown in Tables 28 to 41 below. They can be produced easily by using the methods described in production examples and examples, or methods obvious to one skilled in the art, or modifications thereof.







TABLE 28













 









No
R1
R2





A1
EtN(Me)—
4-Cl-2-The


A2
nPrN(Me)—
4-Cl-2-The


A3
iPrN(Me)—
4-Cl-2-The


A4
iBuN(Me)—
4-Cl-2-The


A5
sBuN(Me)—
4-Cl-2-The


A6
tBuN(Me)—
4-Cl-2-The


A7
tBuCH2N(Me)—
4-Cl-2-The


A8
cPenN(Me)—
4-Cl-2-The


A9
cPrCH2N(Me)—
4-Cl-2-The


A10
cBuCH2N(Me)—
4-Cl-2-The


A11
MeO H(Me)CH2N(Me)—
4-Cl-2-The


A12
nPrN(Et)—
4-Cl-2-The


A13
nBuN(Et)—
4-Cl-2-The


A14
iPrN(Et)—
4-Cl-2-The


A15
iBuN(Et)—
4-Cl-2-The


A16
sBuN(Et)—
4-Cl-2-The


A17
tBuN(Et)—
4-Cl-2-The


A18
tBuCH2N(Et)—
4-Cl-2-The


A19
cPrN(Et)—
4-Cl-2-The


A20
cBuN(Et)—
4-Cl-2-The


A21
cPenN(Et)—
4-Cl-2-The


A22
cHexN(Et)—
4-Cl-2-The


A23
cPrCH2N(Et)—
4-Cl-2-The


A24
cBuCH2N(Et)—
4-Cl-2-The


A25
MeO(CH2)2N(Et)—
4-Cl-2-The


A26
MeOCH2CH(Me)N(Et)—
4-Cl-2-The


A27
MeOCH(Me)CH2N(Et)—
4-Cl-2-The


A28
(MeO(CH2)2)2N—
4-Cl-2-The


A29
MeO(CH2)2—N(cPr)—
4-Cl-2-The


A30
MeO(CH2)2—N(cBu)—
4-Cl-2-The


A31
EtO(CH2)2N(Et)—
4-Cl-2-The


A32
nPrO(CH2)2N(Et)—
4-Cl-2-The


A33
iPrO(CH2)2N(Et)—
4-Cl-2-The


A34
MeO(CH2)3N(Et)—
4-Cl-2-The


A35
2-Me-azet
4-Cl-2-The


A36
3-Me-azet
4-Cl-2-The


A37
3,3-diMe-azet
4-Cl-2-The


A38
cPrCH2N(Et)—
4-Me-2-The


A39
cBuCH2N(Et)—
4-Me-2-The


A40
2-Me-pyrr
4-Cl-2-The


A41
3-Me-pyrr
4-Cl-2-The


A42
3,4-diMe-pyrr
4-Cl-2-The


A43
3,3-diMe-pyrr
4-Cl-2-The


A44
2-Me-pipe
4-Cl-2-The


A45
3-Me-pipe
4-Cl-2-The


A46
4-Me-pipe
4-Cl-2-The


A47
3,3-diMe-pipe
4-Cl-2-The


A48
4,4-diMe-pipe
4-Cl-2-The


A49
EtN(Me)—
4-Me-2-The


A50
nPrN(Me)—
4-Me-2-The


A51
sBuN(Me)—
4-Me-2-The


A52
tBuN(Me)—
4-Me-2-The


A53
tBuCH2N(Me)—
4-Me-2-The


A54
cPrN(Me)—
4-Me-2-The


A55
cPenN(Me)—
4-Me-2-The


A56
cPrCH2N(Me)—
4-Me-2-The


A57
cBuCH2N(Me)—
4-Me-2-The


A58
MeO(CH2)2N(Me)—
4-Me-2-The


A59
MeOCH2OH(Me)N(Me)—
4-Me-2-The


A60
MeOCH(Me)CH2N(Me)—
4-Me-2-The


A61
EtO(CH2)2N(Me)—
4-Me-2-The


A62
nPrO(CH2)2N(Me)—
4-Me-2-The


A63
iPrO(CH2)2N(Me)—
4-Me-2-The


A64
MeO(CH2)3N(Me)—
4-Me-2-The


A65
Et2N—
4-Me-2-The


A66
nPrN(Et)—
4-Me-2-The


A67
nBuN(Et)—
4-Me-2-The


A68
iPrN(Et)—
4-Me-2-The


A69
iBuN(Et)—
4-Me-2-The


A70
sBuN(Et)—
4-Me-2-The


A71
tBuN(Et)—
4-Me-2-The


A72
tBuCH2N(Et)—
4-Me-2-The


A73
cPrN(Et)—
4-Me-2-The


A74
cBuN(Et)—
4-Me-2-The


A75
cPenN(Et)—
4-Me-2-The


A76
cHexN(Et)—
4-Me-2-The


A77
MeO(CH2)2N(Me)—
4-Br-2-The


A78
pipe
4-Br-2-The


A79
MeO(CH2)2N(Et)—
4-Me-2-The


A80
MeOCH2CH(Me)N(Et)—
4-Me-2-The


A81
MeOCH(Me)CH2N(Et)—
4-Me-2-The


A82
EtO(CH2)2N(Et)—
4-Me-2-The


A83
nPrO(CH2)2N(Et)—
4-Me-2-The


A84
iPrO(CH2)2N(Et)—
4-Me-2-The


A85
MeO(CH2)3N(Et)—
4-Me-2-The


A86
azet
4-Me-2-The


A87
pyrr
4-Me-2-The


A88
pipe
4-Me-2-The


A89
Azepan-1-yl
4-Me-2-The


A90
Azocan-1-yl
4-Me-2-The


A91
2-Me-azet
4-Me-2-The


A92
3-Me-azet
4-Me-2-The


A93
3,3-diMe-azet
4-Me-2-The


A94
2-Me-pyrr
4-Me-2-The


A95
3-Me-pyrr
4-Me-2-The


A96
3,4-diMe-pyrr
4-Me-2-The


A97
3,3-diMe-pyrr
4-Me-2-The


A98
2-Me-pipe
4-Me-2-The


A99
3-Me-pipe
4-Me-2-The


A100
4-Me-pipe
4-Me-2-The


A101
3,3-diMe-pipe
4-Me-2-The


A102
4,4-diMe-pipe
4-Me-2-The


A103
Me2N—
4-Br-2-The


A104
nBuN(Me)—
4-Br-2-The


A105
cHexN(Me)—
4-Br-2-The


A106
2-Et-azet
4-Cl-2-The


A107
3-Et-azet
4-Cl-2-The


A108
2-Et-pyrr
4-Cl-2-The


A109
3-Et-pyrr
4-Cl-2-The


A110
2-Et-pipe
4-Cl-2-The


A111
3-Et-pipe
4-Cl-2-The


A112
4-Et-pipe
4-Cl-2-The


A113
2-MeOCH2-azet
4-Cl-2-The


A114
3-MeOCH2-azet
4-Cl-2-The


A115
2-MeOCH2-pyrr
4-Cl-2-The


A116
3-MeOCH2-pyrr
4-Cl-2-The


A117
2-MeOCH2-pipe
4-Cl-2-The


A118
3-MeOCH2-pipe
4-Cl-2-The


A119
4-MeOCH2-pipe
4-Cl-2-The


A120
3-MeO-azet
4-Cl-2-The


A121
3-MeO-pyrr
4-Cl-2-The


A122
3-MeO-pipe
4-Cl-2-The


A123
Me2N—
4-F-2-The


A124
nBuN(Me)—
4-F-2-The


A125
cHexN(Me)—
4-F-2-The


A126
MeO(CH2)2N(Me)—
4-F-2-The


A127
pipe
4-F-2-The


A128
Me2N—
4-Et-2-The


A129
nBuN(Me)—
4-Et-2-The


A130
cHexN(Me)—
4-Et-2-The


A131
MeO(CH2)2N(Me)—
4-Et-2-The


A132
pipe
4-Et-2-The


A133
Me2N—
5-Cl-2-The


A134
nBuN(Me)—
5-Cl-2-The


A135
cHexN(Me)—
5-Cl-2-The


A136
MeO(CH2)2N(Me)—
5-Cl-2-The


A137
pipe
5-Cl-2-The


A138
Me2N—
4-F—Ph


A139
cHexN(Me)—
4-F—Ph


A140
MeO(CH2)2N(Me)—
4-F—Ph


A141
Me2N—
3-Cl—Ph


A142
nBuN(Me)—
3-Cl—Ph


A143
cHex(Me)—
3-Cl—Ph


A144
MeO(CH2)2N(Me)—
3-Cl—Ph


A145
pipe
3-Cl—Ph


A146
Me2N—
3-F3C—Ph


A147
nBuN(Me)—
3-F3C—Ph


A148
cHexN(Me)—
3-F3C—Ph


A149
MeO(CH2)2N(Me)—
3-F3C—Ph


A150
2-Et-azet
4-Me-2-The


A151
3-Et-azet
4-Me-2-The


A152
2-Et-pyrr
4-Me-2-The


A153
3-Et-pyrr
4-Me-2-The


A154
2-Et-pipe
4-Me-2-The


A155
3-Et-pipe
4-Me-2-The


A156
4-Et-pipe
4-Me-2-The


A157
2-MeOCH2-azet
4-Me-2-The


A158
3-MeOCH2-azet
4-Me-2-The


A159
2-MeOCH2-pyrr
4-Me-2-The


A160
3-MeOCH2-pyrr
4-Me-2-The


A161
2-MeOCH2-pipe
4-Me-2-The


A162
3-MeOCH2-pipe
4-Me-2-The


A163
4-MeOCH2-pipe
4-Me-2-The


A164
3-MeO-azet
4-Me-2-The


A165
3-MeO-pyrr
4-Me-2-The


A166
3-MeO-pipe
4-Me-2-The


A167
4-MeO-pipe
4-Cl-2-The


A168
3-F-azet
4-Cl-2-The


A169
3-F-pyrr
4-Cl-2-The


A170
3-F-pipe
4-Cl-2-The


A171
4-F-pipe
4-Cl-2-The


A172
4-MeO-pipe
4-Me-2-The


A173
3-F-azet
4-Me-2-The


A174
3-F-pyrr
4-Me-2-The


A175
3-F-pipe
4-Me-2-The


A176
4-F-pipe
4-Me-2-The
















TABLE 29













 










No
R1







B1
Me2NCH(Me)—



B2
Me2NC(Me)2—



B3
Me2N(CH2)2—



B4
Me2N(CH2)3—



B5
nBuN(Me)—CH(Me)—



B6
nBuN(Me)—C(Me)2—



B7
nBuN(Me)—(CH2)3—



B8
cHexN(Me)—CH(Me)—



B9
cHexN(Me)—C(Me)2—



B10
cHexN(Me)—(CH2)2—



B11
cHexN(Me)—(CH2)3—



B12
MeO(CH2)2N(Me)—CH(Me)—



B13
MeO(CH2)2N(Me)—C(Me)2—



B14
MeO(CH2)2N(Me)—(CH2)2—



B15
MeO(CH2)2N(Me)—(CH2)3—



B16
pipe-CH(Me)—



B17
pipe-C(Me)2—



B18
pipe-(CH2)2—



B19
pipe-(CH2)3—



B20
(Azepan-1-yl)-CH(Me)—



B21
(Azepan-1-yl)-C(Me)2—



B22
(Azepan-1-yl)-(CH2)2—



B23
(Azepan-1-yl)-(CH2)3—



B24
(Azocan-1-yl)-CH(Me)—



B25
(Azocan-1-yl)-C(Me)2—



B26
(Azocan-1-yl)-(CH2)2—



B27
(Azocan-1-yl)-(CH2)3—

















TABLE 30













 










No
R12







C1
Me



C2
Et



C3
nPr



C4
iPr



C5
iBu



C6
sBu



C7
tBu



C8
tBuCH2—



C9
cPr



C10
cBu



C11
cPen



C12
cHex



C13
cPrCH2—



C14
cBuCH2—



C15
MeOCH2CH(Me)—



C16
MeO CH(Me)CH2—



C17
EtO(CH2)2—



C18
nPrO(CH2)2—



C19
iPrO(CH2)2—



C20
MeO(CH2)3—

















TABLE 31













 











No
X
R







D1
Cl
3-HO2C-pipe



D2
Cl
4-HO2CCH2-pipe



D3
Cl
4-HO2CCH2-pipa



D4
Cl
3-HO2CCH2-pyrr



D5
Cl
3-HO2CCH2-azet



D6
Cl
4-HO-pipe



D7
Cl
3-HO-pipe



D8
Cl
3-HO-pyrr



D9
Cl
4-HOCH2-pipe



D10
Cl
3-HO-4-HO2C-pipe



D11
Cl
4-HO-4-HO2C-pipe



D12
Cl
4-HO-4-HO2CCH2-pipe



D13
Cl
4-HO2CCH(OH)-pipe



D14
Cl
HO(CH2)2NH—



D15
Cl
HO(CH2)3N(Me)—



D16
Cl
HO(CH2)2N(Me)—



D17
Cl
HO(CH2)3O—



D18
Cl
HO(CH2)2O—



D19
Cl
HO2C(CH2)2NH—



D20
Cl
HO2CCH2NH—



D21
Cl
HO2C(CH2)3N(Me)—



D22
Cl
HO2C(CH2)2N(Me)—



D23
Cl
HO2CCH2N(Me)—



D24
Cl
HO2C(CH2)3O—



D25
Cl
HO2C(CH2)2O—



D26
Cl
HO2CCH2O—



D27
F
4-HO2C-pipe



D28
F
3-HO2C-pipe



D29
F
3-HO2C-pyrr



D30
F
4-HO2CCH2-pipe



D31
F
4-HO2CCH2-pipa



D32
F
3-HO2CCH2-pyrr



D33
F
3-HO2CCH2-azet



D34
F
4-HO-pipe



D35
F
3-HO-pipe



D36
F
3-HO-pyrr



D37
F
4-HOCH2-pipe



D38
F
4-HO2CCH2O-pipe



D39
F
3-HO-4-HO2C-pipe



D40
F
4-HO-4-HO2C-pipe



D41
F
4-HO-4-HO2CCH2-pipe



D42
F
4-HO2CCH(OH)-pipe



D43
F
HO(CH2)3NH—



D44
F
HO(CH2)2NH—



D45
F
HO(CH2)3N(Me)—



D46
F
HO(CH2)2N(Me)—



D47
F
HO(CH2)3O—



D48
F
HO(CH2)2O—



D49
F
HO2C(CH2)3NH—



D50
H
4-HO2C-pipe



D51
H
3-HO2C-pipe



D52
H
3-HO2C-pyrr



D53
H
3-HO2C-azet



D54
H
4-HO2CCH2-pipe



D55
H
4-HO2CCH2-pipa



D56
H
3-HO2CCH2-pyrr



D57
H
3-HO2CCH2-azet



D58
H
HO2C(CH2)3NH—



D59
H
HO2C(CH2)2NH—



D60
H
HO2CCH2NH—



D61
H
HO2C(CH2)3N(Me)—



D62
H
HO2C(CH2)2N(Me)—



D63
H
HO2CCH2N(Me)—



D64
H
HO2C(CH2)3O—



D65
H
HO2C(CH2)2O—



D66
H
HO2CCH2O—



D67
Br
4-HO2C-pipe



D68
Br
3-HO2C-pipe



D69
Br
3-HO2C-pyrr



D70
Br
3-HO2C-azet



D71
Br
4-HO2CCH2-pipe



D72
Br
4-HO2CCH2-pipa



D73
Br
3-HO2CCH2-pyrr



D74
Br
3-HO2CCH2-azet



D75
Br
HO2C(CH2)3NH—



D76
Br
HO2C(CH2)2NH—



D77
Br
HO2CCH2NH—



D78
Br
HO2C(CH2)3N(Me)—



D79
Br
HO2C(CH2)2N(Me)—



D80
Br
HO2CCH2N(Me)—



D81
Br
HO2C(CH2)3O—



D82
Br
HO2C(CH2)2O—



D83
Br
HO2CCH2O—



D84
CF3
4-HO2C-pipe



D85
F
HO2C(CH2)2NH—



D86
F
HO2CCH2NH—



D87
F
HO2C(CH2)3N(Me)—



D88
F
HO2C(CH2)2N(Me)—



D89
F
HO2CCH2N(Me)—



D90
F
HO2C(CH2)3O—



D91
F
HO2C(CH2)2O—



D92
F
HO2CCH2O—



D93
Me
4-HO2C-pipe



D94
Me
3-HO2C-pipe



D95
Me
3-HO2C-pyrr



D96
Me
3-HO2C-azet



D97
Me
4-HO2CCH2-pipe



D98
Me
4-HO2CCH2-pipa



D99
Me
3-HO2CCH2-pyrr



D100
Me
3-HO2CCH2-azet



D101
Me
HO2C(CH2)3NH—



D102
Me
HO2C(CH2)2NH—



D103
Me
HO2CCH2NH—



D104
Me
HO2C(CH2)3N(Me)—



D105
Me
HO2C(CH2)2N(Me)—



D106
Me
HO2CCH2N(Me)—



D107
Me
HO2C(CH2)3O—



D108
Me
HO2C(CH2)2O—



D109
Me
HO2CCH2O—



D110
MeO
4-HO2C-pipe



D111
MeO
3-HO2C-pipe



D112
MeO
3-HO2C-pyrr



D113
MeO
3-HO2C-azet



D114
MeO
4-HO2CCH2-pipe



D115
MeO
4-HO2CCH2-pipa



D116
MeO
3-HO2CCH2-pyrr



D117
MeO
3-HO2CCH2-azet



D118
MeO
HO2C(CH2)3NH—



D119
MeO
HO2C(CH2)2NH—



D120
MeO
HO2CCH2NH—



D121
CF3
3-HO2C-pipe



D122
CF3
3-HO2C-pyrr



D123
CF3
3-HO2C-azet



D124
CF3
4-HO2CCH2-pipe



D125
CF3
4-HO2CCH2-pipa



D126
CF3
3-HO2CCH2-pyrr



D127
CF3
3-HO2CCH2-azet



D128
CF3
HO2C(CH2)3NH—



D129
CF3
HO2C(CH2)2NH—



D130
CF3
HO2CCH2NH—



D131
CF3
HO2C(CH2)3N(Me)—



D132
CF3
HO2C(CH2)2N(Me)—



D133
CF3
HO2CCH2N(Me)—



D134
CF3
HO2C(CH2)3O—



D135
CF3
HO2C(CH2)2O—



D136
CF3
HO2CCH2O—



D137
MeO
HO2C(CH2)3N(Me)—



D138
MeO
HO2C(CH2)2N(Me)—



D139
MeO
HO2CCH2N(Me)—



D140
MeO
HO2C(CH2)3O—



D141
MeO
HO2C(CH2)2O—



D142
MeO
HO2CCH2O—



D143
Cl
3-HO2C-azet



D144
F
3-HO2C-azet

















TABLE 32













 










No
X
Y
R





E1
F
H
HO(CH2)3NH—


E2
F
H
HO(CH2)2NH—


E3
F
H
HO(CH2)3N(Me)—


E4
F
H
HO(CH2)2N(Me)—


E5
F
H
HO(CH2)3O—


E6
F
H
HO(CH2)2O—


E7
F
H
HO2C(CH2)3NH—


E8
F
H
HO2C(CH2)2NH—


E9
F
H
HO2CCH2NH—


E10
F
H
HO2C(CH2)3N(Me)—


E11
F
H
HO2C(CH2)2N(Me)—


E12
F
H
HO2CCH2N(Me)—


E13
F
H
HO2C(CH2)2O—


E14
F
H
HO2CCH2O—


E15
Cl
H
HO(CH2)3NH—


E16
Cl
H
HO(CH2)2NH—


E17
Cl
H
HO(CH2)3N(Me)—


E18
Cl
H
HO(CH2)2N(Me)—


E19
Cl
H
HO(CH2)3O—


E20
Cl
H
HO(CH2)2O—


E21
Cl
H
HO2C(CH2)3NH—


E22
Cl
H
HO2C(CH2)2NH—


E23
Cl
H
HO2CCH2NH—


E24
Cl
H
HO2C(CH2)3N(Me)—


E25
Cl
H
HO2C(CH2)2N(Me)—


E26
Cl
H
HO2CCH2N(Me)—


E27
F
F
HO(CH2)2NH—


E28
F
F
HO(CH2)3N(Me)—


E29
F
F
HO(CH2)2N(Me)—


E30
F
F
HO(CH2)3O—


E31
F
F
HO(CH2)2O—


E32
F
F
HO2C(CH2)3NH—


E33
F
F
HO2C(CH2)2NH—


E34
F
F
HO2CCH2NH—


E35
F
F
HO2C(CH2)3N(Me)—


E36
F
F
HO2C(CH2)2N(Me)—


E37
F
F
HO2CCH2N(Me)—


E38
F
F
HO2C(CH2)3O—


E39
F
F
HO2C(CH2)2O—


E40
F
F
HO2CCH2O—


E41
Cl
F
HO(CH2)3NH—


E42
Cl
F
HO(CH2)2NH—


E43
Cl
F
HO(CH2)3N(Me)—


E44
Cl
F
HO(CH2)2N(Me)—


E45
Cl
F
HO(CH2)3O—


E46
Cl
F
HO(CH2)2O—


E47
Cl
F
HO2C(CH2)3NH—


E48
Cl
F
HO2C(CH2)2NH—


E49
Cl
F
HO2CCH2NH—


E50
Cl
F
HO2C(CH2)3N(Me)—


E51
Cl
F
HO2C(CH2)2N(Me)—


E52
Cl
F
HO2CCH2N(Me)—


E53
Cl
H
HO2C(CH2)3O—


E54
Cl
H
HO2C(CH2)2O—


E55
Cl
H
HO2CCH2O—


E56
F
F
HO(CH2)3NH—


E57
H
H
4-HO2C-pipe


E58
H
H
3-HO2C-pipe


E59
H
H
3-HO2C-pyrr


E60
H
H
3-HO2C-azet


E61
H
H
4-HO2CCH2-pipe


E62
H
H
4-HO2CCH2-pipa


E63
H
H
3-HO2CCH2-pyrr


E64
H
H
3-HO2CCH2-azet


E65
H
H
HO2C(CH2)3NH—


E66
H
H
HO2C(CH2)2NH—


E67
H
H
HO2CCH2NH—


E68
H
H
HO2C(CH2)3N(Me)—


E69
H
H
HO2C(CH2)2N(Me)—


E70
H
H
HO2CCH2N(Me)—


E71
H
H
HO2C(CH2)3O—


E72
H
H
HO2C(CH2)2O—


E73
H
H
HO2CCH2O—


E74
Br
H
4-HO2C-pipe


E75
Br
H
3-HO2C-pipe


E76
Br
H
3-HO2C-pyrr


E77
Br
H
3-HO2C-azet


E78
Br
H
4-HO2CCH2-pipe


E79
Br
H
4-HO2CCH2-pipa


E80
Br
H
3-HO2CCH2-pyrr


E81
Br
H
3-HO2CCH2-azet


E82
Br
H
HO2C(CH2)3NH—


E83
Br
H
HO2C(CH2)2NH—


E84
Br
H
HO2CCH2NH—


E85
Br
H
HO2C(CH2)3N(Me)—


E86
Br
H
HO2C(CH2)2N(Me)—


E87
Br
H
HO2CCH2N(Me)—


E88
Br
H
HO2C(CH2)3O—


E89
Br
H
HO2C(CH2)2O—


E90
Br
H
HO2CCH2O—


E91
CF3
H
4-HO2C-pipe


E92
CF3
H
3-HO2C-pipe


E93
CF3
H
3-HO2C-pyrr


E94
CF3
H
3-HO2C-azet


E95
CF3
H
4-HO2CCH2-pipe


E96
CF3
H
4-HO2CCH2-pipa


E97
Cl
F
HO2C(CH2)3O—


E98
Cl
F
HO2C(CH2)2O—


E99
Cl
F
HO2CCH2O—


E100
Me
H
4-HO2C-pipe


E101
Me
H
3-HO2C-pipe


E102
Me
H
3-HO2C-pyrr


E103
Me
H
3-HO2C-azet


E104
Me
H
4-HO2CCH2-pipe


E105
Me
H
4-HO2CCH2-pipa


E106
Me
H
3-HO2CCH2-pyrr


E107
Me
H
3-HO2CCH2-azet


E108
Me
H
HO2C(CH2)3NH—


E109
Me
H
HO2C(CH2)2NH—


E110
Me
H
HO2CCH2NH—


E111
Me
H
HO2C(CH2)3N(Me)—


E112
Me
H
HO2C(CH2)2N(Me)—


E113
Me
H
HO2CCH2N(Me)—


E114
Me
H
HO2C(CH2)3O—


E115
Me
H
HO2C(CH2)2O—


E116
Me
H
HO2CCH2O—


E117
MeO
H
4-HO2C-pipe


E118
MeO
H
3-HO2C-pipe


E119
MeO
H
3-HO2C-pyrr


E120
MeO
H
3-HO2C-azet


E121
MeO
H
4-HO2CCH2-pipe


E122
MeO
H
4-HO2CCH2-pipa


E123
MeO
H
3-HO2CCH2-pyrr


E124
MeO
H
3-HO2CCH2-azet


El25
MeO
H
HO2C(CH2)3NH—


E126
MeO
H
HO2C(CH2)2NH—


E127
MeO
H
HO2CCH2NH—


E128
MeO
H
HO2C(CH2)3N(Me)—


E129
MeO
H
HO2C(CH2)2N(Me)—


E130
MeO
H
HO2CCH2N(Me)—


E131
MeO
H
HO2C(CH2)3O—


E132
MeO
H
HO2C(CH2)2O—


E133
MeO
H
HO2CCH2O—


E134
Cl
H
4-HO2C-pipe


E135
Cl
H
3-HO2C-pipe


E136
Cl
H
3-HO2C-pyrr


El37
Cl
H
3-HO2C-azet


E138
Cl
H
4-HO2CCH2-pipe


E139
Cl
H
4-HO2CCH2-pipa


E140
Cl
H
3-HO2CCH2-pyrr


E141
CF3
H
3-HO2CCH2-pyrr


E142
CF3
H
3-HO2CCH2-azet


E143
CF3
H
HO2C(CH2)3NH—


E144
CF3
H
HO2C(CH2)2NH—


E145
CF3
H
HO2CCH2NH—


E146
CF3
H
HO2C(CH2)2NH—


E147
CF3
H
HO2CCH2N(Me)—


E148
CF3
H
HO2C(CH2)3O—


E149
CF3
H
HO2C(CH2)2O—


E150
CF3
H
HO2CCH2O—


E151
Cl
H
3-HO2CCH2-azet


E152
F
H
4-HO2C-pipe


E153
F
H
3-HO2C-pipe


E154
F
H
3-HO2C-pyrr


E155
CF3
H
HO2C(CH2)3N(Me)—


E156
F
H
3-HO2C-azet


E157
F
H
4-HO2CCH2-pipe


E158
F
H
4-HO2CCH2-pipa


E159
F
H
3-HO2CCH2-pyrr


E160
F
H
3-HO2CCH2-azet
















TABLE 33













 








No
R1





F1
1-Me-piperidin-2-yl


F2
1-Me-pyrrolidin-2-yl


F3
1-Me-azepan-2-yl


F4
1-Et-piperidin-2-yl


F5
1,4-diMe-piperidin-2-yl


F6
1-Me-4-nPr-piperidin-2-yl


F7
1-Me-4-nPrO-piperidin-2-yl


F8
1-Me-4-F-piperidin-2-yl


F9
1,5-diMe-piperidin-2-yl


F10
1-Me-5-nPr-piperidin-2-yl


F11
1-Me-5-nPrO-piperidin-2-yl


F12
1-Me-5-F-piperidin-2-yl


F13
1,6-diMe-piperidin-2-yl


F14
1-Me-6-nPr-piperidin-2-yl
















TABLE 34













 











No
R1
R







G1
2-Me-pyrr
4-HO2C-pipe



G2
2-Me-pyrr
3-HO2C-pipe



G3
2-Me-pyrr
3-HO2C-pyrr



G4
2-Me-pyrr
3-HO2C-azet



G5
2-Me-pyrr
4-HO2CCH2-pipe



G6
2-Me-pyrr
4-HO2CCH2-pipa



G7
2-Me-pyrr
3-HO2CCH2-pyrr



G8
2-Me-pyrr
3-HO2CCH2-azet



G9
3-Me-pyrr
4-HO2C-pipe



G10
3-Me-pyrr
3-HO2C-pipe



G11
3-Me-pyrr
3-HO2C-pyrr



G12
3-Me-pyrr
3-HO2C-azet



G13
3-Me-pyrr
4-HO2CCH2-pipe



G14
3-Me-pyrr
4-HO2CCH2-pipa



G15
3-Me-pyrr
3-HO2CCH2-pyrr



G16
3-Me-pyrr
3-HO2CCH2-azet



G17
2-Me-pyrr
HO2C(CH2)3NH—



G18
2-Me-pyrr
HO2C(CH2)2NH—



G19
2-Me-pyrr
HO2CCH2NH—



G20
2-Me-pyrr
HO2C(CH2)3N(Me)—



G21
2-Me-pyrr
HO2C(CH2)2N(Me)—



G22
2-Me-pyrr
HO2CCH2N(Me)—



G23
2-Me-pyrr
HO2C(CH2)3O—



G24
2-Me-pyrr
HO2C(CH2)2O—



G25
2-Me-pyrr
HO2CCH2O—



G26
iBuN(Me)—
4-HO2C-pipe



G27
iBuN(Me)—
3-HO2C-pipe



G28
iBuN(Me)—
3-HO2C-pyrr



G29
iBuN(Me)—
3-HO2C-azet



G30
iBuN(Me)—
4-HO2CCH2-pipe



G31
iBuN(Me)—
4-HO2CCH2-pipa



G32
iBuN(Me)—
3-HO2CCH2-pyrr



G33
iBuN(Me)—
3-HO2CCH2-azet



G34
iBuN(Me)—
HO2C(CH2)3NH—



G35
iBuN(Me)—
HO2C(CH2)2NH—



G36
iBuN(Me)—
HO2CCH2NH—



G37
iBuN(Me)—
HO2C(CH2)3N(Me)—



G38
iBuN(Me)—
HO2C(CH2)2N(Me)—



G39
iBuN(Me)—
HO2CCH2N(Me)—



G40
iBuN(Me)—
HO2C(CH2)3O—



G41
iBuN(Me)—
HO2C(CH2)2O—



G42
iBuN(Me)—
HO2CCH2O—



G43
iPrN(Me)—
4-HO2C-pipe



G44
iPrN(Me)—
3-HO2C-pipe



G45
iPrN(Me)—
3-HO2C-pyrr



G46
iPrN(Me)—
3-HO2C-azet



G47
iPrN(Me)—
4-HO2CCH2-pipe



G48
iPrN(Me)—
4-HO2CCH2-pipa



G49
iPrN(Me)—
3-HO2CCH2-pyrr



G50
iPrN(Me)—
3-HO2CCH2-azet



G51
iPrN(Me)—
HO2C(CH2)3NH—



G52
iPrN(Me)—
HO2C(CH2)2NH—



G53
iPrN(Me)—
HO2CCH2NH—



G54
iPrN(Me)—
HO2C(CH2)3N(Me)—



G55
iPrN(Me)—
HO2C(CH2)2N(Me)—



G56
iPrN(Me)—
HO2CCH2N(Me)—



G57
iPrN(Me)—
HO2C(CH2)3O—



G58
iPrN(Me)—
HO2C(CH2)2O—



G59
iPrN(Me)—
HO2CCH2O—



G60
3-Me-pyrr
HO2C(CH2)3NH—



G61
3-Me-pyrr
HO2C(CH2)2NH—



G62
3-Me-pyrr
HO2CCH2NH—



G63
3-Me-pyrr
HO2C(CH2)3N(Me)—



G64
3-Me-pyrr
HO2C(CH2)2N(Me)—



G65
3-Me-pyrr
HO2CCH2N(Me)—



G66
3-Me-pyrr
HO2C(CH2)3O—



G67
3-Me-pyrr
HO2C(CH2)2O—



G68
3-Me-pyrr
HO2CCH2O—



G69
cBuN(Me)—
4-HO2C-pipe



G70
cBuN(Me)—
3-HO2C-pipe



G71
cBuN(Me)—
3-HO2C-pyrr



G72
cBuN(Me)—
3-HO2C-azet



G73
cBuN(Me)—
4-HO2CCH2-pipe



G74
cBuN(Me)—
4-HO2CCH2-pipa



G75
cBuN(Me)—
3-HO2CCH2-pyrr



G76
cBuN(Me)—
3-HO2CCH2-azet



G77
cBuN(Me)—
HO2C(CH2)3NH—



G78
cBuN(Me)—
HO2C(CH2)2NH—



G79
cBuN(Me)—
HO2CCH2NH—



G80
cBuN(Me)—
HO2C(CH2)3N(Me)—



G81
cBuN(Me)—
HO2C(CH2)2N(Me)—



G82
cBuN(Me)—
HO2CCH2N(Me)—



G83
cBuN(Me)—
HO2C(CH2)3O—



G84
cBuN(Me)—
HO2C(CH2)2O—



G85
cBuN(Me)—
HO2CCH2O—



G86
Me2N—
4-HO2C-pipe



G87
Me2N—
3-HO2C-pipe



G88
Me2N—
3-HO2C-pyrr



G89
Me2N—
3-HO2C-azet



G90
Me2N—
4-HO2CCH2-pipe



G91
Me2N—
4-HO2CCH2-pipa



G92
Me2N—
3-HO2CCH2-pyrr



G93
Me2N—
3-HO2CCH2-azet



G94
Me2N—
HO2C(CH2)3NH—



G95
Me2N—
HO2C(CH2)2NH—



G96
Me2N—
HO2CCH2NH—



G97
Me2N—
HO2C(CH2)3N(Me)—



G98
Me2N—
HO2C(CH2)2N(Me)—



G99
Me2N—
HO2CCH2N(Me)—



G100
Me2N—
HO2C(CH2)3O—



G101
Me2N—
HO2C(CH2)2O—



G102
Me2N—
HO2CCH2O—

















TABLE 35













 











No
R1
R







H1
2-Me-pyrr
4-HO2C-pipe



H2
2-Me-pyrr
3-HO2C-pipe



H3
2-Me-pyrr
3-HO2C-pyrr



H4
2-Me-pyrr
3-HO2C-azet



H5
2-Me-pyrr
4-HO2CCH2-pipe



H6
2-Me-pyrr
4-HO2CCH2-pipa



H7
2-Me-pyrr
3-HO2CCH2-pyrr



H8
2-Me-pyrr
3-HO2CCH2-azet



H9
2-Me-pyrr
HO2C(CH2)3NH—



H10
2-Me-pyrr
HO2C(CH2)2NH—



H11
2-Me-pyrr
HO2CCH2NH—



H12
2-Me-pyrr
HO2C(CH2)3N(Me)—



H13
2-Me-pyrr
HO2C(CH2)2N(Me)—



H14
2-Me-pyrr
HO2CCH2N(Me)—



H15
2-Me-pyrr
HO2C(CH2)3O—



H16
2-Me-pyrr
HO2C(CH2)2O—



H17
2-Me-pyrr
HO2CCH2O—



H18
iBuN(Me)—
4-HO2C-pipe



H19
iBuN(Me)—
3-HO2C-pipe



H20
iBuN(Me)—
3-HO2C-pyrr



H21
iBuN(Me)—
3-HO2C-azet



H22
iBuN(Me)—
4-HO2CCH2-pipe



H23
iBuN(Me)—
4-HO2CCH2-pipa



H24
iBuN(Me)—
3-HO2CCH2-pyrr



H25
iBuN(Me)—
3-HO2CCH2-azet



H26
iBuN(Me)—
HO2C(CH2)3NH—



H27
iBuN(Me)—
HO2C(CH2)2NH—



H28
iBuN(Me)—
HO2CCH2NH—



H29
iBuN(Me)—
HO2C(CH2)3N(Me)—



H30
iBuN(Me)—
HO2C(CH2)2N(Me)—



H31
iBuN(Me)—
HO2CCH2N(Me)—



H32
iBuN(Me)—
HO2C(CH2)3O—



H33
iBuN(Me)—
HO2C(CH2)2O—



H34
iBuN(Me)—
HO2CCH2O—



H35
iPrN(Me)—
4-HO2C-pipe



H36
iPrN(Me)—
3-HO2C-pipe



H37
iPrN(Me)—
3-HO2C-pyrr



H38
iPrN(Me)—
3-HO2C-azet



H39
iPrN(Me)—
4-HO2CCH2-pipe



H40
3-Me-pyrr
4-HO2C-pipe



H41
3-Me-pyrr
3-HO2C-pipe



H42
3-Me-pyrr
3-HO2C-pyrr



H43
3-Me-pyrr
3-HO2C-azet



H44
3-Me-pyrr
4-HO2CCH2-pipe



H45
3-Me-pyrr
4-HO2CCH2-pipa



H46
3-Me-pyrr
3-HO2CCH2-pyrr



H47
3-Me-pyrr
3-HO2CCH2-azet



H48
3-Me-pyrr
HO2C(CH2)3NH—



H49
3-Me-pyrr
HO2C(CH2)2NH—



H50
3-Me-pyrr
HO2CCH2NH—



H51
3-Me-pyrr
HO2C(CH2)3N(Me)—



H52
3-Me-pyrr
HO2C(CH2)2N(Me)—



H53
3-Me-pyrr
HO2CCH2N(Me)—



H54
3-Me-pyrr
HO2C(CH2)3O—



H55
3-Me-pyrr
HO2C(CH2)2O—



H56
3-Me-pyrr
HO2CCH2O—



H57
cBuN(Me)—
4-HO2C-pipe



H58
cBuN(Me)—
3-HO2C-pipe



H59
cBuN(Me)—
3-HO2C-pyrr



H60
cBuN(Me)—
3-HO2C-azet



H61
cBuN(Me)—
4-HO2CCH2-pipe



H62
cBuN(Me)—
4-HO2CCH2-pipa



H63
cBuN(Me)—
3-HO2CCH2-pyrr



H64
cBuN(Me)—
3-HO2CCH2-azet



H65
cBuN(Me)—
HO2C(CH2)3NH—



H66
cBuN(Me)—
HO2C(CH2)2NH—



H67
cBuN(Me)—
HO2CCH2NH—



H68
cBuN(Me)—
HO2C(CH2)3N(Me)—



H69
cBuN(Me)—
HO2C(CH2)2N(Me)—



H70
cBuN(Me)—
HO2CCH2N(Me)—



H71
cBuN(Me)—
HO2C(CH2)3O—



H72
cBuN(Me)—
HO2C(CH2)2O—



H73
cBuN(Me)—
HO2CCH2O—



H74
Me2N—
4-HO2C-pipe



H75
Me2N—
3-HO2C-pipe



H76
Me2N—
3-HO2C-pyrr



H77
Me2N—
3-HO2C-azet



H78
Me2N—
4-HO2CCH2-pipe



H79
iPrN(Me)—
4-HO2CCH2-pipa



H80
iPrN(Me)—
3-HO2CCH2-pyrr



H81
iPrN(Me)—
3-HO2CCH2-azet



H82
iPrN(Me)—
HO2C(CH2)3NH—



H83
iPrN(Me)—
HO2C(CH2)2NH—



H84
iPrN(Me)—
HO2CCH2NH—



H85
iPrN(Me)—
HO2C(CH2)3N(Me)—



H86
iPrN(Me)—
HO2C(CH2)2N(Me)—



H87
iPrN(Me)—
HO2CCH2N(Me)—



H88
iPrN(Me)—
HO2C(CH2)3O—



H89
iPrN(Me)—
HO2C(CH2)2O—



H90
iPrN(Me)—
HO2CCH2O—



H91
Me2N—
4-HO2CCH2-pipa



H92
Me2N—
3-HO2CCH2-pyrr



H93
Me2N—
3-HO2CCH2-azet



H94
Me2N—
HO2C(CH2)3NH—



H95
Me2N—
HO2C(CH2)2NH—



H96
Me2N—
HO2CCH2NH—



H97
Me2N—
HO2C(CH2)3N(Me)—



H98
Me2N—
HO2C(CH2)2N(Me)—



H99
Me2N—
HO2CCH2N(Me)—



H100
Me2N—
HO2C(CH2)3O—



H101
Me2N—
HO2C(CH2)2O—



H102
Me2N—
HO2CCH2O—

















TABLE 36













 











No
R2
X
Y
R





I1
4-Cl-2-The
N
Cl
4-HO(CH2)2-pipe


I2
4-Cl-2-The
N
Cl
4-MeO-pipe


I3
4-Cl-2-The
N
Cl
MeO(CH2)3O—


I4
4-Cl-2-The
N
Cl
MeO(CH2)2O—


I5
4-Cl-2-The
N
Cl
H2O3P—(CH2)3NH—


I6
4-Cl-2-The
N
Cl
4-H2O3P-pipe


I7
4-Cl-2-The
N
Cl
(EtO)2(O)P—(CH2)3NH—


I8
4-Cl-2-The
N
Cl
4-(EtO)2(O)P-pipe


I9
4-Cl-2-The
N
Cl
4-NC-pipe


I10
4-Cl-2-The
N
Cl
3-oxo-pipa


I11
4-Cl-2-The
C—H
Cl
4-HO-pipe


I12
4-Cl-2-The
C—H
Cl
4-HOCH2-pipe


I13
4-Cl-2-The
C—H
Cl
4-HO(CH2)2-pipe


I14
4-Cl-2-The
C—H
Cl
4-MeO-pipe


I15
4-Cl-2-The
C—H
Cl
MeO(CH2)3O—


I16
4-Cl-2-The
C—H
Cl
MeO(CH2)2O—


I17
4-Cl-2-The
C—H
Cl
H2O3P—(CH2)3NH—


I18
4-Cl-2-The
C—H
Cl
4-H2O3P-pipe


I19
4-Cl-2-The
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


I20
4-Cl-2-The
C—H
Cl
4-(EtO)2(O)P-pipe


I21
4-Cl-2-The
C—H
Cl
4-NC-pipe


I22
4-Cl-2-The
C—H
Cl
3-oxo-pipa


I23
4-Cl-2-The
C—F
F
4-HO-pipe


I24
4-Cl-2-The
C—F
F
4-HOCH2-pipe


I25
4-Cl-2-The
C—F
F
4-HO(CH2)2-pipe


I26
4-Cl-2-The
C—F
F
4-MeO-pipe


I27
4-Cl-2-The
C—F
F
MeO(CH2)3O—


I28
4-Cl-2-The
C—F
F
MeO(CH2)2O—


I29
4-Cl-2-The
C—F
F
H2O3P—(CH2)3NH—


I30
4-Cl-2-The
C—F
F
4-H2O3P-pipe


I31
4-Cl-2-The
C—F
F
(EtO)2(O)P—(CH2)3NH—


I32
4-Cl-2-The
C—F
F
4-(EtO)2(O)P-pipe


I33
4-Cl-2-The
C—F
F
4-NC-pipe


I34
4-Cl-2-The
C—F
F
3-oxo-pipa


I35
4-Me-2-The
N
Cl
HO(CH2)3NH—


I36
4-Me-2-The
N
Cl
HO(CH2)3N(Me)—


I37
4-Me-2-The
N
Cl
HO(CH2)3O—


I38
4-Me-2-The
N
Cl
HO(CH2)2O—


I39
4-Me-2-The
N
Cl
4-HO-pipe


I40
4-Me-2-The
N
Cl
4-HOCH2-pipe


I41
4-Me-2-The
N
Cl
4-HO(CH2)2-pipe


I42
4-Me-2-The
N
Cl
4-MeO-pipe


I43
4-Me-2-The
N
Cl
MeO(CH2)3O—


I44
4-Me-2-The
N
Cl
MeO(CH2)2O—


I45
4-Me-2-The
N
Cl
H2O3P—(CH2)3NH—


I46
4-Me-2-The
N
Cl
4-H2O3P-pipe


I47
4-Me-2-The
N
Cl
(EtO)2(O)P—(CH2)3NH—


I48
4-Me-2-The
N
Cl
4-(EtO)2(O)P-pipe


I49
4-Me-2-The
N
Cl
4-NC-pipe


I50
4-Me-2-The
N
Cl
3-oxo-pipa


I51
4-Me-2-The
C—H
Cl
HO(CH2)3NH—


I52
4-Me-2-The
C—H
Cl
HO(CH2)3N(Me)—


I53
4-Me-2-The
C—H
Cl
HO(CH2)3O—


I54
4-Me-2-The
C—H
Cl
HO(CH2)2O—


I55
4-Me-2-The
C—H
Cl
4-HO-pipe


I56
4-Me-2-The
C—H
Cl
4-HOCH2-pipe


I57
4-Me-2-The
C—H
Cl
4-HO(CH2)2-pipe


I58
4-Me-2-The
C—H
Cl
4-MeO-pipe


I59
4-Me-2-The
C—H
Cl
MeO(CH2)3O—


I60
4-Me-2-The
C—H
Cl
MeO(CH2)2O—


I61
4-Me-2-The
C—H
Cl
H2O3P—(CH2)3NH—


I62
4-Me-2-The
C—H
Cl
4-H2O3P-pipe


I63
4-Me-2-The
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


I64
4-Me-2-The
C—H
Cl
4-(EtO)2(O)P-pipe


I65
4-Me-2-The
C—H
Cl
4-NC-pipe


I66
4-Me-2-The
C—H
Cl
3-oxo-pipa


I67
4-Me-2-The
C—F
F
HO(CH2)3NH—


I68
4-Me-2-The
C—F
F
HO(CH2)3N(Me)—


I69
4-Me-2-The
C—F
F
HO(CH2)3O—


I70
4-Me-2-The
C—F
F
HO(CH2)2O—


I71
4-Me-2-The
C—F
F
4-HO-pipe


I72
4-Me-2-The
C—F
F
4-HOCH2-pipe


I73
4-Me-2-The
C—F
F
4-HO(CH2)2-pipe


I74
4-Me-2-The
C—F
F
4-MeO-pipe


I75
4-Me-2-The
C—F
F
MeO(CH2)3O—


I76
4-Me-2-The
C—F
F
MeO(CH2)2O—


I77
4-Me-2-The
C—F
F
H2O3P—(CH2)3NH—


I78
4-Me-2-The
C—F
F
4-H2O3P-pipe


I79
4-Me-2-The
C—F
F
(EtO)2(O)P-(CH2)3NH—


I80
4-Me-2-The
C—F
F
4-(EtO)2(O)P-pipe


I81
4-Me-2-The
C—F
F
4-NC-pipe


I82
4-Me-2-The
C—F
F
3-oxo-pipa


I83
3-F3C-Ph
N
Cl
HO(CH2)3NH—


I84
3-F3C-Ph
N
Cl
HO(CH2)3N(Me)—


I85
3-F3C-Ph
N
Cl
HO(CH2)3O—


I86
3-F3C-Ph
N
Cl
HO(CH2)2O—


I87
3-F3C-Ph
N
Cl
4-HO-pipe


I88
3-F3C-Ph
N
Cl
4-HOCH2-pipe


I89
3-F3C-Ph
N
Cl
4-HO(CH2)2-pipe


I90
3-F3C-Ph
N
Cl
4-MeO-pipe


I91
3-F3C-Ph
N
Cl
MeO(CH2)3O—


I92
3-F3C-Ph
N
Cl
MeO(CH2)2O—


I93
3-F3C-Ph
N
Cl
H2O3P—(CH2)3NH—


I94
3-F3C-Ph
N
Cl
4-H2O3P-pipe


I95
3-F3C-Ph
N
Cl
(EtO)2(O)P-(CH2)3NH—


I96
3-F3C-Ph
N
Cl
4-(EtO)2(O)P-pipe


I97
3-F3C-Ph
N
Cl
4-NC-pipe


I98
3-F3C-Ph
N
Cl
3-oxo-pipa


I99
3-F3C-Ph
C—H
Cl
HO(CH2)3NH—


I100
3-F3C-Ph
C—H
Cl
HO(CH2)3N(Me)—


I101
3-F3C-Ph
C—H
Cl
HO(CH2)3O—


I102
3-F3C-Ph
C—H
Cl
HO(CH2)2O—


I103
3-F3C-Ph
C—H
Cl
4-HO-pipe


I104
3-F3C-Ph
C—H
Cl
4-HOCH2-pipe


I105
3-F3C-Ph
C—H
Cl
4-HO(CH2)2-pipe


I106
3-F3C-Ph
C—H
Cl
4-MeO-pipe


I107
3-F3C-Ph
C—H
Cl
MeO(CH2)3O—


I108
3-F3C-Ph
C—H
Cl
MeO(CH2)2O—


I109
3-F3C-Ph
C—H
Cl
H2O3P—(CH2)3NH—


I110
3-F3C-Ph
C—H
Cl
4-H2O3P-pipe


I111
3-F3C-Ph
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


I112
3-F3C-Ph
C—H
Cl
4-(EtO)2(O)P-pipe


I113
3-F3C-Ph
C—H
Cl
4-NC-pipe


I114
3-F3C-Ph
C—H
Cl
3-oxo-pipa


I115
3-F3C-Ph
C—F
F
HO(CH2)3NH—


I116
3-F3C-Ph
C—F
F
HO(CH2)3N(Me)—


I117
3-F3C-Ph
C—F
F
HO(CH2)3O—


I118
3-F3C-Ph
C—F
F
HO(CH2)2O—


I119
3-F3C-Ph
C—F
F
4-HO-pipe


I120
3-F3C-Ph
C—F
F
4-HOCH2-pipe


I121
3-F3C-Ph
C—F
F
4-HO(CH2)2-pipe


I122
3-F3C-Ph
C—F
F
4-MeO-pipe


I123
3-F3C-Ph
C—F
F
MeO(CH2)3O—


I124
3-F3C-Ph
C—F
F
MeO(CH2)2O—


I125
3-F3C-Ph
C—F
F
H2O3P—(CH2)3NH—


I126
3-F3C-Ph
C—F
F
4-H2O3P-pipe


I127
3-F3C-Ph
C—F
F
(EtO)2(O)P—(CH2)3NH—


I128
3-F3C-Ph
C—F
F
4-(EtO)2(O)P-pipe


I129
3-F3C-Ph
C—F
F
4-NC-pipe


I130
3-F3C-Ph
C—F
F
3-oxo-pipa
















TABLE 37













 











No
R1
X
Y
R





J1
cBuN(Me)—
N
Cl
HO(CH2)3NH—


J2
cBuN(Me)—
N
Cl
HO(CH2)3N(Me)—


J3
cBuN(Me)—
N
Cl
HO(CH2)3O—


J4
cBuN(Me)—
N
Cl
HO(CH2)2O—


J5
cBuN(Me)—
N
Cl
4-HO-pipe


J6
cBuN(Me)—
N
Cl
4-HOCH2-pipe


J7
cBuN(Me)—
N
Cl
4-HO(CH2)2-pipe


J8
cBuN(Me)—
N
Cl
4-MeO-pipe


J9
cBuN(Me)—
N
Cl
MeO(CH2)3O—


J10
cBuN(Me)—
N
Cl
MeO(CH2)2O—


J11
cBuN(Me)—
N
Cl
H2O3P—(CH2)3NH—


J12
cBuN(Me)—
N
Cl
4-H2O3P-pipe


J13
cBuN(Me)—
N
Cl
(EtO)2(O)P—(CH2)3NH—


J14
cBuN(Me)—
N
Cl
4-(EtO)2(O)P-pipe


J15
cBuN(Me)—
N
Cl
4-NC-pipe


J16
cBuN(Me)—
N
Cl
3-oxo-pipa


J17
cBuN(Me)—
C—H
Cl
HO(CH2)3NH—


J18
cBuN(Me)—
C—H
Cl
HO(CH2)3N(Me)—


J19
cBuN(Me)—
C—H
Cl
HO(CH2)3O—


J20
cBuN(Me)—
C—H
Cl
HO(CH2)2O—


J21
cBuN(Me)—
C—H
Cl
4-HO-pipe


J22
cBuN(Me)—
C—H
Cl
4-HOCH2-pipe


J23
cBuN(Me)—
C—H
Cl
4-HO(CH2)2-pipe


J24
cBuN(Me)—
C—H
Cl
4-MeO-pipe


J25
cBuN(Me)—
C—H
Cl
MeO(CH2)3O—


J26
cBuN(Me)—
C—H
Cl
MeO(CH2)2O—


J27
cBuN(Me)—
C—H
Cl
H2O3P—(CH2)3NH—


J28
cBuN(Me)—
C—H
Cl
4-H2O3P-pipe


J29
cBuN(Me)—
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J30
cBuN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


J31
cBuN(Me)—
C—H
Cl
4-NC-pipe


J32
cBuN(Me)—
C—H
Cl
3-oxo-pipa


J33
iBuN(Me)—
N
Cl
HO(CH2)3NH—


J34
iBuN(Me)—
N
Cl
HO(CH2)3N(Me)—


J35
iBuN(Me)—
N
Cl
HO(CH2)3O—


J36
iBuN(Me)—
N
Cl
HO(CH2)2O—


J37
iBuN(Me)—
N
Cl
4-HO-pipe


J38
iBuN(Me)—
N
Cl
4-HOCH2-pipe


J39
iBuN(Me)—
N
Cl
4-HO(CH2)2-pipe


J40
iBuN(Me)—
N
Cl
4-MeO-pipe


J41
iBuN(Me)—
N
Cl
MeO(CH2)3O—


J42
iBuN(Me)—
N
Cl
MeO(CH2)2O—


J43
iBuN(Me)—
N
Cl
H2O3P—(CH2)3NH—


J44
iBuN(Me)—
N
Cl
4-H2O3P-pipe


J45
iBuN(Me)—
N
Cl
(EtO)2(O)P—(CH2)3NH—


J46
iBuN(Me)—
N
Cl
4-(EtO)2(O)P-pipe


J47
iBuN(Me)—
N
Cl
4-NC-pipe


J48
iBuN(Me)—
N
Cl
3-oxo-pipa


J49
iBuN(Me)—
C—H
Cl
HO(CH2)3NH—


J50
iBuN(Me)—
C—H
Cl
HO(CH2)3N(Me)—


J51
iBuN(Me)—
C—H
Cl
HO(CH2)3O—


J52
iBuN(Me)—
C—H
Cl
HO(CH2)2O—


J53
iBuN(Me)—
C—H
Cl
4-HO-pipe


J54
iBuN(Me)—
C—H
Cl
4-HOCH2-pipe


J55
iBuN(Me)—
C—H
Cl
4-HO(CH2)2-pipe


J56
iBuN(Me)—
C—H
Cl
4-MeO-pipe


J57
iBuN(Me)—
C—H
Cl
MeO(CH2)3O—


J58
iBuN(Me)—
C—H
Cl
MeO(CH2)2O—


J59
iBuN(Me)—
C—H
Cl
H2O3P—(CH2)3NH—


J60
iBuN(Me)—
C—H
Cl
4-H2O3P-pipe


J61
iBuN(Me)—
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J62
iBuN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


J63
iBuN(Me)—
C—H
Cl
4-NC-pipe


J64
iBuN(Me)—
C—H
Cl
3-oxo-pipa


J65
pipe
N
Cl
HO(CH2)3NH—


J66
pipe
N
Cl
HO(CH2)3N(Me)—


J67
pipe
N
Cl
HO(CH2)3O—


J68
pipe
N
Cl
HO(CH2)2O—


J69
pipe
N
Cl
4-HO-pipe


J70
pipe
N
Cl
4-HOCH2-pipe


J71
pipe
N
Cl
4-HO(CH2)2-pipe


J72
pipe
N
Cl
4-MeO-pipe


J73
pipe
N
Cl
MeO(CH2)3O—


J74
pipe
N
Cl
MeO(CH2)2O—


J75
pipe
N
Cl
H2O3P—(CH2)3NH—


J76
pipe
N
Cl
4-H2O3P-pipe


J77
pipe
N
Cl
(EtO)2(O)P—(CH2)3NH—


J78
pipe
N
Cl
4-(EtO)2(O)P-pipe


J79
pipe
N
Cl
4-NC-pipe


J80
pipe
N
Cl
3-oxo-pipa


J81
pipe
C—H
Cl
HO(CH2)3NH—


J82
pipe
C—H
Cl
HO(CH2)3N(Me)—


J83
pipe
C—H
Cl
HO(CH2)3O—


J84
pipe
C—H
Cl
HO(CH2)2O—


J85
pipe
C—H
Cl
4-HO-pipe


J86
pipe
C—H
Cl
4-HOCH2-pipe


J87
pipe
C—H
Cl
4-HO(CH2)2-pipe


J88
pipe
C—H
Cl
4-MeO-pipe


J89
pipe
C—H
Cl
MeO(CH2)3O—


J90
pipe
C—H
Cl
MeO(CH2)2O—


J91
pipe
C—H
Cl
H2O3P—(CH2)3NH—


J92
pipe
C—H
Cl
4-H2O3P-pipe


J93
pipe
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J94
pipe
C—H
Cl
4-(EtO)2(O)P-pipe


J95
pipe
C—H
Cl
4-NC-pipe


J96
pipe
C—H
Cl
3-oxo-pipa


J97
2-Me-pyrr
N
Cl
HO(CH2)3NH—


J98
2-Me-pyrr
N
Cl
HO(CH2)3N(Me)—


J99
2-Me-pyrr
N
Cl
HO(CH2)3O—


J100
2-Me-pyrr
N
Cl
HO(CH2)2O—


J101
2-Me-pyrr
N
Cl
4-HO-pipe


J102
2-Me-pyrr
N
Cl
4-HOCH2-pipe


J103
2-Me-pyrr
N
Cl
4-HO(CH2)2-pipe


J104
2-Me-pyrr
N
Cl
4-MeO-pipe


J105
2-Me-pyrr
N
Cl
MeO(CH2)3O—


J106
2-Me-pyrr
N
Cl
MeO(CH2)2O—


J107
2-Me-pyrr
N
Cl
H2O3P—(CH2)3NH—


J108
2-Me-pyrr
N
Cl
4-H2O3P-pipe


J109
2-Me-pyrr
N
Cl
(EtO)2(O)P—(CH2)3NH—


J110
2-Me-pyrr
N
Cl
4-(EtO)2(O)P-pipe


J111
2-Me-pyrr
N
Cl
4-NC-pipe


J112
2-Me-pyrr
N
Cl
3-oxo-pipa


J113
2-Me-pyrr
C—H
Cl
HO(CH2)3NH—


J114
2-Me-pyrr
C—H
Cl
HO(CH2)3N(Me)—


J115
2-Me-pyrr
C—H
Cl
HO(CH2)3O—


J116
2-Me-pyrr
C—H
Cl
HO(CH2)2O—


J117
2-Me-pyrr
C—H
Cl
4-HO-pipe


J118
2-Me-pyrr
C—H
Cl
4-HOCH2-pipe


J119
2-Me-pyrr
C—H
Cl
4-HO(CH2)2-pipe


J120
2-Me-pyrr
C—H
Cl
4-MeO-pipe


J121
2-Me-pyrr
C—H
Cl
MeO(CH2)3O—


J122
2-Me-pyrr
C—H
Cl
MeO(CH2)2O—


J123
2-Me-pyrr
C—H
Cl
H2O3P—(CH2)3NH—


J124
2-Me-pyrr
C—H
Cl
4-H2O3P-pipe


J125
2-Me-pyrr
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J126
2-Me-pyrr
C—H
Cl
4-(EtO)2(O)P-pipe


J127
2-Me-pyrr
C—H
Cl
4-NC-pipe


J128
2-Me-pyrr
C—H
Cl
3-oxo-pipa


J129
3-Me-pyrr
N
Cl
HO(CH2)3NH—


J130
3-Me-pyrr
N
Cl
HO(CH2)3N(Me)—


J131
3-Me-pyrr
N
Cl
HO(CH2)3O—


J132
3-Me-pyrr
N
Cl
HO(CH2)2O—


J133
3-Me-pyrr
N
Cl
4-HO-pipe


J134
3-Me-pyrr
N
Cl
4-HOCH2-pipe


J135
3-Me-pyrr
N
Cl
4-HO(CH2)2-pipe


J136
3-Me-pyrr
N
Cl
4-MeO-pipe


J137
3-Me-pyrr
N
Cl
MeO(CH2)3O—


J138
3-Me-pyrr
N
Cl
MeO(CH2)2O—


J139
3-Me-pyrr
N
Cl
H2O3P—(CH2)3NH—


J140
3-Me-pyrr
N
Cl
4-H2O3P-pipe


J141
3-Me-pyrr
N
Cl
(EtO)2(O)P—(CH2)3NH—


J142
3-Me-pyrr
N
Cl
4-(EtO)2(O)P-pipe


J143
3-Me-pyrr
N
Cl
4-NC-pipe


J144
3-Me-pyrr
N
Cl
3-oxo-pipa


J145
3-Me-pyrr
C—H
Cl
HO(CH2)3NH—


J146
3-Me-pyrr
C—H
Cl
HO(CH2)3N(Me)—


J147
3-Me-pyrr
C—H
Cl
HO(CH2)3O—


J148
3-Me-pyrr
C—H
Cl
HO(CH2)2O—


J149
3-Me-pyrr
C—H
Cl
4-HO-pipe


J150
3-Me-pyrr
C—H
Cl
4-HOCH2-pipe


J151
3-Me-pyrr
C—H
Cl
4-HO(CH2)2-pipe


J152
3-Me-pyrr
C—H
Cl
4-MeO-pipe


J153
3-Me-pyrr
C—H
Cl
MeO(CH2)3O—


J154
3-Me-pyrr
C—H
Cl
MeO(CH2)2O—


J155
3-Me-pyrr
C—H
Cl
H2O3P—(CH2)3NH—


J156
3-Me-pyrr
C—H
Cl
4-H2O3P-pipe


J157
3-Me-pyrr
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J158
3-Me-pyrr
C—H
Cl
4-(EtO)2(O)P-pipe


J159
3-Me-pyrr
C—H
Cl
4-NC-pipe


J160
3-Me-pyrr
C—H
Cl
3-oxo-pipa


J161
iPrN(Me)—
N
Cl
HO(CH2)3NH—


J162
iPrN(Me)—
N
Cl
HO(CH2)3N(Me)—


J163
iPrN(Me)—
N
Cl
HO(CH2)3O—


J164
iPrN(Me)—
N
Cl
HO(CH2)2O—


J165
iPrN(Me)—
N
Cl
4-HO-pipe


J166
iPrN(Me)—
N
Cl
4-HOCH2-pipe


J167
iPrN(Me)—
N
Cl
4-HO(CH2)2-pipe


J168
iPrN(Me)—
N
Cl
4-MeO-pipe


J169
iPrN(Me)—
N
Cl
MeO(CH2)3O—


J170
iPrN(Me)—
N
Cl
MeO(CH2)2O—


J171
iPrN(Me)—
N
Cl
H2O3P—(CH2)3NH—


J172
iPrN(Me)—
N
Cl
4-H2O3P-pipe


J173
iPrN(Me)—
N
Cl
(EtO)2(O)P—(CH2)3NH—


J174
iPrN(Me)—
N
Cl
4-(EtO)2(O)P-pipe


J175
iPrN(Me)—
N
Cl
4-NC-pipe


J176
iPrN(Me)—
N
Cl
3-oxo-pipa


J177
iPrN(Me)—
C—H
Cl
HO(CH2)3NH—


J178
iPrN(Me)—
C—H
Cl
HO(CH2)3N(Me)—


J179
iPrN(Me)—
C—H
Cl
HO(CH2)3O—


J180
iPrN(Me)—
C—H
Cl
HO(CH2)2O—


J181
iPrN(Me)—
C—H
Cl
4-HO-pipe


J182
iPrN(Me)—
C—H
Cl
4-HOCH2-pipe


J183
iPrN(Me)—
C—H
Cl
4-HO(CH2)2-pipe


J184
iPrN(Me)—
C—H
Cl
4-MeO-pipe


J185
iPrN(Me)—
C—H
Cl
MeO(CH2)3O—


J186
iPrN(Me)—
C—H
Cl
MeO(CH2)2O—


J187
iPrN(Me)—
C—H
Cl
H2O3P—(CH2)3NH—


J188
iPrN(Me)—
C—H
Cl
4-H2O3P-pipe


J189
iPrN(Me)—
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J190
iPrN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


J191
iPrN(Me)—
C—H
Cl
4-NC-pipe


J192
iPrN(Me)—
C—H
Cl
3-oxo-pipa


J193
Me2N—
N
Cl
HO(CH2)3NH—


J194
Me2N—
N
Cl
HO(CH2)3N(Me)—


J195
Me2N—
N
Cl
HO(CH2)3O—


J196
Me2N—
N
Cl
HO(CH2)2O—


J197
Me2N—
N
Cl
4-HO-pipe


J198
Me2N—
N
Cl
4-HOCH2-pipe


J199
Me2N—
N
Cl
4-HO(CH2)2-pipe


J200
Me2N—
N
Cl
4-MeO-pipe


J201
Me2N—
N
Cl
MeO(CH2)3O—


J202
Me2N—
N
Cl
MeO(CH2)2O—


J203
Me2N—
N
Cl
H2O3P—(CH2)3NH—


J204
Me2N—
N
Cl
4-H2O3P-pipe


J205
Me2N—
N
Cl
(EtO)2(O)P—(CH2)3NH—


J206
Me2N—
N
Cl
4-(EtO)2(O)P-pipe


J207
Me2N—
N
Cl
4-NC-pipe


J208
Me2N—
N
Cl
3-oxo-pipa


J209
Me2N—
C—H
Cl
HO(CH2)3NH—


J210
Me2N—
C—H
Cl
HO(CH2)3N(Me)—


J211
Me2N—
C—H
Cl
HO(CH2)3O—


J212
Me2N—
C—H
Cl
HO(CH2)2O—


J213
Me2N—
C—H
Cl
4-HO-pipe


J214
Me2N—
C—H
Cl
4-HOCH2-pipe


J215
Me2N—
C—H
Cl
4-HO(CH2)2-pipe


J216
Me2N—
C—H
Cl
4-MeO-pipe


J217
Me2N—
C—H
Cl
MeO(CH2)3O—


J218
Me2N—
C—H
Cl
MeO(CH2)2O—


J219
Me2N—
C—H
Cl
H2O3P—(CH2)3NH—


J220
Me2N—
C—H
Cl
4-H2O3P-pipe


J221
Me2N—
C—H
Cl
(EtO)2(O)P—(CH2)3NH—


J222
Me2N—
C—H
Cl
4-(EtO)2(O)P-pipe


J223
Me2N—
C—H
Cl
4-NC-pipe


J224
Me2N—
C—H
Cl
3-oxo-pipa
















TABLE 38













 













No
R1
X
Y
R















K1
nBuN(Me)—
C—H
Cl
4-H2NOC-pipe


K2
nBuN(Me)—
C—F
F
4-H2NOC-pipe


K3
cBuN(Me)—
C—H
Cl
4-HO-pipe


K4
cBuN(Me)—
C—H
Cl
4-MeO-pipe


K5
cBuN(Me)—
C—H
Cl
4-H2O3P-pipe


K6
cBuN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


K7
cBuN(Me)—
C—H
Cl
4-NC-pipe


K8
cBuN(Me)—
C—H
Cl
4-H2NOC-pipe


K9
cBuN(Me)—
C—F
F
4-HO-pipe


K10
cBuN(Me)—
C—F
F
4-MeO-pipe


K11
cBuN(Me)—
C—F
F
4-H2O3P-pipe


K12
cBuN(Me)—
C—F
F
4-(EtO)2(O)P-pipe


K13
cBuN(Me)—
C—F
F
4-NC-pipe


K14
cBuN(Me)—
C—F
F
4-H2NOC-pipe


K15
iBuN(Me)—
C—H
Cl
4-HO-pipe


K16
iBuN(Me)—
C—H
Cl
4-MeO-pipe


K17
iBuN(Me)—
C—H
Cl
4-H2O3P-pipe


K18
iBuN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


K19
iBuN(Me)—
C—H
Cl
4-NC-pipe


K20
iBuN(Me)—
C—H
Cl
4-H2NOC-pipe


K21
iBuN(Me)—
C—F
F
4-HO-pipe


K22
iBuN(Me)—
C—F
F
4-MeO-pipe


K23
iBuN(Me)—
C—F
F
4-H2O3P-pipe


K24
iBuN(Me)—
C—F
F
4-(EtO)2(O)P-pipe


K25
iBuN(Me)—
C—F
F
4-NC-pipe


K26
iBuN(Me)—
C—F
F
4-H2NOC-pipe


K27
pipe
C—H
Cl
4-HO-pipe


K28
pipe
C—H
Cl
4-MeO-pipe


K29
pipe
C—H
Cl
4-H2O3P-pipe


K30
pipe
C—H
Cl
4-(EtO)2(O)P-pipe


K31
pipe
C—H
Cl
4-NC-pipe


K32
pipe
C—H
Cl
4-H2NOC-pipe


K33
pipe
C—F
F
4-HO-pipe


K34
pipe
C—F
F
4-MeO-pipe


K35
pipe
C—F
F
4-H2O3P-pipe


K36
pipe
C—F
F
4-(EtO)2(O)P-pipe


K37
pipe
C—F
F
4-NC-pipe


K38
pipe
C—F
F
4-H2NOC-pipe


K39
2-Me-pyrr
C—H
Cl
4-HO-pipe


K40
2-Me-pyrr
C—H
Cl
4-MeO-pipe


K41
2-Me-pyrr
C—H
Cl
4-H2O3P-pipe


K42
2-Me-pyrr
C—H
Cl
4-(EtO)2(O)P-pipe


K43
2-Me-pyrr
C—H
Cl
4-NC-pipe


K44
2-Me-pyrr
C—H
Cl
4-H2NOC-pipe


K45
2-Me-pyrr
C—F
F
4-HO-pipe


K46
2-Me-pyrr
C—F
F
4-MeO-pipe


K47
2-Me-pyrr
C—F
F
4-H2O3P-pipe


K48
2-Me-pyrr
C—F
F
4-(EtO)2(O)P-pipe


K49
2-Me-pyrr
C—F
F
4-NC-pipe


K50
2-Me-pyrr
C—F
F
4-H2NOC-pipe


K51
3-Me-pyrr
C—H
Cl
4-HO-pipe


K52
3-Me-pyrr
C—H
Cl
4-MeO-pipe


K53
3-Me-pyrr
C—H
Cl
4-H2O3P-pipe


K54
3-Me-pyrr
C—H
Cl
4-(EtO)2(O)P-pipe


K55
3-Me-pyrr
C—H
Cl
4-NC-pipe


K56
3-Me-pyrr
C—H
Cl
4-H2NOC-pipe


K57
3-Me-pyff
C—F
F
4-HO-pipe


K58
3-Me-pyrr
C—F
F
4-MeO-pipe


K59
3-Me-pyrr
C—F
F
4-H2O3P-pipe


K60
3-Me-pyrr
C—F
F
4-(EtO)2(O)P-pipe


K61
3-Me-pyrr
C—F
F
4-NC-pipe


K62
3-Me-pyrr
C—F
F
4-H2NOC-pipe


K63
iPrN(Me)—
C—H
Cl
4-HO-pipe


K64
iPrN(Me)—
C—H
Cl
4-MeO-pipe


K65
iPrN(Me)—
C—H
Cl
4-H2O3P-pipe


K66
iPrN(Me)—
C—H
Cl
4-(EtO)2(O)P-pipe


K67
iPrN(Me)—
C—H
Cl
4-NC-pipe


K68
iPrN(Me)—
C—H
Cl
4-H2NOC-pipe


K69
iPrN(Me)—
C—F
F
4-HO-pipe


K70
iPrN(Me)—
C—F
F
4-MeO-pipe


K71
iPrN(Me)—
C—F
F
4-H2O3P-pipe


K72
iPrN(Me)—
C—F
F
4-(EtO)2(O)P-pipe


K73
iPrN(Me)—
C—F
F
4-NC-pipe


K74
iPrN(Me)—
C—F
F
4-H2NOC-pipe


K75
Me2N—
C—H
Cl
4-HO-pipe


K76
Me2N—
C—H
Cl
4-MeO-pipe


K77
Me2N—
C—H
Cl
4-H2O3P-pipe


K78
Me2N—
C—H
Cl
4-(EtO)2(O)P-pipe


K79
Me2N—
C—H
Cl
4-NC-pipe


K80
Me2N—
C—H
Cl
4-H2NOC-pipe


K81
Me2N—
C—F
F
4-HO-pipe


K82
Me2N—
C—F
F
4-MeO-pipe


K83
Me2N—
C—F
F
4-H2O3P-pipe


K84
Me2N—
C—F
F
4-(EtO)2(O)P-pipe


K85
Me2N—
C—F
F
4-NC-pipe


K86
Me2N—
C—F
F
4-H2NOC-pipe
















TABLE 39













 










No
R







L1
3-HOCH2-pyrr



L2
3-HO(CH2)2-pyrr



L3
3-HOCH2-azet



L4
3-HO(CH2)2-azet



L5
3-HO-azet



L6
MeO(CH2)3NH—



L7
MeO(CH2)2NH—



L8
MeO(CH2)3N(Me)—



L9
MeO(CH2)2N(Me)—



L10
3-MeO-pipe



L11
3-MeO-pyrr



L12
4-MeOCH2-pipe



L13
4-MeO(CH2)2-pipe



L14
3-MeOCH2-pyrr



L15
3-MeO(CH2)2-pyrr



L16
3-MeOCH2-azet



L17
3-MeO(CH2)2-azet



L18
NC-(CH2)3NH—



L19
NC-(CH2)2NH—



L20
NC-(CH2)3N(Me)—



L21
NC-(CH2)2N(Me)—



L22
NC-(CH2)3O—



L23
NC-(CH2)2O—



L24
3-NC-pipe



L25
3-NC-pyrr



L26
4-NC-CH2-pipe



L27
4-NC-(CH2)2-pipe



L28
3-NCCH2-pyrr



L29
3-H2O3P(CH2)2-pyrr



L30
3-H2O3P CH2-azet



L31
3-H2O3P(CH2)2-azet



L32
(EtO)2(O)P—(CH2)2NH—



L33
(EtO)2(O)P—(CH2)3N(Me)—



L34
(EtO)2(O)P—(CH2)2N(Me)—



L35
(EtO)2(O)P—(CH2)3O—



L36
(EtO)2(O)P—(CH2)2O—



L37
3-(EtO)2(O)P-pipe



L38
3-(EtO)2(O)P-pyrr



L39
4-(EtO)2(O)P-CH2-pipe



L40
4-(EtO)2(O)P-(CH2)2-pipe



L41
3-(EtO)2(O)P-CH2-pyrr



L42
3-(EtO)2(O)P-(CH2)2-pyrr



L43
3-(EtO)2(O)P-CH2-azet



L44
3-(EtO)2(O)P-(CH2)2-azet



L45
HOCH(Me)(CH2)2NH—



L46
HOCH(Me)CH2NH—



L47
HOCH2CH(OH)CH2NH—



L48
HOCH(Me)(CH2)2N(Me)—



L49
HOCH(Me)CH2N(Me)—



L50
HOCH2CH(OH)CH2N(Me)—



L5i
HOCH(Me)(CH2)2O—



L52
HOCH(Me)CH2O—



L53
HOCH2CH(OH)CH2O—



L54
Mor



L55
MsNH(CH2)3—NH—



L56
MsNH(CH2)2N(Me)—



L57
3-NC(CH2)2-pyrr



L58
3-NCCH2-azet



L59
3-NC(CH2)2-azet



L60
4-Me-3-oxo-pipa



L61
5-oxo-1,4-diazepan-1-yl



L62
Me2NOC-pipe



L63
3-F-pyrr



L64
4-F-pipe



L65
4-(tetrazol-5-yl)-pipe



L66
4-H2O3P—(CH2)2-pipe



L67
3-H2O3P—CH2-pyrr



L68
H2NO2S—(CH2)2—NH—



L69
H2NO2S—(CH2)3—NH—



L70
H2NO2S—(CH2)2—N(Me)—



L71
H2NO2S—(CH2)3—N(Me)—



L72
HO3S—(CH2)2—NH—



L73
MsNH(CH2)3—N(Me)—



L74
HO3S—(CH2)3—NH—



L75
HO3S—(CH2)2—N(Me)—



L76
HO3S—(CH2)3—N(Me)—



L77
3-THP-O—



L78
4-THP-O—



L79
2-THF-CH2O—



L80
3-THF-CH2O—



L81
3-THF-NH—



L82
4-THP-NH—



L83
2-THF-CH2NH—



L84
3-THF-CH2NH—



L85
3-THF-N(Me)—



L86
4-THP-N(Me)—



L87
2-THF-CH2N(Me)—



L88
3-THF-CH2N(Me)—

















TABLE 40













 










No
R







M1
quinolin-2-yl



M2
quinolin-3-yl



M3
quinolin-4-yl



M4
quinolin-6-yl



M5
quinolin-7-yl



M6
2-HO-quinolin-6-yl



M7
2-MeO-quinolin-6-yl

















TABLE 41













 












No
R1
X
R







N1
cBuN(Me)—
C—H
4-HO-pipe



N2
cBuN(Me)—
C—H
mor



N3
cBuN(Me)—
C—H
4-H2O3P-pipe



N4
cBuN(Me)—
C—H
4-NC-pipe



N5
cBuN(Me)—
C—H
3-oxo-pipa



N6
cBuN(Me)—
N
4-HO-pipe



N7
cBuN(Me)—
N
mor



N8
cBuN(Me)—
N
4-H2O3P-pipe



N9
cBuN(Me)—
N
4-NC-pipe



N10
cBuN(Me)—
N
3-oxo-pipa



N11
iBuN(Me)—
C—H
4-HO-pipe



N12
iBuN(Me)—
C—H
mor



N13
iBuN(Me)—
C—H
4-H2O3P-pipe



N14
iBuN(Me)—
C—H
4-NC-pipe



N15
iBuN(Me)—
C—H
3-oxo-pipa



N16
iBuN(Me)—
N
4-HO-pipe



N17
iBuN(Me)—
N
mor



N18
iBuN(Me)—
N
4-H2O3P-pipe



N19
iBuN(Me)—
N
4-NC-pipe



N20
iBuN(Me)—
N
3-oxo-pipa



N21
2-Me-pyrr
C—H
4-HO-pipe



N22
2-Me-pyrr
C—H
mor



N23
2-Me-pyrr
C—H
4-H2O3P-pipe



N24
2-Me-pyrr
C—H
4-NC-pipe



N25
2-Me-pyrr
C—H
3-oxo-pipa



N26
2-Me-pyrr
N
4-HO-pipe



N27
2-Me-pyrr
N
mor



N28
2-Me-pyrr
N
4-H2O3P-pipe



N29
2-Me-pyrr
N
4-NC-pipe



N30
2-Me-pyrr
N
3-oxo-pipa



N31
iPrN(Me)—
C—H
4-HO-pipe



N32
iPrN(Me)—
C—H
mor



N33
iPrN(Me)—
C—H
4-H2O3P-pipe



N34
iPrN(Me)—
C—H
4-NC-pipe



N35
iPrN(Me)—
C—H
3-oxo-pipa



N36
iPrN(Me)—
N
4-HO-pipe



N37
iPrN(Me)—
N
mor



N38
iPrN(Me)—
N
4-H2O3P-pipe



N39
iPrN(Me)—
N
4-NC-pipe



N40
iPrN(Me)—
N
3-oxo-pipa

## Claims

1. A pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient




wherein
A is methylene;
R1 is a group represented by the formula (II), or cyclic amino which may be substituted




 wherein
R11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2 or when A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and
R12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen; and
R3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

2. The pharmaceutical composition according to claim 1, which is a thrombocytopenia treating agent.

3. The pharmaceutical composition according to claim 1, which is a c-Mpl ligand.

4. A compound of formula (III) or a pharmaceutically acceptable salt thereof




wherein
B is a lower alkylene;
R4 is a group represented by the formula (II), or cyclic amino which may be substituted





wherein
R11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when B represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R5 or when B represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by B; and
R12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R5 is thienyl or phenyl, each of which may be substituted; and
R6 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted provided that unsubstituted phenyl and indole which may be substituted are excluded.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein B is methylene.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R5 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting of a lower alkyl which may be substituted with one or more halogens, and a halogen.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R6 is pyridyl which may be substituted, or phenyl which is substituted.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R6 is pyridin-3-yl whose 5-position is substituted with a group selected from the group consisting of chloro and fluoro, and whose 6-position is substituted, or phenyl whose 3-position is substituted with a group selected from the group consisting of chloro and fluoro, whose 5-position is 5 substituted with a group selected from the member consisting of —H, chloro and fluoro, and whose 4-position is substituted.

9. The compound of claim 4, wherein the compound is
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl)piperidine-4-carboxylic acid,
1-(5-([5-{(butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylic acid,
1-{5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2yl)carbamoyl]-3-fluoro-2-pyridyl)piperidin-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(dimethylaminomethyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
4-[{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}(methyl)amino]butyric acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,
1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[[(2S)-2-methoxypropyl](methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl)piperidine-4-carboxylic acid,
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[(3-hydroxypropyl)amino]nicotinamide,
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-(3-oxopiperazin-1-yl)nicotinamide or
N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[4-(hydroxymethyl)piperidino]nicotinamide, or
a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound according to any one of claims 4 to 9 as an active ingredient.

11. The pharmaceutical composition according to claim 10, which is a platelet increasing agent.

12. The pharmaceutical composition according to claim 10, which is a thrombocytopenia treating agent.

13. The pharmaceutical composition according to claim 10, which is a c-Mpl ligand.

14. A method of increasing platelets in a patient comprising administering to the patient a pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient




wherein
A: a lower alkylene;
R1 is a group represented by the formula (II), or cyclic amino which may be substituted




wherein
R11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2 or when A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and
R12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R2 is thienyl or phenyl, each of which may be is substituted; and
R3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

15. The method according to claim 14, wherein A is methylene.

16. The method according to claim 15, wherein R2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

17. The method according to claim 14, wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

18. The method according to claim 17, wherein the daily amount is administered in one, two, three, or four doses.

19. The method according to claim 14, wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.

20. A method of treating thrombocytopenia in a patient comprising administering to the patient a pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient




wherein
A: a lower alkylene;
R1 is a group represented by the formula (II), or cyclic amino which may be substituted




wherein
R11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2 or when A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and
R12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R2 is thienyl or phenyl, each of which may be is substituted; and
R3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

21. The method according to claim 20, wherein A is methylene.

22. The method according to claim 21, wherein R2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

23. The method according to claim 20, wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

24. The method according to claim 23, wherein the daily amount is administered in one, two, three, or four doses.

25. The method according to claim 20, wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.

26. The method according to claim 20, wherein the thrombocytopenia is caused by one or more of anemia, myelodysplastic syndrome, chemotherapy, radiotherapy, idiopathic thrombocytopenic purpura, hepatic diseases, and human immunodeficiency virus (HIV).

27. A method of regulating c-Mpl activity for the treatment of thrombocytopenia comprising administering a c-Mpl ligand to a patient, wherein the c-Mpl ligand comprises a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient




wherein
A: a lower alkylene;
R1 is a group represented by the formula (II), or cyclic amino which may be substituted




wherein
R11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R11 may be present as methylene which is bridged to thienyl or phenyl represented by R2 or when A represents methylene, R11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and
R12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R2 is thienyl or phenyl, each of which may be is substituted; and
R3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

28. The method according to claim 27, wherein A is methylene.

29. The method according to claim 28, wherein R2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

30. The method according to claim 27, wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

31. The method according to claim 30, wherein the daily amount is administered in one, two, three, or four doses.

32. The method according to claim 27, wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.